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Kraus Z, Birla S, Powell T, Petrovskaya S, Mills F, Dement-Brown J, Culhane C, Dokhaee K, Tolnay M. Secretory IgA binding to FCRL3 triggers shared inflammatory cytokine secretion by human regulatory T cells and effector T cells. J Leukoc Biol 2025; 117:qiaf054. [PMID: 40313182 DOI: 10.1093/jleuko/qiaf054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 02/14/2025] [Accepted: 04/29/2025] [Indexed: 05/03/2025] Open
Abstract
Several human lymphocyte subsets express the novel secretory IgA receptor FCRL3 (Fc receptor-like 3). Secretory IgA binding to FCRL3 diminishes the inhibitory capacity of regulatory T cells and promotes a T helper 17-like phenotype. Here, we report that in CD4+ regulatory T cells and CD8+ terminal effector T cells secretory IgA induced a shared inflammatory gene signature that included PTGS2 encoding COX2, and the prototypic inflammatory cytokine genes IL1A, IL1B, and IL8. Secretory IgA in regulatory T cells also elevated gene transcripts required for lineage identity and function. Secretory IgA promoted interleukin (IL)-1β, IL-6, IL-8, IL-10, interferon γ, and tumor necrosis factor α protein secretion by both T cell types. Moreover, secretory IgA promoted NLRP3 inflammasome activation in regulatory T cells. Pharmacologic COX2 and NLRP3 inhibitors partially rescued the inhibitory competence of regulatory T cells, suggesting respective mechanistic roles. We propose that secretory IgA provokes a coordinated inflammatory response in regulatory and effector T cells to facilitate mucosal pathogen clearance.
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Affiliation(s)
- Zachary Kraus
- Office of Pharmaceutical Quality Assessment III, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, United States
| | - Shama Birla
- Office of Pharmaceutical Quality Research, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, United States
| | - Taylor Powell
- Office of Pharmaceutical Quality Research, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, United States
| | - Svetlana Petrovskaya
- Office of Pharmaceutical Quality Research, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, United States
| | - Frederick Mills
- Office of Pharmaceutical Quality Research, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, United States
| | - Jessica Dement-Brown
- Office of Pharmaceutical Quality Research, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, United States
| | - Casey Culhane
- Office of Pharmaceutical Quality Research, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, United States
| | - Kimia Dokhaee
- Office of Pharmaceutical Quality Research, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, United States
| | - Mate Tolnay
- Office of Pharmaceutical Quality Research, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, United States
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2
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Li M, Sun Y, Shan X, Tong Y, Fu Y, Ma X, Sun Z, Xiang Y, Zhu Y, Wang T, Wang X, Zhang J, Niu D. Roles of Immunity and Endogenous Retroelements in the Pathogenesis of Rheumatoid Arthritis and Treatment Strategies. Funct Integr Genomics 2025; 25:85. [PMID: 40205241 DOI: 10.1007/s10142-025-01583-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 02/24/2025] [Accepted: 03/17/2025] [Indexed: 04/11/2025]
Abstract
Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease that primarily affects the joints. RA usually results in synovial hyperplasia, expansion of "pannus" and destruction of cartilage. The etiology and pathogenesis of RA are not fully understood, but immunity has been shown to play an important role in the development of autoimmune diseases such as RA. In addition, endogenous retroelements, the remnants of ancient retroviruses in the human genome, are involved in cancer and/or immune disorders. As evidenced by increasing evidences that the aberrant expression of retroelements induces innate immunity, despite the fact that the expression of most retroelements has been epigenetically suppressed over a long period of evolution. With the continuous development of disease-modifying anti-rheumatic drugs (DMARDs), RA disease activity has been alleviated and improved. Unfortunately, some patients have a limited response to DMARDs, and the drugs also have the disadvantages of some side effects and high economic costs. This review summarizes the pathogenic mechanisms of RA and endogenous retroelements in autoimmunity, and concludes with a summary of treatments for RA, along with new therapeutic recommendations.
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Affiliation(s)
- Mingyang Li
- College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, 666 Wusu Street, Hangzhou, 311300, Zhejiang, China
| | - Yuanyuan Sun
- College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, 666 Wusu Street, Hangzhou, 311300, Zhejiang, China
| | - Xueting Shan
- College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, 666 Wusu Street, Hangzhou, 311300, Zhejiang, China
| | - Yuhong Tong
- Fourth School of Clinical Medicine, Zhejiang University of Traditional Chinese Medicine, Hangzhou, 310053, China
| | - Yite Fu
- Nanjing Outstanding Gene Technology Co, Nanjing, 210018, Jiangsu, China
| | - Xiang Ma
- College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, 666 Wusu Street, Hangzhou, 311300, Zhejiang, China
| | - Zhongxin Sun
- Department of Plastic, Reconstructive & Hand Microsurgery, Ningbo NO.6 Hospital, Ningbo, 315000, Zhejiang, China
| | - Yun Xiang
- Jinhua Academy of Agricultural Sciences, Jinhua, 321000, Zhejiang, China
| | - Yidan Zhu
- Jinhua Academy of Agricultural Sciences, Jinhua, 321000, Zhejiang, China
| | - Tao Wang
- Nanjing Outstanding Gene Technology Co, Nanjing, 210018, Jiangsu, China
| | - Xin Wang
- Department of Plastic, Reconstructive & Hand Microsurgery, Ningbo NO.6 Hospital, Ningbo, 315000, Zhejiang, China.
| | - Jufang Zhang
- Department of Plastic and Aesthetic Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, Zhejiang, China.
| | - Dong Niu
- College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, 666 Wusu Street, Hangzhou, 311300, Zhejiang, China.
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3
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Terui T, Murakami M, Okubo Y, Hayama K, Fujita H. Palmoplantar Pustulosis as an Immune-Mediated Inflammatory Disease with a Possible Relevance of Th17 Cell Plasticity: A Narrative Review. Dermatol Ther (Heidelb) 2025; 15:797-810. [PMID: 40088419 PMCID: PMC11971112 DOI: 10.1007/s13555-025-01382-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 03/03/2025] [Indexed: 03/17/2025] Open
Abstract
Palmoplantar pustulosis (PPP) is an immune-mediated inflammatory disease (IMID) of the skin that causes the formation of sterile pustules on the palms and soles. The clinical course of PPP is variable, with some patients having persistent skin lesions and others having lesions that wax and wane repeatedly. PPP has been treated with drugs such as those used for plaque psoriasis. The efficacy of biologics targeting the interleukin (IL)-23-helper T (Th)17 axis is not as conspicuous in PPP as in plaque psoriasis. Traditionally, CD4+ Th cell subsets have been defined by the expression of a small number of cytokines; however, recent advances in immunology have shown that some Th cell subsets can express cytokines of other Th subsets in response to changes in the environment. Recent studies have suggested the involvement of unique Th17 cells with Th2 cell characteristics in the pathogenesis of PPP. Thus, the insufficient efficacy of biologics targeting the IL-23-Th17 axis in PPP raises the question of whether Th17 cell plasticity is involved in the pathogenesis of PPP. In this review, we discuss the complexity of PPP pathogenesis with some speculation, compare the new knowledge obtained by other IMIDs or their mouse models with that of PPP elucidated thus far, and contribute to the development of future research.
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Affiliation(s)
- Tadashi Terui
- University Research Center, Nihon University, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo, 173-8610, Japan
- Division of Cutaneous Science, Department of Dermatology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo, 173-8610, Japan
| | - Masamoto Murakami
- Department of Anatomy, Histochemistry and Cell Biology, Faculty of Medicine, Miyazaki University, 5600 Kihara, Kiyotake, Miyazaki, 889-1692, Japan
- Atsuta Skin Clinic, 2-44 Nakanohonnmachi, Nakagawa-ku, Nagoya, 454-0047, Japan
| | - Yukari Okubo
- Department of Dermatology, Tokyo Medical University, 6 Chome-7-1 Nishishinjuku, Shinjuku, Tokyo, 160-0023, Japan
| | - Koremasa Hayama
- Division of Cutaneous Science, Department of Dermatology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo, 173-8610, Japan
| | - Hideki Fujita
- Division of Cutaneous Science, Department of Dermatology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo, 173-8610, Japan.
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4
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Ramón-Vázquez A, Flood P, Cashman TL, Patil P, Ghosh S. T lymphocyte plasticity in chronic inflammatory diseases: The emerging role of the Ikaros family as a key Th17-Treg switch. Autoimmun Rev 2025; 24:103735. [PMID: 39719186 DOI: 10.1016/j.autrev.2024.103735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 12/14/2024] [Accepted: 12/20/2024] [Indexed: 12/26/2024]
Abstract
T helper (Th) 17 and regulatory T (Treg) cells are highly plastic CD4+ Th cell subsets, being able not only to actively adapt to their microenvironment, but also to interconvert, acquiring mixed identity markers. These phenotypic changes are underpinned by transcriptional control mechanisms, chromatin reorganization events and epigenetic modifications, that can be hereditable and stable over time. The Ikaros family of transcription factors have a predominant role in T cell subset specification through mechanisms of transcriptional program regulation that enable phenotypical diversification. They are crucial factors in maintaining Th17/Treg balance and therefore, homeostatic conditions in the tissues. However, they are also implicated in pathogenic processes, where their transcriptional repression contributes to the control of autoimmune processes. In this review, we discuss how T cell fate, specifically in humans, is regulated by the Ikaros family and its interplay with additional factors like the Notch signaling pathway, gut microbiota and myeloid-T cell interactions. Further, we highlight how the transcriptional activity of the Ikaros family impacts the course of T cell mediated chronic inflammatory diseases like rheumatoid and psoriatic arthritis, inflammatory bowel disease, systemic lupus erythematosus and multiple sclerosis. We conclude by discussing recently developed therapeutics designed to target Ikaros family members.
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Affiliation(s)
| | - P Flood
- APC Microbiome Ireland, University College Cork, Ireland
| | - T L Cashman
- APC Microbiome Ireland, University College Cork, Ireland
| | - P Patil
- APC Microbiome Ireland, University College Cork, Ireland
| | - S Ghosh
- APC Microbiome Ireland, University College Cork, Ireland; College of Medicine and Health, University College Cork, Ireland
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5
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Jagasia P, Taritsa I, Bagdady K, Shah S, Fracol M. Silicone breast implant-associated pathologies and T cell-mediated responses. Inflamm Res 2025; 74:33. [PMID: 39891670 DOI: 10.1007/s00011-025-02006-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 01/21/2025] [Accepted: 01/28/2025] [Indexed: 02/03/2025] Open
Abstract
Silicone breast implants elicit a foreign body response (FBR) defined by a complex cascade of various immune cells. Studies have shown that the capsule around silicone breast implants that forms as a result of the FBR contains large T cell populations. T cells are implicated in pathologies such as capsular contracture, which is defined by an excessively fibrotic capsule, and breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), a non-Hodgkin's lymphoma. In this article, we provide a synthesis of 17 studies reporting on T cell-mediated responses to silicone breast implants and highlight recent developments on this topic. The lymphocytes present in the breast implant capsule are predominantly Th1 and Th17 cells. Patients with advanced capsular contracture had fewer T-regulatory (Treg) cells present in the capsules that were less able to suppress T effector cells such as Th17 cells, which can promote fibrosis in autoimmune conditions. Textured silicone implants, which are associated with BIA-ALCL, created a more robust T cell response, especially CD30 + T cells in the peri-implant fluid and CD4 + T cells in the capsule. Cultivating a deeper understanding of T cell-mediated responses to silicone breast implants may allow for novel treatments of breast implant-associated complications and malignancies.
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Affiliation(s)
- Puja Jagasia
- Division of Plastic & Reconstructive Surgery, Northwestern Memorial Hospital, 259 E Erie St. Suite 2060, Chicago, IL, 60611, USA
| | - Iulianna Taritsa
- Division of Plastic & Reconstructive Surgery, Northwestern Memorial Hospital, 259 E Erie St. Suite 2060, Chicago, IL, 60611, USA
| | - Kazimir Bagdady
- Division of Plastic & Reconstructive Surgery, Northwestern Memorial Hospital, 259 E Erie St. Suite 2060, Chicago, IL, 60611, USA
| | - Shivani Shah
- Division of Plastic & Reconstructive Surgery, Northwestern Memorial Hospital, 259 E Erie St. Suite 2060, Chicago, IL, 60611, USA
| | - Megan Fracol
- Division of Plastic & Reconstructive Surgery, Northwestern Memorial Hospital, 259 E Erie St. Suite 2060, Chicago, IL, 60611, USA.
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Pan J, Chen S, Chen X, Song Y, Cheng H. Histone Modifications and DNA Methylation in Psoriasis: A Cellular Perspective. Clin Rev Allergy Immunol 2025; 68:6. [PMID: 39871086 DOI: 10.1007/s12016-024-09014-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/08/2024] [Indexed: 01/29/2025]
Abstract
In recent years, epigenetic modifications have attracted significant attention due to their unique regulatory mechanisms and profound biological implications. Acting as a bridge between environmental stimuli and changes in gene activity, they reshape gene expression patterns, providing organisms with regulatory mechanisms to respond to environmental changes. A growing body of evidence indicates that epigenetic regulation plays a crucial role in the pathogenesis and progression of psoriasis. A deeper understanding of these epigenetic mechanisms not only helps unveil the molecular mechanisms underlying the initiation and progression of psoriasis but may also provide new insights into diagnostic and therapeutic strategies. Given the unique roles and significant contributions of various cell types involved in the process of psoriasis, a thorough analysis of specific epigenetic patterns in different cell types becomes a key entry point for elucidating the mechanisms of disease development. Although epigenetic modifications encompass multiple complex layers, this review will focus on histone modifications and DNA methylation, describing how they function in different cell types and subsequently impact the pathophysiological processes of psoriasis. Finally, we will summarize the current problems in research concerning histone modifications and DNA methylation in psoriasis and discuss the clinical application prospects and challenges of targeting epigenetic modifications as therapeutic strategies for psoriasis.
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Affiliation(s)
- Jing Pan
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Siji Chen
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xianzhen Chen
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yinjing Song
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
| | - Hao Cheng
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
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7
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Lauten TH, Elkhatib SK, Natour T, Reed EC, Jojo CN, Case AJ. T H17/Treg lymphocyte balance is regulated by beta adrenergic and cAMP signaling. Brain Behav Immun 2025; 123:1061-1070. [PMID: 39542072 PMCID: PMC11967417 DOI: 10.1016/j.bbi.2024.11.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 10/10/2024] [Accepted: 11/08/2024] [Indexed: 11/17/2024] Open
Abstract
BACKGROUND Post-traumatic stress disorder (PTSD) is a debilitating psychological disorder that also presents with neuroimmune irregularities. Patients display elevated sympathetic tone and are at an increased risk of developing secondary autoimmune diseases. Previously, using a mouse model of repeated social defeat stress (RSDS) that recapitulates certain features of PTSD, we demonstrated that elimination of sympathetic signaling to T-lymphocytes specifically limited their ability to produce pro-inflammatory interleukin 17A (IL-17A); a cytokine implicated in the development of many autoimmune disorders. However, the mechanism linking sympathetic signaling to T-lymphocyte IL-17A production remained unclear. METHODS Using a modified version of RSDS that allows for both males and females, as well as ex vivo models of T-lymphocyte polarization, we assessed the impact and mechanism of adrenergic receptor blockade (genetically and pharmacologically) and catecholamine depletion on T-lymphocyte differentiation to IL-17A-producing subtypes (i.e., TH17). RESULTS Only pharmacological inhibition of the beta 1 and 2 adrenergic receptors (β1/2) significantly decreased circulating IL-17A levels after RSDS, but did not impact other pro-inflammatory cytokines (e.g.,IL-6, TNF-α, and IL-10). This finding was confirmed using RSDS with both global β1/2 receptor knock-out mice, as well as by adoptively transferring β1/2 knock-out T-lymphocytes into immunodeficient hosts. Ex vivo polarized T-lymphocytes produced significantly less IL-17A with the blockade of β1/2 signaling, even in the absence of exogenous sympathetic neurotransmitter supplementation, which suggested T-lymphocyte-produced catecholamines may be involved in IL-17A production. Furthermore, cyclic AMP (cAMP) was demonstrated to be mechanistically involved in driving IL-17A production in T-lymphocytes, and amplifying cAMP signaling could restore IL-17A deficits caused by the absence of β1/2 signaling. Last, removal of β1/2 and cAMP signaling, even in IL-17A polarizing conditions, promoted regulatory T-lymphocyte (Treg) polarization, suggesting adrenergic signaling plays a role in the switching between pro- and anti-inflammatory T-lymphocyte subtypes. CONCLUSIONS Our data depict a novel role for β1/2 adrenergic and cAMP signaling in the balance of TH17/Treg lymphocytes. These findings provide a new target for pharmacological therapy in both psychiatric and autoimmune diseases associated with IL-17A-related pathology.
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MESH Headings
- Animals
- Mice
- Th17 Cells/metabolism
- Th17 Cells/immunology
- Signal Transduction
- Cyclic AMP/metabolism
- Male
- T-Lymphocytes, Regulatory/metabolism
- T-Lymphocytes, Regulatory/immunology
- Female
- Receptors, Adrenergic, beta-2/metabolism
- Mice, Inbred C57BL
- Interleukin-17/metabolism
- Mice, Knockout
- Receptors, Adrenergic, beta-1/metabolism
- Stress, Psychological/metabolism
- Stress, Psychological/immunology
- Social Defeat
- Disease Models, Animal
- Cell Differentiation
- Adrenergic beta-Antagonists/pharmacology
- Receptors, Adrenergic, beta/metabolism
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Affiliation(s)
- Tatlock H Lauten
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, United States; Department of Medical Physiology, Texas A&M University, Bryan, TX, United States
| | - Safwan K Elkhatib
- Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Boston, MA, United States
| | - Tamara Natour
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, United States; Department of Medical Physiology, Texas A&M University, Bryan, TX, United States
| | - Emily C Reed
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, United States; Department of Medical Physiology, Texas A&M University, Bryan, TX, United States
| | - Caroline N Jojo
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, United States; Department of Medical Physiology, Texas A&M University, Bryan, TX, United States
| | - Adam J Case
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, United States; Department of Medical Physiology, Texas A&M University, Bryan, TX, United States.
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8
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Mazzola A, Roger C, Lhotte R, Mallet M, Thabut D, Taupin JL, Conti F. HLA evolutionary divergence effect on bacterial infection risk in cirrhotic liver transplant candidates. Clin Immunol 2025; 270:110399. [PMID: 39561928 DOI: 10.1016/j.clim.2024.110399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 10/21/2024] [Accepted: 11/10/2024] [Indexed: 11/21/2024]
Abstract
Bacterial infections are common in cirrhosis patients, increasing the risk of decompensation and death. The impact of HLA evolutionary divergence (HED) on infection risk hasn't been studied in humans before. We conducted a retrospective study on cirrhosis patients awaiting liver transplantation (LT) from January 2019 to February 2022, examining class I and II-HED effects on bacterial infections and cirrhosis decompensation. We included 269 cirrhosis patients. Among them, 98 experienced 153 bacterial infections. Multivariable analysis after variable selection revealed that higher class II-HED was linked to fewer bacterial infections (p = 0.034), while class I-HED showed no effect (p = 0.074). Independent risk factors for bacterial infections included invasive procedures (p < 0.001), ICU hospitalization (p < 0.001), recent antibiotic treatment (p = 0.046), rifaximin use (p = 0.043), and cirrhosis decompensation (p = 0.002). Neither class I nor II-HED affected decompensation risk. This pioneering study shows that high class II-HED levels may protect against bacterial infections in cirrhosis patients awaiting LT, suggesting an immunological mechanism at play.
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Affiliation(s)
- Alessandra Mazzola
- Sorbonne Université, Unité médicale de transplantation hépatique, hépato-gastroentérologie, AP-HP, Hôpital Pitié-Salpêtrière, 75013 Paris, France; MICS-Research laboratory in Mathematics and Computer Science at CentraleSupélec, Gif-Sur-Yvette, France.
| | - Clémentine Roger
- Sorbonne Université, Unité médicale de transplantation hépatique, hépato-gastroentérologie, AP-HP, Hôpital Pitié-Salpêtrière, 75013 Paris, France.
| | - Romain Lhotte
- CHU Paris-GH St-Louis Lariboisière F. Widal, Laboratoire d'immunologie-Histocomptabilité, Hôpital Saint-Louis, 75010 Paris, France; MICS-Research laboratory in Mathematics and Computer Science at CentraleSupélec, Gif-Sur-Yvette, France.
| | - Maxime Mallet
- Sorbonne Université, Unité médicale de transplantation hépatique, hépato-gastroentérologie, AP-HP, Hôpital Pitié-Salpêtrière, 75013 Paris, France.
| | - Dominique Thabut
- Sorbonne Université, Unité médicale de transplantation hépatique, hépato-gastroentérologie, AP-HP, Hôpital Pitié-Salpêtrière, 75013 Paris, France.
| | - Jean-Luc Taupin
- CHU Paris-GH St-Louis Lariboisière F. Widal, Laboratoire d'immunologie-Histocomptabilité, Hôpital Saint-Louis, 75010 Paris, France.
| | - Filomena Conti
- Sorbonne Université, Unité médicale de transplantation hépatique, hépato-gastroentérologie, AP-HP, Hôpital Pitié-Salpêtrière, 75013 Paris, France.
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Schnell JT, Briviesca RL, Kim T, Charbonnier LM, Henderson LA, van Wijk F, Nigrovic PA. The 'T reg paradox' in inflammatory arthritis. Nat Rev Rheumatol 2025; 21:9-21. [PMID: 39653758 DOI: 10.1038/s41584-024-01190-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/06/2024] [Indexed: 12/12/2024]
Abstract
Classic regulatory T (Treg) cells expressing CD4 and the hallmark transcription factor FOXP3 are integral to the prevention of multi-system autoimmunity. However, immune-mediated arthritis is often associated with increased numbers of Treg cells in the inflamed joints. To understand these seemingly conflicting observations, which we collectively describe as 'the Treg paradox', we provide an overview of Treg cell biology with a focus on Treg cell heterogeneity, function and dysfunction in arthritis. We discuss how the inflamed environment constrains the immunosuppressive activity of Treg cells while also promoting the differentiation of TH17-like Treg cell, exTreg cell (effector T cells that were formerly Treg cells), and osteoclastogenic Treg cell subsets that mediate tissue injury. We present a new framework to understand Treg cells in joint inflammation and define potential strategies for Treg cell-directed interventions in human inflammatory arthritis.
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Affiliation(s)
- Julia T Schnell
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA, USA
- Department of Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Taehyeung Kim
- Division of Immunology, Boston Children's Hospital, Boston, MA, USA
| | | | | | - Femke van Wijk
- Centre for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Peter A Nigrovic
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA, USA.
- Division of Immunology, Boston Children's Hospital, Boston, MA, USA.
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10
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Anvar MT, Rashidan K, Arsam N, Rasouli-Saravani A, Yadegari H, Ahmadi A, Asgari Z, Vanan AG, Ghorbaninezhad F, Tahmasebi S. Th17 cell function in cancers: immunosuppressive agents or anti-tumor allies? Cancer Cell Int 2024; 24:355. [PMID: 39465401 PMCID: PMC11514949 DOI: 10.1186/s12935-024-03525-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 10/08/2024] [Indexed: 10/29/2024] Open
Abstract
T helper (Th) 17 cells, a distinct subset of Th lymphocytes, are known for their prominent interleukin (IL)-17 production and other pro-inflammatory cytokines. These cells exhibit remarkable plasticity, allowing them to exhibit different phenotypes in the cancer microenvironment. This adaptability enables Th17 cells to promote tumor progression by immunosuppressive activities and angiogenesis, but also mediate anti-tumor immune responses through employing immune cells in tumor setting or even by directly converting toward Th1 phenotype and producing interferon-gamma (IFN-γ). This dual role of Th17 cells in cancer makes it a double-edged sword in encountering cancer. In this review, we aim to elucidate the complexities of Th17 cell function in cancer by summarizing recent studies and, ultimately, to design novel therapeutic strategies, especially targeting Th17 cells in the tumor milieu, which could pave the way for more effective cancer treatments.
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Affiliation(s)
- Milad Taghizadeh Anvar
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kimiya Rashidan
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nima Arsam
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ashkan Rasouli-Saravani
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamidreza Yadegari
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Ahmadi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zeynab Asgari
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ahmad Ghorbani Vanan
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Farid Ghorbaninezhad
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Safa Tahmasebi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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11
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Wendering DJ, Amini L, Schlickeiser S, Farrera-Sal M, Schulenberg S, Peter L, Mai M, Vollmer T, Du W, Stein M, Hamm F, Malard A, Castro C, Yang M, Ranka R, Rückert T, Durek P, Heinrich F, Gasparoni G, Salhab A, Walter J, Wagner DL, Mashreghi MF, Landwehr-Kenzel S, Polansky JK, Reinke P, Volk HD, Schmueck-Henneresse M. Effector memory-type regulatory T cells display phenotypic and functional instability. SCIENCE ADVANCES 2024; 10:eadn3470. [PMID: 39231218 PMCID: PMC11421655 DOI: 10.1126/sciadv.adn3470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 07/30/2024] [Indexed: 09/06/2024]
Abstract
Regulatory T cells (Treg cells) hold promise for sustainable therapy of immune disorders. Recent advancements in chimeric antigen receptor development and genome editing aim to enhance the specificity and function of Treg cells. However, impurities and functional instability pose challenges for the development of safe gene-edited Treg cell products. Here, we examined different Treg cell subsets regarding their fate, epigenomic stability, transcriptomes, T cell receptor repertoires, and function ex vivo and after manufacturing. Each Treg cell subset displayed distinct features, including lineage stability, epigenomics, surface markers, T cell receptor diversity, and transcriptomics. Earlier-differentiated memory Treg cell populations, including a hitherto unidentified naïve-like memory Treg cell subset, outperformed late-differentiated effector memory-like Treg cells in regulatory function, proliferative capacity, and epigenomic stability. High yields of stable, functional Treg cell products could be achieved by depleting the small effector memory-like Treg cell subset before manufacturing. Considering Treg cell subset composition appears critical to maintain lineage stability in the final cell product.
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Affiliation(s)
- Désirée Jacqueline Wendering
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Development of Biomarkers and Regenerative Therapies, Augustenburger Platz 1, 13353 Berlin, Germany
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Leila Amini
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Cell Therapy and Personalized Immunosuppression, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Center for Advanced Therapies (BeCAT) at Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Stephan Schlickeiser
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Development of Biomarkers and Regenerative Therapies, Augustenburger Platz 1, 13353 Berlin, Germany
- CheckImmune GmbH, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Martí Farrera-Sal
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Experimental Immunotherapy, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Sarah Schulenberg
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Experimental Immunotherapy, Augustenburger Platz 1, 13353 Berlin, Germany
- Einstein Center for Regenerative Therapies at Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Lena Peter
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Experimental Immunotherapy, Augustenburger Platz 1, 13353 Berlin, Germany
- Einstein Center for Regenerative Therapies at Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Marco Mai
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Experimental Immunotherapy, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Tino Vollmer
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Experimental Immunotherapy, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Weijie Du
- Berlin Center for Advanced Therapies (BeCAT) at Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Gene Editing for Cell Therapy, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Maik Stein
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Cell Therapy and Personalized Immunosuppression, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Gene Editing for Cell Therapy, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Frederik Hamm
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Immuno-Epigenetics, Augustenburger Platz 1, 13353 Berlin, Germany
- Deutsches Rheuma-Forschungszentrum Berlin, an Institute of the Leibniz Association, Charitéplatz 1, 10117 Berlin, Germany
| | - Alisier Malard
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Immuno-Epigenetics, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Carla Castro
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Immuno-Epigenetics, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Mingxing Yang
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Immuno-Epigenetics, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Ramon Ranka
- Deutsches Rheuma-Forschungszentrum Berlin, an Institute of the Leibniz Association, Charitéplatz 1, 10117 Berlin, Germany
| | - Timo Rückert
- Deutsches Rheuma-Forschungszentrum Berlin, an Institute of the Leibniz Association, Charitéplatz 1, 10117 Berlin, Germany
| | - Pawel Durek
- Deutsches Rheuma-Forschungszentrum Berlin, an Institute of the Leibniz Association, Charitéplatz 1, 10117 Berlin, Germany
| | - Frederik Heinrich
- Deutsches Rheuma-Forschungszentrum Berlin, an Institute of the Leibniz Association, Charitéplatz 1, 10117 Berlin, Germany
| | - Gilles Gasparoni
- Saarland University, Institute for Genetics/Epigenetics, Saarbrücken, Germany
| | - Abdulrahman Salhab
- Saarland University, Institute for Genetics/Epigenetics, Saarbrücken, Germany
| | - Jörn Walter
- Saarland University, Institute for Genetics/Epigenetics, Saarbrücken, Germany
| | - Dimitrios Laurin Wagner
- Berlin Center for Advanced Therapies (BeCAT) at Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Gene Editing for Cell Therapy, Augustenburger Platz 1, 13353 Berlin, Germany
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Transfusion Medicine, Charitéplatz 1, 10117 Berlin, Germany
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Immunology, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Mir-Farzin Mashreghi
- Deutsches Rheuma-Forschungszentrum Berlin, an Institute of the Leibniz Association, Charitéplatz 1, 10117 Berlin, Germany
| | - Sybille Landwehr-Kenzel
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Cell Therapy and Personalized Immunosuppression, Augustenburger Platz 1, 13353 Berlin, Germany
- Hannover Medical School, Department of Pediatric Pulmonology, Allergy and Neonatology, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Julia K Polansky
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Immuno-Epigenetics, Augustenburger Platz 1, 13353 Berlin, Germany
- Deutsches Rheuma-Forschungszentrum Berlin, an Institute of the Leibniz Association, Charitéplatz 1, 10117 Berlin, Germany
| | - Petra Reinke
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Cell Therapy and Personalized Immunosuppression, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Center for Advanced Therapies (BeCAT) at Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Hans-Dieter Volk
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Development of Biomarkers and Regenerative Therapies, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Center for Advanced Therapies (BeCAT) at Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- CheckImmune GmbH, Augustenburger Platz 1, 13353 Berlin, Germany
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Immunology, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Michael Schmueck-Henneresse
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Experimental Immunotherapy, Augustenburger Platz 1, 13353 Berlin, Germany
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12
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Cui Y, Hackett RG, Ascue J, Muralidaran V, Patil D, Kang J, Kaufman SS, Khan K, Kroemer A. Innate and Adaptive Immune Responses in Intestinal Transplant Rejection: Through the Lens of Inflammatory Bowel and Intestinal Graft-Versus-Host Diseases. Gastroenterol Clin North Am 2024; 53:359-382. [PMID: 39068000 DOI: 10.1016/j.gtc.2024.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
Intestinal transplantation is a life-saving procedure utilized for patients failing total parenteral nutrition. However, intestinal transplantattion remains plagued with low survival rates and high risk of allograft rejection. The authors explore roles of innate (macrophages, natural killer cells, innate lymphoid cells) and adaptive immune cells (Th1, Th2, Th17, Tregs) in inflammatory responses, particularly inflammatory bowel disease and graft versus host disease, and correlate these findings to intestinal allograft rejection, highlighting which effectors exacerbate or suppress intestinal rejection. Better understanding of this immunology can open further investigation into potential biomolecular targets to develop improved therapeutic treatment options and immunomonitoring techniques to combat allograft rejection and enhance patient lives.
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Affiliation(s)
- Yuki Cui
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Ryan G Hackett
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Jhalen Ascue
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Vinona Muralidaran
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Digvijay Patil
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Jiman Kang
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA; Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC, USA
| | - Stuart S Kaufman
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Khalid Khan
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA
| | - Alexander Kroemer
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC, USA.
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13
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Liu R, Zhang L, Zhang K. Histone modification in psoriasis: Molecular mechanisms and potential therapeutic targets. Exp Dermatol 2024; 33:e15151. [PMID: 39090854 DOI: 10.1111/exd.15151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 06/24/2024] [Accepted: 07/19/2024] [Indexed: 08/04/2024]
Abstract
Psoriasis is an immune-mediated, inflammatory disease. Genetic and environmental elements are involved in the nosogenesis of this illness. Epigenetic inheritance serves as the connection between genetic and environmental factors. Histone modification, an epigenetic regulatory mechanism, is implicated in the development of numerous diseases. The basic function of histone modification is to regulate cellular functions by modifying gene expression. Modulation of histone modification, such as regulation of enzymes pertinent to histone modification, can be an alternative approach for treating some diseases, including psoriasis. Herein, we reviewed the regulatory mechanisms and biological effects of histone modifications and their roles in the pathogenesis of psoriasis.
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Affiliation(s)
- Ruifeng Liu
- Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, China
| | - Luyao Zhang
- Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Kaiming Zhang
- Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, China
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14
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Tolomeo M, Cascio A. The Complex Dysregulations of CD4 T Cell Subtypes in HIV Infection. Int J Mol Sci 2024; 25:7512. [PMID: 39062756 PMCID: PMC11276885 DOI: 10.3390/ijms25147512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 07/04/2024] [Accepted: 07/07/2024] [Indexed: 07/28/2024] Open
Abstract
Human immunodeficiency virus (HIV) infection remains an important global public health problem. About 40 million people are infected with HIV, and this infection caused about 630,000 deaths in 2022. The hallmark of HIV infection is the depletion of CD4+ T helper lymphocytes (Th cells). There are at least seven different Th subtypes, and not all are the main targets of HIV. Moreover, the effect of the virus in a specific subtype can be completely different from that of the others. Although the most compromised Th subtype in HIV infection is Th17, HIV can induce important dysregulations in other subtypes, such as follicular Th (Tfh) cells and regulatory Th cells (Treg cells or Tregs). Several studies have shown that HIV can induce an increase in the immunosuppressive activity of Tregs without causing a significant reduction in their numbers, at least in the early phase of infection. The increased activity of this Th subtype seems to play an important role in determining the immunodeficiency status of HIV-infected patients, and Tregs may represent a new target for innovative anti-HIV therapies, including the so-called "Kick and Kill" therapeutic method whose goal is the complete elimination of the virus and the healing of HIV infection. In this review, we report the most important findings on the effects of HIV on different CD4+ T cell subtypes, the molecular mechanisms by which the virus impairs the functions of these cells, and the implications for new anti-HIV therapeutic strategies.
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Affiliation(s)
- Manlio Tolomeo
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties, University of Palermo, 90127 Palermo, Italy;
- Department of Infectious Diseases, A.O.U.P. Palermo, 90127 Palermo, Italy
| | - Antonio Cascio
- Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties, University of Palermo, 90127 Palermo, Italy;
- Department of Infectious Diseases, A.O.U.P. Palermo, 90127 Palermo, Italy
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15
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Khokhar M, Dey S, Tomo S, Jaremko M, Emwas AH, Pandey RK. Unveiling Novel Drug Targets and Emerging Therapies for Rheumatoid Arthritis: A Comprehensive Review. ACS Pharmacol Transl Sci 2024; 7:1664-1693. [PMID: 38898941 PMCID: PMC11184612 DOI: 10.1021/acsptsci.4c00067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 05/09/2024] [Accepted: 05/14/2024] [Indexed: 06/21/2024]
Abstract
Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disease, that causes joint damage, deformities, and decreased functionality. In addition, RA can also impact organs like the skin, lungs, eyes, and blood vessels. This autoimmune condition arises when the immune system erroneously targets the joint synovial membrane, resulting in synovitis, pannus formation, and cartilage damage. RA treatment is often holistic, integrating medication, physical therapy, and lifestyle modifications. Its main objective is to achieve remission or low disease activity by utilizing a "treat-to-target" approach that optimizes drug usage and dose adjustments based on clinical response and disease activity markers. The primary RA treatment uses disease-modifying antirheumatic drugs (DMARDs) that help to interrupt the inflammatory process. When there is an inadequate response, a combination of biologicals and DMARDs is recommended. Biological therapies target inflammatory pathways and have shown promising results in managing RA symptoms. Close monitoring for adverse effects and disease progression is critical to ensure optimal treatment outcomes. A deeper understanding of the pathways and mechanisms will allow new treatment strategies that minimize adverse effects and maintain quality of life. This review discusses the potential targets that can be used for designing and implementing precision medicine in RA treatment, spotlighting the latest breakthroughs in biologics, JAK inhibitors, IL-6 receptor antagonists, TNF blockers, and disease-modifying noncoding RNAs.
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Affiliation(s)
- Manoj Khokhar
- Department
of Biochemistry, All India Institute of
Medical Sciences, Jodhpur, 342005 Rajasthan, India
| | - Sangita Dey
- CSO
Department, Cellworks Research India Pvt
Ltd, Bengaluru, 560066 Karnataka, India
| | - Sojit Tomo
- Department
of Biochemistry, All India Institute of
Medical Sciences, Jodhpur, 342005 Rajasthan, India
| | - Mariusz Jaremko
- Smart-Health
Initiative (SHI) and Red Sea Research Center (RSRC), Division of Biological
and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955 Jeddah, Saudi Arabia
| | - Abdul-Hamid Emwas
- Core
Laboratories, King Abdullah University of
Science and Technology (KAUST), Thuwal 23955-6900, Kingdom of Saudi Arabia
| | - Rajan Kumar Pandey
- Department
of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm 17177, Sweden
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Thonhoff JR, Beers DR, Zhao W, Faridar A, Thome A, Wen S, Zhang A, Wang J, Appel SH. A phase 1 proof-of-concept study evaluating safety, tolerability, and biological marker responses with combination therapy of CTLA4-Ig and interleukin-2 in amyotrophic lateral sclerosis. Front Neurol 2024; 15:1415106. [PMID: 38915796 PMCID: PMC11195540 DOI: 10.3389/fneur.2024.1415106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 05/23/2024] [Indexed: 06/26/2024] Open
Abstract
Objective To determine whether a combination therapy with abatacept (CTLA4-Ig) and interleukin-2 (IL-2) is safe and suppresses markers of oxidative stress, inflammation, and degeneration in ALS. Methods In this open-label study, four participants with ALS received subcutaneous injections of low dose IL-2 (1 × 106 IU/injection/day) for 5 consecutive days every 2 weeks and one subcutaneous injection of CTLA4-Ig (125 mg/mL/injection) every 2 weeks coinciding with the first IL-2 injection of each treatment cycle. Participants received a total of 24 treatment cycles during the first 48 weeks in this 56-week study. They were closely monitored for treatment-emergent adverse events (TEAEs) and disease progression with the ALSFRS-R. Phenotypic changes within T cell populations and serum biological markers of oxidative stress [4-hydroxynonenal (4-HNE) and oxidized-LDL (ox-LDL)], inflammation (IL-18), and structural neuronal degeneration [neurofilament light chain (Nf-L)] were assessed longitudinally. Results CTLA4-Ig/IL-2 therapy was safe and well-tolerated in all four participants over the 56-week study. During the first 24 weeks, the average rate of change in the ALSFRS-R was +0.04 points/month. Over the 48-week treatment period, the average rate of change was -0.13 points/month with one participant improving by 0.9 points/month while the other three participants experienced an average decrease of -0.47 points/month, which is slower than the average - 1.1 points/month prior to initiation of therapy. Treg suppressive function and numbers increased during treatment. Responses in the biological markers during the first 16 weeks coincided with minimal clinical progression. Mean levels of 4-HNE decreased by 30%, ox-LDL decreased by 19%, IL-18 decreased by 23%, and Nf-L remained the same, on average, in all four participants. Oxidized-LDL levels decreased in all four participants, 4-HNE and IL-18 levels decreased in three out of four participants, and Nf-L decreased in two out of four participants. Conclusion The combination therapy of CTLA4-Ig and IL-2 in ALS is safe and well-tolerated with promising results of clinical efficacy and suppression of biomarkers of oxidative stress, neuroinflammation and neuronal degeneration. In this open-label study, the efficacy as measured by the ALSFRS-R and corresponding biomarkers suggests the therapeutic potential of this treatment and warrants further study in a phase 2 double-blind, placebo-controlled trial. Clinical trial registration ClinicalTrials.gov, NCT06307301.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Stanley H. Appel
- Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, United States
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17
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Kommoju V, Mariaselvam CM, Bulusu SN, Ganapathy CK, Narasimhan PB, Thabah MM, Negi VS. Conventional Tregs in treatment-naïve rheumatoid arthritis are deficient in suppressive function with an increase in percentage of CXCR3 and CCR6 expressing Tregs. Immunol Res 2024; 72:396-408. [PMID: 38151700 DOI: 10.1007/s12026-023-09444-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 11/26/2023] [Indexed: 12/29/2023]
Abstract
In rheumatoid arthritis (RA), immune homeostasis is maintained by T regulatory cells (Tregs) that in an inflammatory milieu can change towards T-helper-like phenotypes (Th-like Tregs). Our aim was to examine the phenotypic and functional characteristics of CD4+CD25+CD127lo/- Tregs, Th-like Tregs and T effector (Teff) cells in the peripheral blood (PB) and synovial fluid (SF) of treatment-naïve early RA, as compared to osteoarthritis (OA) and healthy control (HC) peripheral blood. Frequencies of Tregs, CXCR3, CCR6 expressing Tregs (Th-like Tregs), and Teff cells were analyzed using flow cytometry in RA (n = 80), OA (n = 20), and HC (n = 40). Cytokine concentrations of the respective T cell subsets in plasma and SF were measured using flow cytometric bead array. Tregs sorted from RA and HC PB using magnetic beads were analyzed for functional capacities by CFSE proliferation assay and FOXP3 gene expression using real-time PCR. We observed that the frequencies of Th17 cells in PB and SF were significantly higher in RA when compared to HC, whereas Tregs were lower in PB and high in SF compared to HC and OA respectively. Th1- and Th17-related pro-inflammatory cytokines IL12p70, INF-γ, TNF-α, and IL-6, and IL-17A were significantly higher in the plasma and SF of RA. Tregs expressing CXCR3 (Th1-like Tregs) and CCR6 (Th17-like Treg) were significantly higher in PB and SF of RA compared to controls and was positively associated with seropositivity and disease activity. Treg cells isolated from peripheral blood of RA showed decreased function and reduced FOXP3 gene expression compared to HC. In our study, we have demonstrated higher frequencies of Th1 and Th17 cells and increased circulatory and SF pro-inflammatory cytokines (IL12P70, INF-γ, IL-6, IL-17A, and TNF-α) in RA. This inflammatory milieu might alter total Tregs frequencies and influence conversion of Tregs into Th-like Tregs.
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Affiliation(s)
- Vallayyachari Kommoju
- Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605 006, India
| | - Christina Mary Mariaselvam
- Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605 006, India
| | - Sree Nethra Bulusu
- Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605 006, India
| | - Chengappa Kavadichanda Ganapathy
- Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605 006, India
| | - Prakash Babu Narasimhan
- Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605 006, India
| | - Molly Mary Thabah
- Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605 006, India
| | - Vir Singh Negi
- Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605 006, India.
- All India Institute of Medical Sciences, Bilaspur, Himachal Pradesh, India.
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18
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Qin L, Chen C, Gui Z, Jiang Y. IRX5's influence on macrophage polarization and outcome in papillary thyroid cancer. Front Oncol 2024; 14:1399484. [PMID: 38868535 PMCID: PMC11167072 DOI: 10.3389/fonc.2024.1399484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 05/10/2024] [Indexed: 06/14/2024] Open
Abstract
Background With a rise in recent years, thyroid cancer (TC) is the most prevalent hormonal cancer worldwide. It is essential to investigate the inherent variability at the molecular level and the immune environment within tumors of various thyroid cancer subtypes in order to identify potential targets for therapy and provide precise treatment for patients with thyroid adenocarcinoma. Methods First, we analyzed the expression of IRX5 in pan-cancer and papillary thyroid carcinoma by bioinformatics methods and collected paired samples from our center for validation. Subsequently, we analyzed the significance of IRX5 on the prognosis and diagnosis of PTC. Next, we explored the possible mechanisms by which IRX5 affects the prognosis of thyroid cancer patients by GO/KEGG enrichment analysis, and further investigated the effect of IRX5 on immune infiltration of thyroid cancer. Ultimately, by conducting experiments on cells and animals, we were able to show how IRX5 impacts the aggressive characteristics of thyroid cancer cells and its influence on macrophages within the immune system of thyroid cancer. Results In 11 malignant tumors, including PTC, IRX5 is overexpressed and associated with a poor prognosis. IRX5 may affect the prognosis of PTC through embryonic organ development, ossification, mesenchyme development, etc. Increased IRX5 expression decreases the presence of cytotoxic and Th17 cells in papillary thyroid cancer. IRX5 was highly expressed in different PTC cell lines, such as K-1 and TPC-1. Silencing IRX5 effectively halted the growth and movement of PTC cells while also decreasing M2 polarization and enhancing M1 polarization in tumor-associated macrophages. Conclusion IRX5 could impact the outlook of individuals with PTC by stimulating the shift of macrophages to M2 in the immune surroundings of thyroid cancer growths, suggesting a potential new focus for treating thyroid cancer, particularly through immunotherapy.
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Affiliation(s)
- Lu Qin
- Department of Thyroid Vascular Surgery, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, ;China
| | - Cheng Chen
- Department of Nuclear Medicine, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, ;China
| | - Zhengwei Gui
- Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Department of Thyroid and Breast Surgery, Wuhan, ;China
| | - Yun Jiang
- Department of Ultrasound, Hubei Hospital of Integrated Traditional Chinese and Western Medicines, Wuhan, ;China
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19
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Sherri N, Assaf R, Bitar ER, Znait S, Borghol AH, Kassem A, Rahal EA. Epstein-Barr Virus DNA Exacerbates Arthritis in a Mouse Model via Toll-like Receptor 9. Int J Mol Sci 2024; 25:4661. [PMID: 38731877 PMCID: PMC11083462 DOI: 10.3390/ijms25094661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 04/20/2024] [Accepted: 04/23/2024] [Indexed: 05/13/2024] Open
Abstract
Epstein-Barr virus (EBV) DNA is known to be shed upon reactivation of latent EBV. Based on our previous findings linking Toll-like receptor-9 (TLR9) to an EBV DNA-driven surge in IL-17A production, we aimed to examine the therapeutic potential of TLR9 inhibition in EBV DNA-exacerbated arthritis in a collagen-induced arthritis (CIA) mouse model. C57BL/6J mice were administered either collagen, EBV DNA + collagen, EBV DNA + collagen + TLR9 inhibitor, or only the TLR9 inhibitor. After 70 days, paw thicknesses, clinical scores, and gripping strength were recorded. Moreover, affected joints, footpads, and colons were histologically scored. Furthermore, the number of cells co-expressing IL-17A, IFN-γ, and FOXP3 in joint sections was determined by immunofluorescence assays. Significantly decreased paw thicknesses, clinical scores, and histological scores with a significantly increased gripping strength were observed in the group receiving EBV DNA + collagen + TLR9 inhibitor, compared to those receiving EBV DNA + collagen. Similarly, this group showed decreased IL-17A+ IFN-γ+, IL-17A+ FOXP3+, and IL-17A+ IFN-γ+ FOXP3+ foci counts in joints. We show that inhibiting TLR9 limits the exacerbation of arthritis induced by EBV DNA in a CIA mouse model, suggesting that TLR9 could be a potential therapeutic target for rheumatoid arthritis management in EBV-infected individuals.
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MESH Headings
- Animals
- Mice
- Arthritis, Experimental/virology
- Arthritis, Experimental/pathology
- Arthritis, Experimental/metabolism
- Arthritis, Rheumatoid/metabolism
- Arthritis, Rheumatoid/pathology
- Arthritis, Rheumatoid/virology
- Disease Models, Animal
- DNA, Viral/genetics
- Epstein-Barr Virus Infections/virology
- Epstein-Barr Virus Infections/complications
- Epstein-Barr Virus Infections/pathology
- Herpesvirus 4, Human/physiology
- Interleukin-17/metabolism
- Mice, Inbred C57BL
- Toll-Like Receptor 9/metabolism
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Affiliation(s)
- Nour Sherri
- Department of Experimental Pathology, Immunology, and Microbiology, American University of Beirut, Beirut 1107, Lebanon; (N.S.); (R.A.); (E.R.B.); (S.Z.); (A.H.B.); (A.K.)
| | - Rayan Assaf
- Department of Experimental Pathology, Immunology, and Microbiology, American University of Beirut, Beirut 1107, Lebanon; (N.S.); (R.A.); (E.R.B.); (S.Z.); (A.H.B.); (A.K.)
| | - Elio R. Bitar
- Department of Experimental Pathology, Immunology, and Microbiology, American University of Beirut, Beirut 1107, Lebanon; (N.S.); (R.A.); (E.R.B.); (S.Z.); (A.H.B.); (A.K.)
| | - Sabah Znait
- Department of Experimental Pathology, Immunology, and Microbiology, American University of Beirut, Beirut 1107, Lebanon; (N.S.); (R.A.); (E.R.B.); (S.Z.); (A.H.B.); (A.K.)
| | - Abdul Hamid Borghol
- Department of Experimental Pathology, Immunology, and Microbiology, American University of Beirut, Beirut 1107, Lebanon; (N.S.); (R.A.); (E.R.B.); (S.Z.); (A.H.B.); (A.K.)
| | - Aya Kassem
- Department of Experimental Pathology, Immunology, and Microbiology, American University of Beirut, Beirut 1107, Lebanon; (N.S.); (R.A.); (E.R.B.); (S.Z.); (A.H.B.); (A.K.)
| | - Elias A. Rahal
- Department of Experimental Pathology, Immunology, and Microbiology, American University of Beirut, Beirut 1107, Lebanon; (N.S.); (R.A.); (E.R.B.); (S.Z.); (A.H.B.); (A.K.)
- Center for Infectious Diseases Research (CIDR), American University of Beirut, Beirut 1107, Lebanon
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20
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Hu F, Shi L, Liu X, Chen Y, Zhang X, Jia Y, Liu X, Guo J, Zhu H, Liu H, Xu L, Li Y, Wang P, Fang X, Xue J, Xie Y, Wei C, Song J, Zheng X, Liu YY, Li Y, Ren L, Xu D, Lu L, Qiu X, Mu R, He J, Wang M, Zhang X, Liu W, Li Z. Proinflammatory phenotype of B10 and B10pro cells elicited by TNF-α in rheumatoid arthritis. Ann Rheum Dis 2024; 83:576-588. [PMID: 38302261 DOI: 10.1136/ard-2023-224878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 01/17/2024] [Indexed: 02/03/2024]
Abstract
OBJECTIVES B10 and B10pro cells suppress immune responses via secreting interleukin (IL)-10. However, their regulators and underlying mechanisms, especially in human autoimmune diseases, are elusive. This study aimed to address these questions in rheumatoid arthritis (RA), one of the most common highly disabling autoimmune diseases. METHODS The frequencies and functions of B10 and B10pro cells in healthy individuals and patients with RA were first analysed. The effects of proinflammatory cytokines, particularly tumour necrosis factor (TNF)-α on the quantity, stability and pathogenic phenotype of these cells, were then assessed in patients with RA before and after anti-TNF therapy. The underlying mechanisms were further investigated by scRNA-seq database reanalysis, transcriptome sequencing, TNF-α-/- and B cell-specific SHIP-1-/- mouse disease model studies. RESULTS TNF-α was a key determinant for B10 cells. TNF-α elicited the proinflammatory feature of B10 and B10pro cells by downregulating IL-10, and upregulating interferon-γ and IL-17A. In patients with RA, B10 and B10pro cells were impaired with exacerbated proinflammatory phenotype, while anti-TNF therapy potently restored their frequencies and immunosuppressive functions, consistent with the increased B10 cells in TNF-α-/- mice. Mechanistically, TNF-α diminished B10 and B10pro cells by inhibiting their glycolysis and proliferation. TNF-α also regulated the phosphatidylinositol phosphate signalling of B10 and B10pro cells and dampened the expression of SHIP-1, a dominant phosphatidylinositol phosphatase regulator of these cells. CONCLUSIONS TNF-α provoked the proinflammatory phenotype of B10 and B10pro cells by disturbing SHIP-1 in RA, contributing to the disease development. Reinstating the immunosuppressive property of B10 and B10pro cells might represent novel therapeutic approaches for RA.
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Affiliation(s)
- Fanlei Hu
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Lianjie Shi
- Department of Rheumatology and Immunology, Peking University Shougang Hospital, Beijing, China
| | - Xiaohang Liu
- State Key Laboratory of Membrane Biology, China Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, Institute for Immunology, Tsinghua University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Beijing, China
| | - Yingjia Chen
- State Key Laboratory of Membrane Biology, China Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, Institute for Immunology, Tsinghua University, Beijing, China
| | - Xia Zhang
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Yuan Jia
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Xu Liu
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Jianping Guo
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Huaqun Zhu
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Hongjiang Liu
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Liling Xu
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Yingni Li
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Ping Wang
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Xiangyu Fang
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Jimeng Xue
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Yang Xie
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Chaonan Wei
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Jing Song
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
- Peking-Tsinghua Center for Life Sciences, Beijing, China
| | - Xi Zheng
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
- Peking-Tsinghua Center for Life Sciences, Beijing, China
| | - Yan-Ying Liu
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Yuhui Li
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Limin Ren
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Dakang Xu
- Faculty of Medical Laboratory Science, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Liwei Lu
- Department of Pathology, The University of Hong Kong, Hong Kong, China
| | - Xiaoyan Qiu
- Department of Immunology, School of Basic Medical Science, Peking University, Beijing, China
| | - Rong Mu
- Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China
| | - Jing He
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Min Wang
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Clinical Immunology Center, Chinese Academy of Medical Sciences, Beijing, China
| | - Xuan Zhang
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Clinical Immunology Center, Chinese Academy of Medical Sciences, Beijing, China
| | - Wanli Liu
- State Key Laboratory of Membrane Biology, China Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, Institute for Immunology, Tsinghua University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Beijing, China
| | - Zhanguo Li
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Beijing, China
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21
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Baeten P, Hamad I, Hoeks C, Hiltensperger M, Van Wijmeersch B, Popescu V, Aly L, Somers V, Korn T, Kleinewietfeld M, Hellings N, Broux B. Rapamycin rescues loss of function in blood-brain barrier-interacting Tregs. JCI Insight 2024; 9:e167457. [PMID: 38386413 PMCID: PMC11128200 DOI: 10.1172/jci.insight.167457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 02/15/2024] [Indexed: 02/24/2024] Open
Abstract
In autoimmunity, FOXP3+ Tregs skew toward a proinflammatory, nonsuppressive phenotype and are, therefore, unable to control the exaggerated autoimmune response. This largely affects the success of autologous Treg therapy, which is currently under investigation for autoimmune diseases, including multiple sclerosis (MS). There is a need to ensure in vivo Treg stability before successful application of Treg therapy. Using genetic fate-mapping mice, we demonstrate that inflammatory, cytokine-expressing exFOXP3 T cells accumulate in the CNS during experimental autoimmune encephalomyelitis. In a human in vitro model, we discovered that interaction with inflamed blood-brain barrier endothelial cells (BBB-ECs) induces loss of function by Tregs. Transcriptome and cytokine analysis revealed that in vitro migrated Tregs have disrupted regenerative potential and a proinflammatory Th1/17 signature, and they upregulate the mTORC1 signaling pathway. In vitro treatment of migrated human Tregs with the clinically approved mTORC1 inhibitor rapamycin restored suppression. Finally, flow cytometric analysis indicated an enrichment of inflammatory, less-suppressive CD49d+ Tregs in the cerebrospinal fluid of people with MS. In summary, interaction with BBB-ECs is sufficient to affect Treg function, and transmigration triggers an additive proinflammatory phenotype switch. These insights help improve the efficacy of autologous Treg therapy of MS.
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Affiliation(s)
- Paulien Baeten
- Universitair MS Centrum, Campus Diepenbeek, Belgium
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Ibrahim Hamad
- Universitair MS Centrum, Campus Diepenbeek, Belgium
- VIB Laboratory of Translational Immunomodulation, Center for Inflammation Research (IRC), Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Cindy Hoeks
- Universitair MS Centrum, Campus Diepenbeek, Belgium
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Michael Hiltensperger
- Klinikum Rechts der Isar, Institute for Experimental Neuroimmunology, Technische Universität München, Munich, Germany
| | - Bart Van Wijmeersch
- Universitair MS Centrum, Campus Pelt, Belgium
- Noorderhart, Revalidatie & MS Centrum, Pelt, Belgium
| | - Veronica Popescu
- Universitair MS Centrum, Campus Pelt, Belgium
- Noorderhart, Revalidatie & MS Centrum, Pelt, Belgium
| | - Lilian Aly
- Klinikum Rechts der Isar, Institute for Experimental Neuroimmunology, Technische Universität München, Munich, Germany
| | - Veerle Somers
- Universitair MS Centrum, Campus Diepenbeek, Belgium
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Thomas Korn
- Klinikum Rechts der Isar, Institute for Experimental Neuroimmunology, Technische Universität München, Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Markus Kleinewietfeld
- Universitair MS Centrum, Campus Diepenbeek, Belgium
- VIB Laboratory of Translational Immunomodulation, Center for Inflammation Research (IRC), Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Niels Hellings
- Universitair MS Centrum, Campus Diepenbeek, Belgium
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Bieke Broux
- Universitair MS Centrum, Campus Diepenbeek, Belgium
- Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
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22
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Alvarez F, Liu Z, Bay A, Piccirillo CA. Deciphering the developmental trajectory of tissue-resident Foxp3 + regulatory T cells. Front Immunol 2024; 15:1331846. [PMID: 38605970 PMCID: PMC11007185 DOI: 10.3389/fimmu.2024.1331846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 02/14/2024] [Indexed: 04/13/2024] Open
Abstract
Foxp3+ TREG cells have been at the focus of intense investigation for their recognized roles in preventing autoimmunity, facilitating tissue recuperation following injury, and orchestrating a tolerance to innocuous non-self-antigens. To perform these critical tasks, TREG cells undergo deep epigenetic, transcriptional, and post-transcriptional changes that allow them to adapt to conditions found in tissues both at steady-state and during inflammation. The path leading TREG cells to express these tissue-specialized phenotypes begins during thymic development, and is further driven by epigenetic and transcriptional modifications following TCR engagement and polarizing signals in the periphery. However, this process is highly regulated and requires TREG cells to adopt strategies to avoid losing their regulatory program altogether. Here, we review the origins of tissue-resident TREG cells, from their thymic and peripheral development to the transcriptional regulators involved in their tissue residency program. In addition, we discuss the distinct signalling pathways that engage the inflammatory adaptation of tissue-resident TREG cells, and how they relate to their ability to recognize tissue and pathogen-derived danger signals.
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Affiliation(s)
- Fernando Alvarez
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
- Infectious Diseases and Immunology in Global Health Program, The Research Institute of the McGill University Health Centre (RI-MUHC), Montréal, QC, Canada
- Centre of Excellence in Translational Immunology (CETI), Montréal, QC, Canada
| | - Zhiyang Liu
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
- Infectious Diseases and Immunology in Global Health Program, The Research Institute of the McGill University Health Centre (RI-MUHC), Montréal, QC, Canada
- Centre of Excellence in Translational Immunology (CETI), Montréal, QC, Canada
| | - Alexandre Bay
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
- Infectious Diseases and Immunology in Global Health Program, The Research Institute of the McGill University Health Centre (RI-MUHC), Montréal, QC, Canada
- Centre of Excellence in Translational Immunology (CETI), Montréal, QC, Canada
| | - Ciriaco A. Piccirillo
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada
- Infectious Diseases and Immunology in Global Health Program, The Research Institute of the McGill University Health Centre (RI-MUHC), Montréal, QC, Canada
- Centre of Excellence in Translational Immunology (CETI), Montréal, QC, Canada
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23
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Schreurs RRCE, Koulis A, Booiman T, Boeser-Nunnink B, Cloherty APM, Rader AG, Patel KS, Kootstra NA, Ribeiro CMS. Autophagy-enhancing ATG16L1 polymorphism is associated with improved clinical outcome and T-cell immunity in chronic HIV-1 infection. Nat Commun 2024; 15:2465. [PMID: 38548722 PMCID: PMC10979031 DOI: 10.1038/s41467-024-46606-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 03/04/2024] [Indexed: 04/01/2024] Open
Abstract
Chronic HIV-1 infection is characterized by T-cell dysregulation that is partly restored by antiretroviral therapy. Autophagy is a critical regulator of T-cell function. Here, we demonstrate a protective role for autophagy in HIV-1 disease pathogenesis. Targeted analysis of genetic variation in core autophagy gene ATG16L1 reveals the previously unidentified rs6861 polymorphism, which correlates functionally with enhanced autophagy and clinically with improved survival of untreated HIV-1-infected individuals. T-cells carrying ATG16L1 rs6861(TT) genotype display improved antiviral immunity, evidenced by increased proliferation, revamped immune responsiveness, and suppressed exhaustion/immunosenescence features. In-depth flow-cytometric and transcriptional profiling reveal T-helper-cell-signatures unique to rs6861(TT) individuals with enriched regulation of pro-inflammatory networks and skewing towards immunoregulatory phenotype. Therapeutic enhancement of autophagy recapitulates the rs6861(TT)-associated T-cell traits in non-carriers. These data underscore the in vivo relevance of autophagy for longer-lasting T-cell-mediated HIV-1 control, with implications towards development of host-directed antivirals targeting autophagy to restore immune function in chronic HIV-1 infection.
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Affiliation(s)
- Renée R C E Schreurs
- Amsterdam UMC location University of Amsterdam, Experimental Immunology, Meibergdreef 9, Amsterdam, The Netherlands
- Amsterdam institute for Immunology & Infectious Diseases, Amsterdam, The Netherlands
| | - Athanasios Koulis
- Amsterdam UMC location University of Amsterdam, Experimental Immunology, Meibergdreef 9, Amsterdam, The Netherlands
- Amsterdam institute for Immunology & Infectious Diseases, Amsterdam, The Netherlands
| | - Thijs Booiman
- Amsterdam UMC location University of Amsterdam, Experimental Immunology, Meibergdreef 9, Amsterdam, The Netherlands
- Amsterdam institute for Immunology & Infectious Diseases, Amsterdam, The Netherlands
| | - Brigitte Boeser-Nunnink
- Amsterdam UMC location University of Amsterdam, Experimental Immunology, Meibergdreef 9, Amsterdam, The Netherlands
- Amsterdam institute for Immunology & Infectious Diseases, Amsterdam, The Netherlands
| | - Alexandra P M Cloherty
- Amsterdam UMC location University of Amsterdam, Experimental Immunology, Meibergdreef 9, Amsterdam, The Netherlands
- Amsterdam institute for Immunology & Infectious Diseases, Amsterdam, The Netherlands
| | - Anusca G Rader
- Amsterdam UMC location University of Amsterdam, Experimental Immunology, Meibergdreef 9, Amsterdam, The Netherlands
- Amsterdam institute for Immunology & Infectious Diseases, Amsterdam, The Netherlands
| | - Kharishma S Patel
- Amsterdam UMC location University of Amsterdam, Experimental Immunology, Meibergdreef 9, Amsterdam, The Netherlands
- Amsterdam institute for Immunology & Infectious Diseases, Amsterdam, The Netherlands
| | - Neeltje A Kootstra
- Amsterdam UMC location University of Amsterdam, Experimental Immunology, Meibergdreef 9, Amsterdam, The Netherlands
- Amsterdam institute for Immunology & Infectious Diseases, Amsterdam, The Netherlands
| | - Carla M S Ribeiro
- Amsterdam UMC location University of Amsterdam, Experimental Immunology, Meibergdreef 9, Amsterdam, The Netherlands.
- Amsterdam institute for Immunology & Infectious Diseases, Amsterdam, The Netherlands.
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24
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Guo Y, Chen J, Huang Y, Ke S, Xie F, Li D, Li B, Lu H. Increased infiltration of CD4 + IL-17A + FOXP3 + T cells in Helicobacter pylori-induced gastritis. Eur J Immunol 2024; 54:e2350662. [PMID: 38366919 DOI: 10.1002/eji.202350662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 12/24/2023] [Accepted: 01/09/2024] [Indexed: 02/19/2024]
Abstract
Helicobacter pylori is one of the main predisposing factors for gastric cancer, causing chronic inflammation and proper glands atrophy in the gastric mucosa. Although H. pylori-induced inflammation is a key inducer of precancerous lesions in the gastric mucosa, it remains unclear which precise immune cell subsets are responsible for the progression of H. pylori-induced gastritis. Here, we observed an abundance of CD4+ IL-17A+ FOXP3+ T cells exhibiting a Th17-like phenotype within the microenvironment of H. pylori-induced gastritis. Mechanistically, H. pylori upregulated the expression of IL-6 in Dendritic cells and macrophages, by activating NF-κB signaling through the virulence factor CagA and thus, induced IL-17A expression in FOXP3+ T cells. Moreover, CD4+ IL-17A+ FOXP3+ T cells were positively associated with advanced precancerous lesions. Therefore, these findings offer essential insights into how FOXP3+ T cells sense inflammatory signals from the environment, such as IL-6, during H. pylori infections, thereby guiding the effector immune response and aggravating the gastritis.
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Affiliation(s)
- Yixian Guo
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jinnan Chen
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yu Huang
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Shouyu Ke
- Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Feng Xie
- Department of Immunology and Microbiology, Center for Immune-Related Diseases at Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dan Li
- Department of Immunology and Microbiology, Center for Immune-Related Diseases at Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bin Li
- Department of Immunology and Microbiology, Center for Immune-Related Diseases at Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hong Lu
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Li S, Lv D, Qian C, Jiang J, Zhang P, Xi C, Wu L, Gao X, Fu Y, Zhang D, Chen Y, Huang H, Zhu Y, Wang X, Lai J, Hu S. Circulating T-cell subsets discrepancy between bipolar disorder and major depressive disorder during mood episodes: A naturalistic, retrospective study of 1015 cases. CNS Neurosci Ther 2024; 30:e14361. [PMID: 37491837 PMCID: PMC10848094 DOI: 10.1111/cns.14361] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 06/06/2023] [Accepted: 07/03/2023] [Indexed: 07/27/2023] Open
Abstract
AIMS We aimed to investigate whether peripheral T-cell subsets could be a biomarker to distinguish major depressive disorder (MDD) and bipolar disorder (BD). METHODS Medical records of hospitalized patients in the Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, from January 2015 to September 2020 with a discharge diagnosis of MDD or BD were reviewed. Patients who underwent peripheral blood examination of T-cell subtype proportions, including CD3+, CD4+, CD8+ T-cell, and natural killer (NK) cells, were enrolled. The Chi-square test, t-test, or one-way analysis of variance were used to analyze group differences. Demographic profiles and T-cell data were used to construct a random forest classifier-based diagnostic model. RESULTS Totally, 98 cases of BD mania, 459 cases of BD depression (BD-D), and 458 cases of MDD were included. There were significant differences in the proportions of CD3+, CD4+, CD8+ T-cell, and NK cells among the three groups. Compared with MDD, the BD-D group showed higher CD8+ but lower CD4+ T-cell and a significantly lower ratio of CD4+ and CD8+ proportions. The random forest model achieved an area under the curve of 0.77 (95% confidence interval: 0.71-0.83) to distinguish BD-D from MDD patients. CONCLUSION These findings imply that BD and MDD patients may harbor different T-cell inflammatory patterns, which could be a potential diagnostic biomarker for mood disorders.
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Affiliation(s)
- Shaoli Li
- Department of Psychiatry, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- The Key Laboratory of Mental Disorder's Management in Zhejiang ProvinceHangzhouChina
- Department of Medical Oncology, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Zhejiang Engineering Center for Mathematical Mental HealthHangzhouChina
| | - Duo Lv
- Department of Clinical Pharmacy, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Chao Qian
- Department of Psychiatry, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Shaoxing 7th People's HospitalShaoxingChina
| | - Jiajun Jiang
- Department of Psychiatry, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Peifen Zhang
- Department of Psychiatry, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Caixi Xi
- Department of Psychiatry, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Lingling Wu
- Department of Psychiatry, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xingle Gao
- Department of Psychiatry, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Yaoyang Fu
- Department of Psychiatry, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Danhua Zhang
- Department of Psychiatry, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Yiqing Chen
- Department of Psychiatry, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | | | - Yiyi Zhu
- Wenzhou Medical UniversityWenzhouChina
| | - Xiaorong Wang
- Department of Psychiatry, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Jianbo Lai
- Department of Psychiatry, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- The Key Laboratory of Mental Disorder's Management in Zhejiang ProvinceHangzhouChina
- Zhejiang Engineering Center for Mathematical Mental HealthHangzhouChina
- Department of Neurobiology, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brian Medicine, MOE Frontier Science Center for Brain Science and Brain‐Machine IntegrationZhejiang University School of MedicineHangzhouChina
| | - Shaohua Hu
- Department of Psychiatry, The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- The Key Laboratory of Mental Disorder's Management in Zhejiang ProvinceHangzhouChina
- Zhejiang Engineering Center for Mathematical Mental HealthHangzhouChina
- Department of Neurobiology, NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brian Medicine, MOE Frontier Science Center for Brain Science and Brain‐Machine IntegrationZhejiang University School of MedicineHangzhouChina
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26
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Ye S, Lyu Y, Chen L, Wang Y, He Y, Li Q, Tian L, Liu F, Wang X, Ai F. Construction of a molecular inflammatory predictive model with histone modification-related genes and identification of CAMK2D as a potential response signature to infliximab in ulcerative colitis. Front Immunol 2024; 14:1282136. [PMID: 38274809 PMCID: PMC10808628 DOI: 10.3389/fimmu.2023.1282136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 12/19/2023] [Indexed: 01/27/2024] Open
Abstract
Background Ulcerative colitis (UC) is a lifelong inflammatory disease affecting the rectum and colon with numerous treatment options that require an individualized treatment plan. Histone modifications regulate chromosome structure and gene expression, resulting in effects on inflammatory and immune responses. However, the relationship between histone modification-related genes and UC remains unclear. Methods Transcriptomic data from GSE59071 and GSE66407 were obtained from the Gene Expression Omnibus (GEO), encompassing colonic biopsy expression profiles of UC patients in inflamed and non-inflamed status. Differentially expressed gene (DEG) analyses, functional enrichment analyses, weighted gene co-expression network analysis (WGCNA), and random forest were performed to identify histone modification-related core genes associated with UC inflammation. Features were screened through the least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE), establishing a molecular inflammatory predictive model using logistic regression. The model was validated in the GSE107499 dataset, and the performance of the features was assessed using receiver operating characteristic (ROC) and calibration curves. Immunohistochemistry (IHC) staining of colonic biopsy tissues from UC patients treated with infliximab was used to further confirm the clinical application value. Univariate logistic regression on GSE14580 highlighted features linked to infliximab response. Results A total of 253 histone modification-related DEGs were identified between inflammatory and non-inflammatory patients with UC. Seven key genes (IL-1β, MSL3, HDAC7, IRF4, CAMK2D, AUTS2, and PADI2) were selected using WGCNA and random forest. Through univariate logistic regression, three core genes (CAMK2D, AUTS2, and IL-1β) were further incorporated to construct the molecular inflammatory predictive model. The area under the curve (AUC) of the model was 0.943 in the independent validation dataset. A significant association between CAMK2D protein expression and infliximab response was observed, which was validated in another independent verification set of GSE14580 from the GEO database. Conclusion The molecular inflammatory predictive model based on CAMK2D, AUTS2, and IL-1β could reliably distinguish the mucosal inflammatory status of UC patients. We further revealed that CAMK2D was a predictive marker of infliximab response. These findings are expected to provide a new evidence base for personalized treatment and management strategies for UC patients.
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Affiliation(s)
- Shuyu Ye
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, China
- Hunan Key Laboratory of Non-Resolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yongqing Lyu
- Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
| | - Libin Chen
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, China
- Hunan Key Laboratory of Non-Resolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yiwei Wang
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Yue He
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Quansi Li
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Li Tian
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, China
- Hunan Key Laboratory of Non-Resolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Fen Liu
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, China
- Hunan Key Laboratory of Non-Resolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoyan Wang
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, China
- Hunan Key Laboratory of Non-Resolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Feiyan Ai
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, China
- Hunan Key Laboratory of Non-Resolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, China
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Martinez Villarruel Hinnerskov J, Krogh Nielsen M, Kai Thomsen A, Steffensen MA, Honoré B, Vorum H, Nissen MH, Sørensen TL. Chemokine Receptor Profile of T Cells and Progression Rate of Geographic Atrophy Secondary to Age-related Macular Degeneration. Invest Ophthalmol Vis Sci 2024; 65:5. [PMID: 38165703 PMCID: PMC10768715 DOI: 10.1167/iovs.65.1.5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 12/07/2023] [Indexed: 01/04/2024] Open
Abstract
Purpose Geographic atrophy (GA) secondary to age-related macular degeneration is a progressive retinal degenerative disease. Systemic chemokine receptors and known risk-associated single-nucleotide polymorphisms have been associated with GA pathogenesis. Because halting progression is pivotal for patients, we investigated the association of candidate chemokine receptors and progression rate (PR) of atrophic lesions in patients with GA. Methods This prospective observational study conducted at a single center included 85 patients with GA and 45 healthy controls. Patients were followed up after 13 months on average. Serial fundus autofluorescence images were used to determine the PR of atrophic lesions. The proportion of chemokine receptors on peripheral lymphocytes were determined by flow cytometric analysis. Results Patients with GA had a lower proportion of CCR6 on CD8+T cells compared to healthy controls. Importantly, the proportion of CCR6 on CD4+T cells was lower in patients with fast GA progression compared to patients with slow progression of disease, suggesting that dysregulation of CCR6 could be involved in progression of GA. We also found that GA patients had a markedly higher percentage of CCR5 on CD4+ and CD8+T cells compared to healthy controls. After stratification according to ARMS2 polymorphism, we found a significantly lower level of CCR5 on CD8+T cells among patients with high-risk genotypes compared with patients with the low-risk genotype. Conclusions Our study finds that chemokine receptors are dysregulated in patients with GA and that CCR6 might be involved in GA progression, making it a potential target for intervention.
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Affiliation(s)
- Jenni Martinez Villarruel Hinnerskov
- Department of Ophthalmology, Zealand University Hospital, Roskilde, Denmark
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Alexander Kai Thomsen
- Department of Ophthalmology, Zealand University Hospital, Roskilde, Denmark
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Bent Honoré
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark
| | - Henrik Vorum
- Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark
- Department of Ophthalmology, Aalborg University Hospital, Aalborg, Denmark
| | - Mogens Holst Nissen
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Torben Lykke Sørensen
- Department of Ophthalmology, Zealand University Hospital, Roskilde, Denmark
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Bernaldo-de-Quirós E, Camino M, Martínez-Bonet M, Gil-Jaurena JM, Gil N, Hernández-Flórez D, Fernández-Santos ME, Butragueño L, Dijke IE, Levings MK, West LJ, Pion M, Correa-Rocha R. First-in-human therapy with Treg produced from thymic tissue (thyTreg) in a heart transplant infant. J Exp Med 2023; 220:e20231045. [PMID: 37906166 PMCID: PMC10619578 DOI: 10.1084/jem.20231045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 08/30/2023] [Accepted: 10/06/2023] [Indexed: 11/02/2023] Open
Abstract
Due to their suppressive capacity, regulatory T cells (Tregs) have attracted growing interest as an adoptive cellular therapy for the prevention of allograft rejection, but limited Treg recovery and lower quality of adult-derived Tregs could represent an obstacle to success. To address this challenge, we developed a new approach that provides large quantities of Tregs with high purity and excellent features, sourced from thymic tissue routinely removed during pediatric cardiac surgeries (thyTregs). We report on a 2-year follow-up of the first patient treated worldwide with thyTregs, included in a phase I/II clinical trial evaluating the administration of autologous thyTreg in infants undergoing heart transplantation. In addition to observing no adverse effects that could be attributed to thyTreg administration, we report that the Treg frequency in the periphery was preserved during the 2-year follow-up period. These initial results are consistent with the trial objective, which is to confirm safety of the autologous thyTreg administration and its capacity to restore the Treg pool.
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Affiliation(s)
- Esther Bernaldo-de-Quirós
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain
| | - Manuela Camino
- Department of Pediatric Cardiology, Hospital Gregorio Marañón, Madrid, Spain
| | - Marta Martínez-Bonet
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain
| | | | - Nuria Gil
- Department of Pediatric Cardiology, Hospital Gregorio Marañón, Madrid, Spain
| | - Diana Hernández-Flórez
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain
| | | | - Laura Butragueño
- Pediatric Intensive Care Unit, Hospital Gregorio Marañón, Madrid, Spain
| | - I. Esmé Dijke
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada
- Canadian Donation and Transplantation Research Program Investigator, Edmonton, Canada
- Alberta Transplant Institute, Edmonton, Canada
| | - Megan K. Levings
- Canadian Donation and Transplantation Research Program Investigator, Edmonton, Canada
- Department of Surgery and School of Biomedical Engineering, University of British Columbia, BC Children’s Hospital, Vancouver, Canada
| | - Lori J. West
- Canadian Donation and Transplantation Research Program Investigator, Edmonton, Canada
- Alberta Transplant Institute, Edmonton, Canada
- Department of Pediatrics, University of Alberta/Stollery Children’s Hospital, Edmonton, Canada
| | - Marjorie Pion
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain
| | - Rafael Correa-Rocha
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Madrid, Spain
- Canadian Donation and Transplantation Research Program Investigator, Edmonton, Canada
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Zhang Z, Guo J, Jia R. Treg plasticity and human diseases. Inflamm Res 2023; 72:2181-2197. [PMID: 37878023 DOI: 10.1007/s00011-023-01808-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 10/08/2023] [Accepted: 10/11/2023] [Indexed: 10/26/2023] Open
Abstract
INTRODUCTION As a subset of CD4+ T cells, regulatory T cells (Tregs) with the characteristic expression of transcription factor FOXP3 play a key role in maintaining self-tolerance and regulating immune responses. However, in some inflammatory circumstances, Tregs can express cytokines of other T help (Th) cells by internal reprogramming, which is called Treg plasticity. These reprogrammed Tregs with impaired suppressive ability contribute to the progression of diseases by secreting pro-inflammatory cytokines. However, in the tumor microenvironment (TME), such changes in phenotype rarely occur in Tregs, on the contrary, Tregs usually display a stronger suppressive function and inhibit anti-tumor immunity. It is important to understand the mechanisms of Treg plasticity in inflammatory diseases and cancers. OBJECTIVES In this review, we summarize the characteristics of different Th-like Tregs and discuss the potential mechanisms of these changes in phenotype. Furthermore, we summarize the Treg plasticity in human diseases and discuss the effects of these changes in phenotype on disease progression, as well as the potential application of drugs or reagents that regulate Treg plasticity in human diseases. CONCLUSIONS Treg plasticity is associated with inflammatory diseases and cancers. Regulating Treg plasticity is a promising direction for the treatment of inflammatory diseases and cancers.
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Affiliation(s)
- Zheng Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430072, China
| | - Jihua Guo
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430072, China
- Department of Endodontics, School & Hospital of Stomatology, Wuhan University, Wuhan, 430072, China
| | - Rong Jia
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430072, China.
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Kang JH, Zappasodi R. Modulating Treg stability to improve cancer immunotherapy. Trends Cancer 2023; 9:911-927. [PMID: 37598003 DOI: 10.1016/j.trecan.2023.07.015] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 07/23/2023] [Accepted: 07/25/2023] [Indexed: 08/21/2023]
Abstract
Immunosuppressive regulatory T cells (Tregs) provide a main mechanism of tumor immune evasion. Targeting Tregs, especially in the tumor microenvironment (TME), continues to be investigated to improve cancer immunotherapy. Recent studies have unveiled intratumoral Treg heterogeneity and plasticity, furthering the complexity of the role of Tregs in tumor immunity and immunotherapy response. The phenotypic and functional diversity of intratumoral Tregs can impact their response to therapy and may offer new targets to modulate specific Treg subsets. In this review we provide a unifying framework of critical factors contributing to Treg heterogeneity and plasticity in the TME, and we discuss how this information can guide the development of more specific Treg-targeting therapies for cancer immunotherapy.
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Affiliation(s)
- Jee Hye Kang
- Weill Cornell Medicine, Weill Cornell Medical College of Cornell University, New York, NY, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School, New York, NY, USA
| | - Roberta Zappasodi
- Weill Cornell Medicine, Weill Cornell Medical College of Cornell University, New York, NY, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School, New York, NY, USA.
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Wang X, Sun L, Yang B, Li W, Zhang C, Yang X, Sun Y, Shen X, Gao Y, Ju B, Gao Y, Liu D, Song J, Jia X, Su Y, Jiao A, Liu H, Zhang L, Lan He, Lei L, Chen W, Zhang B. Zfp335 establishes eTreg lineage and neonatal immune tolerance by targeting Hadha-mediated fatty acid oxidation. J Clin Invest 2023; 133:e166628. [PMID: 37843279 PMCID: PMC10575732 DOI: 10.1172/jci166628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 08/15/2023] [Indexed: 10/17/2023] Open
Abstract
Regulatory T cells (Tregs) are instrumental in maintaining immune tolerance and preventing destructive autoimmunity, but how heterogeneous Treg populations are established remains largely unknown. Here, we show that Zfp335 deletion in Tregs failed to differentiate into effector Tregs (eTregs) and lose Treg-suppressive function and that KO mice exhibited early-onset lethal autoimmune inflammation with unrestricted activation of conventional T cells. Single-cell RNA-Seq analyses revealed that Zfp335-deficient Tregs lacked a eTreg population and showed dramatic accumulation of a dysfunctional Treg subset. Mechanistically, Zfp335-deficient Tregs displayed reduced oxidative phosphorylation and dysfunctional mitochondrial activity. Further studies revealed that Zfp335 controlled eTreg differentiation by regulating fatty acid oxidation (FAO) through direct targeting of the FAO enzyme Hadha. Importantly, we demonstrate a positive correlation between ZNF335 and HADHA expression in human eTregs. Our findings reveal that Zfp335 controls FAO-driven eTreg differentiation to establish immune tolerance.
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Affiliation(s)
- Xin Wang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
| | - Lina Sun
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
| | - Biao Yang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
| | - Wenhua Li
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
| | - Cangang Zhang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
| | - Xiaofeng Yang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi’an Jiaotong University), Ministry of Education, Xi’an, Shaanxi, China
- Xi’an Key Laboratory of Immune-Related Diseases, Xi’an, Shannxi, China
| | - Yae Sun
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Xiaonan Shen
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
| | - Yang Gao
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
| | - Bomiao Ju
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Yafeng Gao
- Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Suzhou Institute of Systems Medicine, Suzhou, China
| | - Dan Liu
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Xi’an Medical University, Xi’an, Shaanxi, China
| | - Jiapeng Song
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
| | - Xiaoxuan Jia
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
| | - Yanhong Su
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
| | - Anjun Jiao
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
| | - Haiyan Liu
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
| | - Lianjun Zhang
- Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Suzhou Institute of Systems Medicine, Suzhou, China
| | - Lan He
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Lei Lei
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
| | - WanJun Chen
- Mucosal Immunology Section, National Institute of Dental and Craniofacial Research (NIDCR), NIH, Bethesda, Maryland, USA
| | - Baojun Zhang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi’an Jiaotong University), Ministry of Education, Xi’an, Shaanxi, China
- Xi’an Key Laboratory of Immune-Related Diseases, Xi’an, Shannxi, China
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
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de Silva TA, Apte S, Voisey J, Spann K, Tan M, Divithotawela C, Chambers D, O’Sullivan B. Single-Cell Profiling of Cells in the Lung of a Patient with Chronic Hypersensitivity Pneumonitis Reveals Inflammatory Niche with Abundant CD39+ T Cells with Functional ATPase Phenotype: A Case Study. Int J Mol Sci 2023; 24:14442. [PMID: 37833889 PMCID: PMC10572861 DOI: 10.3390/ijms241914442] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/13/2023] [Accepted: 09/20/2023] [Indexed: 10/15/2023] Open
Abstract
This study investigated immune cell characteristics in chronic hypersensitivity pneumonitis (HP), focusing on CD39-expressing cells' impact on inflammation and tissue remodelling. Lung tissue from an HP patient was analysed using single-cell transcriptomics, flow cytometry, and gene expression profiling. The tissue revealed diverse cell types like macrophages, T cells, fibroblasts, and regulatory T cells (Tregs). CD39-expressing Tregs exhibited heightened ATP hydrolysis capacity and regulatory gene expression. CD39hi cells displayed markers of both Tregs and proinflammatory Th17 cells, suggesting transitional properties. Communication networks involving molecules like SPP1, collagen, CSF1, and IL-1β were identified, hinting at interactions between cell types in HP pathogenesis. This research provides insights into the immune response and cell interactions in chronic HP. CD39-expressing cells dual nature as Tregs and Th17 cells suggests a role in modulating lung inflammation, potentially affecting disease progression. These findings lay the groundwork for further research, underscoring CD39-expressing cells as potential therapeutic targets in HP.
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Affiliation(s)
- Tharushi Ayanthika de Silva
- Centre for Genomics and Personalised Health, Faculty of Health, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, QLD 4000, Australia
- Queensland Lung Transplant Service, Ground Floor, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Chermside, Brisbane, QLD 4000, Australia
| | - Simon Apte
- Queensland Lung Transplant Service, Ground Floor, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Chermside, Brisbane, QLD 4000, Australia
- Facility of Clinical Medicine, The University of Queensland, Brisbane, QLD 4000, Australia
| | - Joanne Voisey
- Centre for Genomics and Personalised Health, Faculty of Health, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, QLD 4000, Australia
| | - Kirsten Spann
- Centre for Immunology and Infection Control, Faculty of Health, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, QLD 4000, Australia
| | - Maxine Tan
- Queensland Lung Transplant Service, Ground Floor, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Chermside, Brisbane, QLD 4000, Australia
- Facility of Clinical Medicine, The University of Queensland, Brisbane, QLD 4000, Australia
| | - Chandima Divithotawela
- Queensland Lung Transplant Service, Ground Floor, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Chermside, Brisbane, QLD 4000, Australia
| | - Daniel Chambers
- Centre for Genomics and Personalised Health, Faculty of Health, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, QLD 4000, Australia
- Queensland Lung Transplant Service, Ground Floor, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Chermside, Brisbane, QLD 4000, Australia
- Facility of Clinical Medicine, The University of Queensland, Brisbane, QLD 4000, Australia
| | - Brendan O’Sullivan
- Centre for Genomics and Personalised Health, Faculty of Health, School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, QLD 4000, Australia
- Queensland Lung Transplant Service, Ground Floor, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Chermside, Brisbane, QLD 4000, Australia
- Facility of Clinical Medicine, The University of Queensland, Brisbane, QLD 4000, Australia
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Alvarez F, Piccirillo CA. The functional adaptation of effector Foxp3 + regulatory T cells to pulmonary inflammation. Eur J Immunol 2023; 53:e2250273. [PMID: 37366319 DOI: 10.1002/eji.202250273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 06/02/2023] [Accepted: 06/02/2023] [Indexed: 06/28/2023]
Abstract
During infections, the timings of effector differentiation of pulmonary immune responses are of paramount importance, as pathogen persistence and unsuppressed inflammation can rapidly lead to a loss of function, increased frailty, and death. Thus, both an efficient clearance of the danger and a rapid resolution of inflammation are critical to host survival. We now know that tissue-localized FoxP3+ regulatory T cells, a subset of CD4+ T cells, are highly attuned to the type of immune response, acquiring unique phenotypic characteristics that allow them to adapt their suppressive functions with the nature of inflammatory cells. To achieve this, activated effector TREG cells acquire specialized TH 1, TH 2, and TH 17-like characteristics that allow them to migrate, survive, and time their function(s) through refined mechanisms. Herein, we describe how this process requires a unique developmental path that includes the acquisition of master transcription factors and the expression of receptors adapted to sense local danger signals that are found during pulmonary inflammation. In turn, we offer an overview of how these characteristics promote the capacity of local effector TREG cells to proliferate, survive, and display suppressive strategies to resolve lung injury.
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Affiliation(s)
- Fernando Alvarez
- Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada
- Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, The Research Institute of the McGill University Health Centre (RI-MUHC), Montréal, Québec, Canada
- Centre of Excellence in Translational Immunology (CETI), McGill University, Montréal, Québec, Canada
| | - Ciriaco A Piccirillo
- Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada
- Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, The Research Institute of the McGill University Health Centre (RI-MUHC), Montréal, Québec, Canada
- Centre of Excellence in Translational Immunology (CETI), McGill University, Montréal, Québec, Canada
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Vaikunthanathan T, Landmann E, Correa DM, Romano M, Trevelin SC, Peng Q, Crespo E, Corrado M, Lozano JJ, Pearce EL, Perpinan E, Zoccarato A, Siew L, Edwards-Hicks J, Khan R, Luu NT, Thursz MR, Newsome PN, Martinez-Llordella M, Shah N, Lechler RI, Shah AM, Sanchez-Fueyo A, Lombardi G, Safinia N. Dysregulated anti-oxidant signalling and compromised mitochondrial integrity negatively influence regulatory T cell function and viability in liver disease. EBioMedicine 2023; 95:104778. [PMID: 37657135 PMCID: PMC10480539 DOI: 10.1016/j.ebiom.2023.104778] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 08/15/2023] [Accepted: 08/15/2023] [Indexed: 09/03/2023] Open
Abstract
BACKGROUND Dysregulated inflammatory responses and oxidative stress are key pathogenic drivers of chronic inflammatory diseases such as liver cirrhosis (LC). Regulatory T cells (Tregs) are essential to prevent excessive immune activation and maintain tissue homeostasis. While inflammatory cues are well known to modulate the function and stability of Tregs, the extent to which Tregs are influenced by oxidative stress has not been fully explored. METHODS The phenotypic and functional properties of CD4+CD25+CD127lo/- Tregs isolated from patients with LC were compared to healthy controls (HC). Treg redox state was investigated by characterizing intracellular reactive oxygen species (ROS), NADPH oxidase-2 (Nox2) activity, mitochondrial function, morphology, and nuclear factor-erythroid 2-related factor (Nrf2) antioxidant signalling. The relevance of Nrf2 and its downstream target, Heme-oxygenase-1 (HO-1), in Treg function, stability, and survival, was further assessed using mouse models and CRISPR/Cas9-mediated HO-1 knock-out. FINDINGS Circulating Tregs from LC patients displayed a reduced suppressive function, correlating with liver disease severity, associated with phenotypic abnormalities and increased apoptosis. Mechanistically, this was linked to a dysregulated Nrf2 signalling with resultant lower levels of HO-1, enhanced Nox2 activation, and impaired mitochondrial respiration and integrity. The functional deficit in LC Tregs could be partially recapitulated by culturing control Tregs in patient sera. INTERPRETATION Our findings reveal that Tregs rely on functional redox homeostasis for their function, stability, and survival. Targeting Treg specific anti-oxidant pathways may have therapeutic potential to reverse the Treg impairment in conditions of oxidative damage such as advanced liver disease. FUNDING This study was funded by the Wellcome Trust (211113/A/18/Z).
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Affiliation(s)
- Trishan Vaikunthanathan
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom.
| | - Emmanuelle Landmann
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom.
| | - Diana Marin Correa
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom.
| | - Marco Romano
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, 5th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom.
| | - Silvia Cellone Trevelin
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom.
| | - Qi Peng
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, 5th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom.
| | - Elena Crespo
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom.
| | - Mauro Corrado
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Juan-José Lozano
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Joseph Stelzmannstrasse 26, 50931, Cologne, Germany.
| | - Erika L Pearce
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), Calle Rossello 153 Bajos, O8036, Barcelona, Spain.
| | - Elena Perpinan
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom.
| | - Anna Zoccarato
- Department of Immunometabolism, Max Planck Institute of Immunobiology & Epigenetics, Stübeweg 51, 79108, Freiburg, Germany.
| | - Leonard Siew
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, 5th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom.
| | - Joy Edwards-Hicks
- Centre for Liver and Gastroenterology Research and Birmingham National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.
| | - Reenam Khan
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, Liver Unit, 10th Floor QEQM Building, St Mary's Hospital, W2 1NY, London, United Kingdom.
| | - Nguyet-Thin Luu
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, Liver Unit, 10th Floor QEQM Building, St Mary's Hospital, W2 1NY, London, United Kingdom.
| | - Mark R Thursz
- Institute of Liver Sciences, King's College Hospital NHS Foundation Trust, London, SE5 9NU, United Kingdom.
| | - Philip N Newsome
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, Liver Unit, 10th Floor QEQM Building, St Mary's Hospital, W2 1NY, London, United Kingdom.
| | - Marc Martinez-Llordella
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom.
| | - Naina Shah
- James Black Centre, Department of Cardiovascular sciences, British Heart Foundation Centre of Excellence, School of Cardiovascular and Metabolic Medicine and Sciences, King's College London, London, SE5 9NU, United Kingdom.
| | - Robert I Lechler
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, 5th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom.
| | - Ajay M Shah
- Department of Immunometabolism, Max Planck Institute of Immunobiology & Epigenetics, Stübeweg 51, 79108, Freiburg, Germany.
| | - Alberto Sanchez-Fueyo
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom.
| | - Giovanna Lombardi
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, 5th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, United Kingdom.
| | - Niloufar Safinia
- Department of Inflammation Biology, Institute of Liver Studies, School of Immunology and Microbial Sciences, James Black Centre, King's College London, London, SE5 9NU, United Kingdom.
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Fadlallah S, Bitar ER, Hussein H, Jallad MA, Matar GM, Rahal EA. The interplay between Epstein-Barr virus DNA and gut microbiota in the development of arthritis in a mouse model. Microbiol Spectr 2023; 11:e0204223. [PMID: 37615438 PMCID: PMC10581075 DOI: 10.1128/spectrum.02042-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 07/02/2023] [Indexed: 08/25/2023] Open
Abstract
Epstein-Barr virus (EBV) DNA may influence the development of autoimmune diseases by increasing the production of proinflammatory cytokines. Such cytokines have been associated with inducing the dysbiosis of colonic microbiota, which, in turn, is a risk factor for autoimmune diseases such as rheumatoid arthritis (RA). Therefore, we investigated the role that EBV DNA may play in modulating the intestinal microbiota and consequent exacerbation of arthritis in a mouse model. Mice were treated with collagen (arthritis-inducing agent), EBV DNA and collagen, EBV DNA, or water. Fecal samples were collected from arthritic and control mice, and 16S rRNA sequencing was performed to determine the effect of EBV DNA on the composition of colonic microbiota. EBV DNA causes a change in the alpha diversity of the microbiota resulting in an increased Chao1 microbial richness and decreased Shannon diversity index in the RA mouse model. In addition, the abundance of particular genera/genus clusters was significantly altered among the various groups, with the EBV DNA-exacerbated arthritic group having the highest number of altered genera/genus cluster abundances. This group also had the highest number of cells co-expressing IL-17A, FOXP3, and IFNγ in the colons. Antimicrobial-cleared mice transplanted with fecal samples from EBV DNA-exacerbated arthritic mice showed a higher incidence and enhanced severity of RA compared to those transplanted with fecal samples from water or collagen-treated mice. IMPORTANCE Epstein-Barr virus (EBV) DNA alters the composition and diversity of the gut microbiota in a rheumatoid arthritis (RA) mouse model. These induced changes are associated with enhanced severity of symptoms. This better understanding of the various factors involved in the development of RA will possibly help in creating individualized treatments for RA patients including target mediators triggered by viral DNA. Given that a large swathe of the population harbors EBV, a significant proportion of subjects with arthritis may benefit from possible approaches that target EBV or mediators triggered by this virus.
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Affiliation(s)
- Sukayna Fadlallah
- Department of Experimental Pathology, Immunology, and Microbiology, American University of Beirut, Beirut, Lebanon
| | - Elio R. Bitar
- Department of Experimental Pathology, Immunology, and Microbiology, American University of Beirut, Beirut, Lebanon
| | - Hadi Hussein
- Department of Experimental Pathology, Immunology, and Microbiology, American University of Beirut, Beirut, Lebanon
- Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon
| | - Mary-Ann Jallad
- Department of Experimental Pathology, Immunology, and Microbiology, American University of Beirut, Beirut, Lebanon
| | - Ghassan M. Matar
- Department of Experimental Pathology, Immunology, and Microbiology, American University of Beirut, Beirut, Lebanon
- Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon
| | - Elias A. Rahal
- Department of Experimental Pathology, Immunology, and Microbiology, American University of Beirut, Beirut, Lebanon
- Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon
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36
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Feilstrecker Balani G, dos Santos Cortez M, Picasky da Silveira Freitas JE, Freire de Melo F, Zarpelon-Schutz AC, Teixeira KN. Immune response modulation in inflammatory bowel diseases by Helicobacter pylori infection. World J Gastroenterol 2023; 29:4604-4615. [PMID: 37662864 PMCID: PMC10472898 DOI: 10.3748/wjg.v29.i30.4604] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 07/01/2023] [Accepted: 07/24/2023] [Indexed: 08/10/2023] Open
Abstract
Many studies point to an association between Helicobacter pylori (H. pylori) infection and inflammatory bowel diseases (IBD). Although controversial, this association indicates that the presence of the bacterium somehow affects the course of IBD. It appears that H. pylori infection influences IBD through changes in the diversity of the gut microbiota, and hence in local chemical characteristics, and alteration in the pattern of gut immune response. The gut immune response appears to be modulated by H. pylori infection towards a less aggressive inflammatory response and the establishment of a targeted response to tissue repair. Therefore, a T helper 2 (Th2)/macrophage M2 response is stimulated, while the Th1/macrophage M1 response is suppressed. The immunomodulation appears to be associated with intrinsic factors of the bacteria, such as virulence factors - such oncogenic protein cytotoxin-associated antigen A, proteins such H. pylori neutrophil-activating protein, but also with microenvironmental changes that favor permanence of H. pylori in the stomach. These changes include the increase of gastric mucosal pH by urease activity, and suppression of the stomach immune response promoted by evasion mechanisms of the bacterium. Furthermore, there is a causal relationship between H. pylori infection and components of the innate immunity such as the NLR family pyrin domain containing 3 inflammasome that directs IBD toward a better prognosis.
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Affiliation(s)
| | | | | | - Fabrício Freire de Melo
- Campus Anísio Teixeira, Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista 45.029-094, Bahia, Brazil
| | - Ana Carla Zarpelon-Schutz
- Campus Toledo, Universidade Federal do Paraná, Toledo 85.919-899, Paraná, Brazil
- Programa de Pós-graduação em Biotecnologia - Setor Palotina, Universidade Federal do Paraná, Palotina 85.950-000, Paraná, Brazil
| | - Kádima Nayara Teixeira
- Campus Toledo, Universidade Federal do Paraná, Toledo 85.919-899, Paraná, Brazil
- Programa Multicêntrico de Pós-graduação em Bioquímica e Biologia Molecular - Setor Palotina, Universidade Federal do Paraná, Palotina 85.950-000, Paraná, Brazil
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Guardalupi F, Sorrentino C, Corradi G, Giancola R, Baldoni S, Ulbar F, Fabi B, Andres Ejarque R, Timms J, Restuccia F, Santarone S, Accorsi P, Sportoletti P, De Falco F, Rosati E, Carotti A, Falzetti F, Velardi A, Martelli MF, Kordasti S, Pierini A, Ruggeri L, Di Ianni M. A pro-inflammatory environment in bone marrow of Treg transplanted patients matches with graft-versus-leukemia effect. Leukemia 2023; 37:1572-1575. [PMID: 37286785 PMCID: PMC10317833 DOI: 10.1038/s41375-023-01932-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 05/03/2023] [Accepted: 05/30/2023] [Indexed: 06/09/2023]
Affiliation(s)
- Francesco Guardalupi
- Department of Medicine and Aging Sciences, University of Chieti-Pescara, Chieti, Italy
| | - Carlo Sorrentino
- Department of Medicine and Aging Sciences, University of Chieti-Pescara, Chieti, Italy
| | - Giulia Corradi
- Department of Medicine and Aging Sciences, University of Chieti-Pescara, Chieti, Italy
| | | | - Stefano Baldoni
- Department of Oncology Hematology, Pescara Hospital, Pescara, Italy
| | - Francesca Ulbar
- Department of Medicine and Aging Sciences, University of Chieti-Pescara, Chieti, Italy
| | - Bianca Fabi
- Department of Medicine and Aging Sciences, University of Chieti-Pescara, Chieti, Italy
| | - Rosa Andres Ejarque
- System Cancer Immunology, Comprehensive Cancer Centre, King's College London, London, United Kingdom
| | - Jessica Timms
- System Cancer Immunology, Comprehensive Cancer Centre, King's College London, London, United Kingdom
| | | | - Stella Santarone
- Department of Oncology Hematology, Pescara Hospital, Pescara, Italy
| | - Patrizia Accorsi
- Department of Oncology Hematology, Pescara Hospital, Pescara, Italy
| | - Paolo Sportoletti
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Filomena De Falco
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Emanuela Rosati
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Alessandra Carotti
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Franca Falzetti
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Andrea Velardi
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Shahram Kordasti
- System Cancer Immunology, Comprehensive Cancer Centre, King's College London, London, United Kingdom
| | - Antonio Pierini
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Loredana Ruggeri
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Mauro Di Ianni
- Department of Medicine and Aging Sciences, University of Chieti-Pescara, Chieti, Italy.
- Department of Oncology Hematology, Pescara Hospital, Pescara, Italy.
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Cao J, Zhan Y, Ji L, Chen P, Cheng L, Li F, Zhuang X, Min Z, Sun L, Hua F, Chen H, Wu B, Cheng Y. Proinflammatory plasticity towards Th17 paradigm of regulatory T cells consistent with elevated prevalence of TGFBR2 variants in elderly patients with primary immune thrombocytopenia. BMC Immunol 2023; 24:6. [PMID: 37029342 PMCID: PMC10082480 DOI: 10.1186/s12865-023-00541-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 03/20/2023] [Indexed: 04/09/2023] Open
Abstract
BACKGROUND Primary immune thrombocytopenia (ITP) is characterized for the skewed Th differentiation towards Th1 and Th17 cells as well as the impaired number and function of regulatory T cells (Tregs). Tregs are capable of co-expressing effector Th markers in different inflammatory milieu, which probably indicates Treg dysfunction and incompetence to counter over-activated immune responses. METHODS Ninety-two primary ITP patients from March 2013 to December 2018 were included, and proinflammatory plasticity in different Treg compartments, age groups, and TGFBR2 variant carrier status were investigated. RESULTS Patients were categorized into elderly (n = 44) and younger (n = 48) groups according to an age of 50 years at disease onset. The overall remission rate was 82.6% after first-line regimens, including 47.8% complete remission. TGFBR2 variants were found in 7 (7.6%) patients with three V216I and four T340M heterozygote carriers. ITP patients demonstrated elevated co-expression of IL-17 and decreased co-expression of both IFN-γ and IL-13 than health control (all p < 0.01). The elderly group demonstrated elevated prevalence of TGFBR2 variants (p = 0.037) and elevated co-expression of IL-17 (p = 0.017) in Tregs, while female predominance was found in the younger group (p = 0.037). In the elderly group, TGFBR2 variant carriers demonstrated further elevated co-expression of IL-17 (p = 0.023) and decreased co-expression of both IFN-γ (p = 0.039) and IL-13 (p = 0.046) in the aTreg compartment. CONCLUSIONS Our findings revealed additional aberrations of Treg proinflammatory plasticity in elderly primary ITP patients, and highlighted the potential role of Treg dysfunction and senescence in the pathogenesis and management among these patients.
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Affiliation(s)
- Jingjing Cao
- Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yanxia Zhan
- Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Lili Ji
- Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Pu Chen
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Luya Cheng
- Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Feng Li
- Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Department of Hematology, Zhongshan Hospital Qingpu Branch, Fudan University, Shanghai, 201700, China
| | - Xibing Zhuang
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai, 201508, China
| | - Zhihui Min
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Lihua Sun
- Department of Hematology, Zhongshan Hospital Qingpu Branch, Fudan University, Shanghai, 201700, China
| | - Fanli Hua
- Department of Hematology, Zhongshan Hospital Qingpu Branch, Fudan University, Shanghai, 201700, China
| | - Hao Chen
- Department of Thoracic Surgery, Zhongshan Hospital Xuhui Branch, Fudan University, Shanghai, 200031, China
| | - Boting Wu
- Department of Transfusion, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Yunfeng Cheng
- Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Department of Hematology, Zhongshan Hospital Qingpu Branch, Fudan University, Shanghai, 201700, China.
- Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai, 201508, China.
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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39
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Gonçalves‐Pereira MH, Santiago L, Ravetti CG, Vassallo PF, de Andrade MVM, Vieira MS, de Fátima Souza de Oliveira F, Carobin NV, Li G, de Paula Sabino A, Nobre V, da Costa Santiago H. Dysfunctional phenotype of systemic and pulmonary regulatory T cells associate with lethal COVID-19 cases. Immunology 2023; 168:684-696. [PMID: 36349514 PMCID: PMC9877711 DOI: 10.1111/imm.13603] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 11/04/2022] [Indexed: 11/10/2022] Open
Abstract
Severe cases of COVID-19 present hyperinflammatory condition that can be fatal. Little is known about the role of regulatory responses in SARS-CoV-2 infection. In this study, we evaluated the phenotype of regulatory T cells in the blood (peripheral blood mononuclear cell) and the lungs (broncho-alveolar) of adult patients with severe COVID-19 under invasive mechanical ventilation. Our results show important dynamic variation on Treg cells phenotype during COVID-19 with changes in number and functional parameters from the day of intubation (Day 1 of intensive care unit admission) to Day 7. We observed that compared with surviving patients, non-survivors presented lower numbers of Treg cells in the blood. In addition, lung Tregs of non-survivors also displayed higher PD1 and lower FOXP3 expressions suggesting dysfunctional phenotype. Further signs of Treg dysregulation were observed in non-survivors such as limited production of IL-10 in the lungs and higher production of IL-17A in the blood and in the lungs, which were associated with increased PD1 expression. These findings were also associated with lower pulmonary levels of Treg-stimulating factors like TNF and IL-2. Tregs in the blood and lungs are profoundly dysfunctional in non-surviving COVID-19 patients.
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Affiliation(s)
- Marcela Helena Gonçalves‐Pereira
- Departamento de Bioquímica e ImunologiaInstituto de Ciências Biológicas, Universidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
| | - Luciana Santiago
- Departamento de Bioquímica e ImunologiaInstituto de Ciências Biológicas, Universidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
- Hospital das ClínicasUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
- Núcleo Interdisciplinar de Investigação em Medicina IntensivaDepartamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
| | - Cecilia Gómez Ravetti
- Núcleo Interdisciplinar de Investigação em Medicina IntensivaDepartamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
- Faculdade de MedicinaUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
| | - Paula Frizera Vassallo
- Núcleo Interdisciplinar de Investigação em Medicina IntensivaDepartamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
- Faculdade de MedicinaUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
| | - Marcus Vinicius Melo de Andrade
- Núcleo Interdisciplinar de Investigação em Medicina IntensivaDepartamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
- Faculdade de MedicinaUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
| | - Mariana Sousa Vieira
- Departamento de Bioquímica e ImunologiaInstituto de Ciências Biológicas, Universidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
| | | | - Natália Virtude Carobin
- Departamento de Análises Clínicas e ToxicológicasFaculdade de Farmácia, Universidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
| | - Guangzhao Li
- Department of MicrobiologyImmunology and Tropical Medicine, The George Washington UniversityWashingtonDistrict of ColumbiaUSA
| | - Adriano de Paula Sabino
- Departamento de Análises Clínicas e ToxicológicasFaculdade de Farmácia, Universidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
| | - Vandack Nobre
- Núcleo Interdisciplinar de Investigação em Medicina IntensivaDepartamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
- Faculdade de MedicinaUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
| | - Helton da Costa Santiago
- Departamento de Bioquímica e ImunologiaInstituto de Ciências Biológicas, Universidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
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Nazri JM, Oikonomopoulou K, de Araujo ED, Kraskouskaya D, Gunning PT, Chandran V. Histone deacetylase inhibitors as a potential new treatment for psoriatic disease and other inflammatory conditions. Crit Rev Clin Lab Sci 2023; 60:300-320. [PMID: 36846924 DOI: 10.1080/10408363.2023.2177251] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2023]
Abstract
Collectively known as psoriatic disease, psoriasis and psoriatic arthritis (PsA) are immune-mediated inflammatory diseases in which patients present with cutaneous and musculoskeletal inflammation. Affecting roughly 2-3% of the world's total population, there remains unmet therapeutic needs in both psoriasis and PsA despite the availability of current immunomodulatory treatments. As a result, patients with psoriatic disease often experience reduced quality of life. Recently, a class of small molecules, commonly investigated as anti-cancer agents, called histone deacetylase (HDAC) inhibitors, have been proposed as a new promising anti-inflammatory treatment for immune- and inflammatory-related diseases. In inflammatory diseases, current evidence is derived from studies on diseases like rheumatoid arthritis (RA) and systematic lupus erythematosus (SLE), and while there are some reports studying psoriasis, data on PsA patients are not yet available. In this review, we provide a brief overview of psoriatic disease, psoriasis, and PsA, as well as HDACs, and discuss the rationale behind the potential use of HDAC inhibitors in the management of persistent inflammation to suggest its possible use in psoriatic disease.
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Affiliation(s)
- Jehan Mohammad Nazri
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | | | - Elvin D de Araujo
- Department of Chemical and Physical Sciences, University of Toronto, Mississauga, Canada
| | - Dziyana Kraskouskaya
- Department of Chemical and Physical Sciences, University of Toronto, Mississauga, Canada
| | - Patrick T Gunning
- Department of Chemical and Physical Sciences, University of Toronto, Mississauga, Canada.,Department of Chemistry, University of Toronto, Toronto, Canada
| | - Vinod Chandran
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.,Schroeder Arthritis Institute, University Health Network, Toronto, Canada.,Department of Medicine, University of Toronto, Toronto, Canada.,Institute of Medical Science, University of Toronto, Toronto, Canada.,Department of Medicine, Memorial University, St. John's, Canada
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Autoreactive T-Cells in Psoriasis: Are They Spoiled Tregs and Can Therapies Restore Their Functions? Int J Mol Sci 2023; 24:ijms24054348. [PMID: 36901778 PMCID: PMC10002349 DOI: 10.3390/ijms24054348] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 02/10/2023] [Accepted: 02/13/2023] [Indexed: 02/25/2023] Open
Abstract
Psoriasis is a chronic inflammatory skin disease, which affects 2-4% of the population worldwide. T-cell derived factors such as Th17 and Th1 cytokines or cytokines such as IL-23, which favors Th17-expansion/differentiation, dominate in the disease. Therapies targeting these factors have been developed over the years. An autoimmune component is present, as autoreactive T-cells specific for keratins, the antimicrobial peptide LL37 and ADAMTSL5 have been described. Both autoreactive CD4 and CD8 T-cells exist, produce pathogenic cytokines, and correlate with disease activity. Along with the assumption that psoriasis is a T-cell-driven disease, Tregs have been studied extensively over the years, both in the skin and in circulation. This narrative review resumes the main findings about Tregs in psoriasis. We discuss how Tregs increase in psoriasis but are impaired in their regulatory/suppressive function. We debate the possibility that Tregs convert into T-effector cells under inflammatory conditions; for instance, they may turn into Th17-cells. We put particular emphasis on therapies that seem to counteract this conversion. We have enriched this review with an experimental section analyzing T-cells specific for the autoantigen LL37 in a healthy subject, suggesting that a shared specificity may exist between Tregs and autoreactive responder T-cells. This suggests that successful psoriasis treatments may, among other effects, restore Tregs numbers and functions.
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Laukova M, Glatman Zaretsky A. Regulatory T cells as a therapeutic approach for inflammatory bowel disease. Eur J Immunol 2023; 53:e2250007. [PMID: 36562391 PMCID: PMC10107179 DOI: 10.1002/eji.202250007] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 11/20/2022] [Accepted: 12/22/2022] [Indexed: 12/24/2022]
Abstract
Foxp3+ T regulatory (Treg) cells suppress inflammation and are essential for maintaining tissue homeostasis. A growing appreciation of tissue-specific Treg functions has built interest in leveraging the endogenous suppressive mechanisms of these cells into cellular therapeutics in organ-specific diseases. Notably, Treg cells play a critical role in maintaining the intestinal environment. As a barrier site, the gut requires Treg cells to mediate interactions with the microbiota, support barrier integrity, and regulate the immune system. Without fully functional Treg cells, intestinal inflammation and microbial dysbiosis ensue. Thus, there is a particular interest in developing Treg cellular therapies for intestinal inflammatory disease, such as inflammatory bowel disease (IBD). This article reviews some of the critical pathways that are dysregulated in IBD, Treg cell mechanisms of suppression, and the efforts and approaches in the field to develop these cells as a cellular therapy for IBD.
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Germline genetic variation and predicting immune checkpoint inhibitor induced toxicity. NPJ Genom Med 2022; 7:73. [PMID: 36564402 PMCID: PMC9789157 DOI: 10.1038/s41525-022-00345-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 12/07/2022] [Indexed: 12/25/2022] Open
Abstract
Immune checkpoint inhibitor (ICI) therapy has revolutionised the treatment of various cancer types. ICIs reinstate T-cell function to elicit an anti-cancer immune response. The resulting immune response can however have off-target effects which manifest as autoimmune type serious immune-related adverse events (irAE) in ~10-55% of patients treated. It is currently challenging to predict both who will experience irAEs and to what severity. Identification of patients at high risk of serious irAE would revolutionise patient care. While the pathogenesis driving irAE development is still unclear, host genetic factors are proposed to be key determinants of these events. This review presents current evidence supporting the role of the host genome in determining risk of irAE. We summarise the spectrum and timing of irAEs following treatment with ICIs and describe currently reported germline genetic variation associated with expression of immuno-modulatory factors within the cancer immunity cycle, development of autoimmune disease and irAE occurrence. We propose that germline genetic determinants of host immune function and autoimmune diseases could also explain risk of irAE development. We also endorse genome-wide association studies of patients being treated with ICIs to identify genetic variants that can be used in polygenic risk scores to predict risk of irAE.
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Paroli M, Caccavale R, Fiorillo MT, Spadea L, Gumina S, Candela V, Paroli MP. The Double Game Played by Th17 Cells in Infection: Host Defense and Immunopathology. Pathogens 2022; 11:pathogens11121547. [PMID: 36558881 PMCID: PMC9781511 DOI: 10.3390/pathogens11121547] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 12/09/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
T-helper 17 (Th17) cells represent a subpopulation of CD4+ T lymphocytes that play an essential role in defense against pathogens. Th17 cells are distinguished from Th1 and Th2 cells by their ability to produce members of the interleukin-17 (IL-17) family, namely IL-17A and IL-17F. IL-17 in turn induces several target cells to synthesize and release cytokines, chemokines, and metalloproteinases, thereby amplifying the inflammatory cascade. Th17 cells reside predominantly in the lamina propria of the mucosa. Their main physiological function is to maintain the integrity of the mucosal barrier against the aggression of infectious agents. However, in an appropriate inflammatory microenvironment, Th17 cells can transform into immunopathogenic cells, giving rise to inflammatory and autoimmune diseases. This review aims to analyze the complex mechanisms through which the interaction between Th17 and pathogens can be on the one hand favorable to the host by protecting it from infectious agents, and on the other hand harmful, potentially generating autoimmune reactions and tissue damage.
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Affiliation(s)
- Marino Paroli
- Division of Clinical Immunology, Department of Clinical, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy
- Correspondence:
| | - Rosalba Caccavale
- Division of Clinical Immunology, Department of Clinical, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy
| | - Maria Teresa Fiorillo
- Department of Biology and Biotechnology “Charles Darwin”, Sapienza University of Rome, 00185 Rome, Italy
| | - Luca Spadea
- Post Graduate School of Public Health, University of Siena, 53100 Siena, Italy
| | - Stefano Gumina
- Department of Anatomy, Histology, Legal Medicine and Orthopedics, Sapienza University of Rome, 00185 Rome, Italy
| | - Vittorio Candela
- Department of Anatomy, Histology, Legal Medicine and Orthopedics, Sapienza University of Rome, 00185 Rome, Italy
| | - Maria Pia Paroli
- Eye Clinic, Department of Sense Organs, Sapienza University of Rome, 00185 Rome, Italy
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Frequency and function of circulating regulatory T-cells in biliary atresia. Pediatr Surg Int 2022; 39:23. [PMID: 36449184 DOI: 10.1007/s00383-022-05307-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/14/2022] [Indexed: 12/03/2022]
Abstract
PURPOSE Although the impairment of regulatory T-cells (Tregs) has been shown in the liver or portal area of biliary atresia (BA) the frequency and function of circulating Tregs in BA patients is poorly understood. We aimed to investigate the frequency and function of circulating Tregs in BA patients. METHODS Peripheral blood mononuclear cells were collected from 25 BA patients and 24 controls. Treg frequency was measured by flow cytometry; function was determined by T-cell proliferation assay. We also assessed the association between Treg frequency/function and clinical parameters in BA cases. RESULTS There was no significant difference between the two groups in both frequency (BA: 3.4%; control: 3.2%; p = 0.97) and function (BA: 22.0%; control: 7.5%; p = 0.23) of Tregs. We further focused on 13 preoperative BA patients and 14 age-matched controls. Neither Treg frequency nor function were significantly different (frequency: BA: 4.6%; control: 3.4%; p = 0.38, function: BA: 2.7%; control: 7.6%; p = 0.89). There was no association between Treg frequency/function and clinical parameters. CONCLUSION Neither the frequency nor function of circulating Tregs was affected in BA patients, suggesting the negative role of circulating Tregs in the pathogenesis of BA. Further investigation of local Treg profiles is warranted.
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Thonhoff JR, Berry JD, Macklin EA, Beers DR, Mendoza PA, Zhao W, Thome AD, Triolo F, Moon JJ, Paganoni S, Cudkowicz M, Appel SH. Combined Regulatory T-Lymphocyte and IL-2 Treatment Is Safe, Tolerable, and Biologically Active for 1 Year in Persons With Amyotrophic Lateral Sclerosis. NEUROLOGY - NEUROIMMUNOLOGY NEUROINFLAMMATION 2022; 9:9/6/e200019. [PMID: 36038262 PMCID: PMC9423710 DOI: 10.1212/nxi.0000000000200019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 06/14/2022] [Indexed: 12/01/2022]
Abstract
Background and Objectives In a phase 1 amyotrophic lateral sclerosis (ALS) study, autologous infusions of expanded regulatory T-lymphocytes (Tregs) combined with subcutaneous interleukin (IL)-2 were safe and well tolerated. Treg suppressive function increased and disease progression stabilized during the study. The present study was conducted to confirm the reliability of these results. Methods Participants with ALS underwent leukapheresis, and their Tregs were isolated and expanded in a current Good Manufacturing Practice facility. Seven participants were randomly assigned in a 1:1 ratio to receive Treg infusions (1 × 106 cells/kg) IV every 4 weeks and IL-2 (2 × 105 IU/m2) injections 3 times/wk or matching placebo in a 24-week randomized controlled trial (RCT). Six participants proceeded into a 24-week dose-escalation open-label extension (OLE). Two additional participants entered directly into the OLE. The OLE included dose escalation of Treg infusions to 2 × 106 cells/kg and 3 × 106 cells/kg at 4-week intervals. Results The Treg/IL-2 treatments were safe and well tolerated, and Treg suppressive function was higher in the active group of the RCT. A meaningful evaluation of progression rates in the RCT between the placebo and active groups was not possible due to the limited number of enrolled participants aggravated by the COVID-19 pandemic. In the 24-week OLE, the Treg/IL-2 treatments were also safe and well tolerated in 8 participants who completed the escalating doses. Treg suppressive function and numbers were increased compared with baseline. Six of 8 participants changed by an average of −2.7 points per the ALS Functional Rating Scale–Revised, whereas the other 2 changed by an average of −10.5 points. Elevated levels of 2 markers of peripheral inflammation (IL-17C and IL-17F) and 2 markers of oxidative stress (oxidized low-density lipoprotein receptor 1 and oxidized LDL) were present in the 2 rapidly progressing participants but not in the slower progressing group. Discussion Treg/IL-2 treatments were safe and well tolerated in the RCT and OLE with higher Treg suppressive function. During the OLE, 6 of 8 participants showed slow to no progression. The 2 of 8 rapid progressors had elevated markers of oxidative stress and inflammation, which may help delineate responsiveness to therapy. Whether Treg/IL-2 treatments can slow disease progression requires a larger clinical study (ClinicalTrials.gov number, NCT04055623). Classification of Evidence This study provides Class IV evidence that Treg infusions and IL-2 injections are safe and effective for patients with ALS.
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Affiliation(s)
- Jason R Thonhoff
- From the Houston Methodist Neurological Institute (J.R.T., D.R.B., P.A.M., W.Z., A.D.T., S.H.A.), Houston Methodist Hospital Research Institute, Stanley H. Appel Department of Neurology, Houston, TX; Neurological Clinical Research Institute (J.D.B., S.P., M.C.), Healey & AMG Center for ALS, Massachusetts General Hospital, Boston, MA; Biostatistics Center (E.A.M.), Massachusetts General Hospital, Boston, MA; Harvard Medical School (E.A.M.), Boston, MA; Department of Pediatric Surgery (F.T.), McGovern Medical School, UTHealth-The University of Texas Health Science Center at Houston, Houston, TX; and Center for Immunology and Inflammatory Diseases (J.J.M.), Massachusetts General Hospital, Boston, MA; and Harvard Medical School (J.J.M.), Boston, MA
| | - James D Berry
- From the Houston Methodist Neurological Institute (J.R.T., D.R.B., P.A.M., W.Z., A.D.T., S.H.A.), Houston Methodist Hospital Research Institute, Stanley H. Appel Department of Neurology, Houston, TX; Neurological Clinical Research Institute (J.D.B., S.P., M.C.), Healey & AMG Center for ALS, Massachusetts General Hospital, Boston, MA; Biostatistics Center (E.A.M.), Massachusetts General Hospital, Boston, MA; Harvard Medical School (E.A.M.), Boston, MA; Department of Pediatric Surgery (F.T.), McGovern Medical School, UTHealth-The University of Texas Health Science Center at Houston, Houston, TX; and Center for Immunology and Inflammatory Diseases (J.J.M.), Massachusetts General Hospital, Boston, MA; and Harvard Medical School (J.J.M.), Boston, MA
| | - Eric A Macklin
- From the Houston Methodist Neurological Institute (J.R.T., D.R.B., P.A.M., W.Z., A.D.T., S.H.A.), Houston Methodist Hospital Research Institute, Stanley H. Appel Department of Neurology, Houston, TX; Neurological Clinical Research Institute (J.D.B., S.P., M.C.), Healey & AMG Center for ALS, Massachusetts General Hospital, Boston, MA; Biostatistics Center (E.A.M.), Massachusetts General Hospital, Boston, MA; Harvard Medical School (E.A.M.), Boston, MA; Department of Pediatric Surgery (F.T.), McGovern Medical School, UTHealth-The University of Texas Health Science Center at Houston, Houston, TX; and Center for Immunology and Inflammatory Diseases (J.J.M.), Massachusetts General Hospital, Boston, MA; and Harvard Medical School (J.J.M.), Boston, MA
| | - David R Beers
- From the Houston Methodist Neurological Institute (J.R.T., D.R.B., P.A.M., W.Z., A.D.T., S.H.A.), Houston Methodist Hospital Research Institute, Stanley H. Appel Department of Neurology, Houston, TX; Neurological Clinical Research Institute (J.D.B., S.P., M.C.), Healey & AMG Center for ALS, Massachusetts General Hospital, Boston, MA; Biostatistics Center (E.A.M.), Massachusetts General Hospital, Boston, MA; Harvard Medical School (E.A.M.), Boston, MA; Department of Pediatric Surgery (F.T.), McGovern Medical School, UTHealth-The University of Texas Health Science Center at Houston, Houston, TX; and Center for Immunology and Inflammatory Diseases (J.J.M.), Massachusetts General Hospital, Boston, MA; and Harvard Medical School (J.J.M.), Boston, MA
| | - Patricia A Mendoza
- From the Houston Methodist Neurological Institute (J.R.T., D.R.B., P.A.M., W.Z., A.D.T., S.H.A.), Houston Methodist Hospital Research Institute, Stanley H. Appel Department of Neurology, Houston, TX; Neurological Clinical Research Institute (J.D.B., S.P., M.C.), Healey & AMG Center for ALS, Massachusetts General Hospital, Boston, MA; Biostatistics Center (E.A.M.), Massachusetts General Hospital, Boston, MA; Harvard Medical School (E.A.M.), Boston, MA; Department of Pediatric Surgery (F.T.), McGovern Medical School, UTHealth-The University of Texas Health Science Center at Houston, Houston, TX; and Center for Immunology and Inflammatory Diseases (J.J.M.), Massachusetts General Hospital, Boston, MA; and Harvard Medical School (J.J.M.), Boston, MA
| | - Weihua Zhao
- From the Houston Methodist Neurological Institute (J.R.T., D.R.B., P.A.M., W.Z., A.D.T., S.H.A.), Houston Methodist Hospital Research Institute, Stanley H. Appel Department of Neurology, Houston, TX; Neurological Clinical Research Institute (J.D.B., S.P., M.C.), Healey & AMG Center for ALS, Massachusetts General Hospital, Boston, MA; Biostatistics Center (E.A.M.), Massachusetts General Hospital, Boston, MA; Harvard Medical School (E.A.M.), Boston, MA; Department of Pediatric Surgery (F.T.), McGovern Medical School, UTHealth-The University of Texas Health Science Center at Houston, Houston, TX; and Center for Immunology and Inflammatory Diseases (J.J.M.), Massachusetts General Hospital, Boston, MA; and Harvard Medical School (J.J.M.), Boston, MA
| | - Aaron D Thome
- From the Houston Methodist Neurological Institute (J.R.T., D.R.B., P.A.M., W.Z., A.D.T., S.H.A.), Houston Methodist Hospital Research Institute, Stanley H. Appel Department of Neurology, Houston, TX; Neurological Clinical Research Institute (J.D.B., S.P., M.C.), Healey & AMG Center for ALS, Massachusetts General Hospital, Boston, MA; Biostatistics Center (E.A.M.), Massachusetts General Hospital, Boston, MA; Harvard Medical School (E.A.M.), Boston, MA; Department of Pediatric Surgery (F.T.), McGovern Medical School, UTHealth-The University of Texas Health Science Center at Houston, Houston, TX; and Center for Immunology and Inflammatory Diseases (J.J.M.), Massachusetts General Hospital, Boston, MA; and Harvard Medical School (J.J.M.), Boston, MA
| | - Fabio Triolo
- From the Houston Methodist Neurological Institute (J.R.T., D.R.B., P.A.M., W.Z., A.D.T., S.H.A.), Houston Methodist Hospital Research Institute, Stanley H. Appel Department of Neurology, Houston, TX; Neurological Clinical Research Institute (J.D.B., S.P., M.C.), Healey & AMG Center for ALS, Massachusetts General Hospital, Boston, MA; Biostatistics Center (E.A.M.), Massachusetts General Hospital, Boston, MA; Harvard Medical School (E.A.M.), Boston, MA; Department of Pediatric Surgery (F.T.), McGovern Medical School, UTHealth-The University of Texas Health Science Center at Houston, Houston, TX; and Center for Immunology and Inflammatory Diseases (J.J.M.), Massachusetts General Hospital, Boston, MA; and Harvard Medical School (J.J.M.), Boston, MA
| | - James J Moon
- From the Houston Methodist Neurological Institute (J.R.T., D.R.B., P.A.M., W.Z., A.D.T., S.H.A.), Houston Methodist Hospital Research Institute, Stanley H. Appel Department of Neurology, Houston, TX; Neurological Clinical Research Institute (J.D.B., S.P., M.C.), Healey & AMG Center for ALS, Massachusetts General Hospital, Boston, MA; Biostatistics Center (E.A.M.), Massachusetts General Hospital, Boston, MA; Harvard Medical School (E.A.M.), Boston, MA; Department of Pediatric Surgery (F.T.), McGovern Medical School, UTHealth-The University of Texas Health Science Center at Houston, Houston, TX; and Center for Immunology and Inflammatory Diseases (J.J.M.), Massachusetts General Hospital, Boston, MA; and Harvard Medical School (J.J.M.), Boston, MA
| | - Sabrina Paganoni
- From the Houston Methodist Neurological Institute (J.R.T., D.R.B., P.A.M., W.Z., A.D.T., S.H.A.), Houston Methodist Hospital Research Institute, Stanley H. Appel Department of Neurology, Houston, TX; Neurological Clinical Research Institute (J.D.B., S.P., M.C.), Healey & AMG Center for ALS, Massachusetts General Hospital, Boston, MA; Biostatistics Center (E.A.M.), Massachusetts General Hospital, Boston, MA; Harvard Medical School (E.A.M.), Boston, MA; Department of Pediatric Surgery (F.T.), McGovern Medical School, UTHealth-The University of Texas Health Science Center at Houston, Houston, TX; and Center for Immunology and Inflammatory Diseases (J.J.M.), Massachusetts General Hospital, Boston, MA; and Harvard Medical School (J.J.M.), Boston, MA
| | - Merit Cudkowicz
- From the Houston Methodist Neurological Institute (J.R.T., D.R.B., P.A.M., W.Z., A.D.T., S.H.A.), Houston Methodist Hospital Research Institute, Stanley H. Appel Department of Neurology, Houston, TX; Neurological Clinical Research Institute (J.D.B., S.P., M.C.), Healey & AMG Center for ALS, Massachusetts General Hospital, Boston, MA; Biostatistics Center (E.A.M.), Massachusetts General Hospital, Boston, MA; Harvard Medical School (E.A.M.), Boston, MA; Department of Pediatric Surgery (F.T.), McGovern Medical School, UTHealth-The University of Texas Health Science Center at Houston, Houston, TX; and Center for Immunology and Inflammatory Diseases (J.J.M.), Massachusetts General Hospital, Boston, MA; and Harvard Medical School (J.J.M.), Boston, MA
| | - Stanley H Appel
- From the Houston Methodist Neurological Institute (J.R.T., D.R.B., P.A.M., W.Z., A.D.T., S.H.A.), Houston Methodist Hospital Research Institute, Stanley H. Appel Department of Neurology, Houston, TX; Neurological Clinical Research Institute (J.D.B., S.P., M.C.), Healey & AMG Center for ALS, Massachusetts General Hospital, Boston, MA; Biostatistics Center (E.A.M.), Massachusetts General Hospital, Boston, MA; Harvard Medical School (E.A.M.), Boston, MA; Department of Pediatric Surgery (F.T.), McGovern Medical School, UTHealth-The University of Texas Health Science Center at Houston, Houston, TX; and Center for Immunology and Inflammatory Diseases (J.J.M.), Massachusetts General Hospital, Boston, MA; and Harvard Medical School (J.J.M.), Boston, MA.
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Tang X, Yang ZZ, Kim HJ, Anagnostou T, Yu Y, Wu X, Chen J, Krull JE, Wenzl K, Mondello P, Bhardwaj V, Wang J, Novak AJ, Ansell SM. Phenotype, Function, and Clinical Significance of CD26+ and CD161+Tregs in Splenic Marginal Zone Lymphoma. Clin Cancer Res 2022; 28:4322-4335. [PMID: 35686915 PMCID: PMC10443733 DOI: 10.1158/1078-0432.ccr-22-0977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/17/2022] [Accepted: 06/08/2022] [Indexed: 12/14/2022]
Abstract
PURPOSE Regulatory T-cells (Treg) are essential to Tregs homeostasis and modulate the antitumor immune response in patients with lymphoma. However, the biology and prognostic impact of Tregs in splenic marginal zone lymphoma (SMZL) have not been studied. EXPERIMENTAL DESIGN Biopsy specimens from 24 patients with SMZL and 12 reactive spleens (rSP) from individuals without lymphoma were analyzed by using CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing), CyTOF (mass cytometry) analysis, and flow cytometry to explore the phenotype, transcriptomic profile, and clinical significance of intratumoral Tregs and their subsets. The biological characteristics and cell signaling pathways of intratumoral Treg subsets were confirmed by in vitro functional assays. RESULTS We found that Tregs are more abundant in SMZL patients' spleens than rSP, and Tregs from patients with SMZL and rSP can be separated into CD161+Treg and CD26+Treg subsets. CD161+Tregs are increased in SMZL but have dysregulated immune function. We found that CD161+Treg and CD26+Tregs have unique gene expression and phenotypic profiles and are differentially correlated with patient outcomes. Specifically, increased CD161+Tregs are significantly associated with a favorable prognosis in patients with SMZL, whereas CD26+Tregs are associated with a poor prognosis. Furthermore, activation of the IL2/STAT5 pathway contributes to the induction of CD26+Tregs and can be reversed by STAT5 inhibition. CONCLUSIONS IL2/STAT5-mediated expansion of CD26+Tregs contributes to a poor clinical outcome in SMZL and may represent a therapeutic opportunity in this disease.
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Affiliation(s)
- Xinyi Tang
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Zhi-Zhang Yang
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Hyo Jin Kim
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Theodora Anagnostou
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Yue Yu
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - Xiaosheng Wu
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Jun Chen
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - Jordan E. Krull
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Kerstin Wenzl
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Patrizia Mondello
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Vaishali Bhardwaj
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Junwen Wang
- Department of Quantitative Health Sciences and Center for Individualized Medicine, Mayo Clinic, Scottsdale, Arizona
| | - Anne J. Novak
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Stephen M. Ansell
- Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
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Hajam EY, Panikulam P, Chu CC, Jayaprakash H, Majumdar A, Jamora C. The expanding impact of T-regs in the skin. Front Immunol 2022; 13:983700. [PMID: 36189219 PMCID: PMC9521603 DOI: 10.3389/fimmu.2022.983700] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/26/2022] [Indexed: 11/29/2022] Open
Abstract
As the interface between the body and the environment, the skin functions as the physical barrier against external pathogens and toxic agents. In addition, the skin is an immunologically active organ with a plethora of resident adaptive and innate immune cells, as well as effector molecules that provide another layer of protection in the form of an immune barrier. A major subpopulation of these immune cells are the Foxp3 expressing CD4 T cells or regulatory T cells (T-regs). The canonical function of T-regs is to keep other immune cells in check during homeostasis or to dissipate a robust inflammatory response following pathogen clearance or wound healing. Interestingly, recent data has uncovered unconventional roles that vary between different tissues and we will highlight the emerging non-lymphoid functions of cutaneous T-regs. In light of the novel functions of other immune cells that are routinely being discovered in the skin, their regulation by T-regs implies that T-regs have executive control over a broad swath of biological activities in both homeostasis and disease. The blossoming list of non-inflammatory functions, whether direct or indirect, suggests that the role of T-regs in a regenerative organ such as the skin will be a field ripe for discovery for decades to come.
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Affiliation(s)
- Edries Yousaf Hajam
- IFOM ETS- The AIRC Institute of Molecular Oncology Joint Research Laboratory, Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore, Karnataka, India
- School of Chemical and Biotechnology, Shanmugha Arts, Science, Technology and Research Academy (SASTRA) University, Thanjavur, Tamil Nadu, India
| | - Patricia Panikulam
- IFOM ETS- The AIRC Institute of Molecular Oncology Joint Research Laboratory, Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore, Karnataka, India
| | | | - Haarshadri Jayaprakash
- IFOM ETS- The AIRC Institute of Molecular Oncology Joint Research Laboratory, Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore, Karnataka, India
| | | | - Colin Jamora
- IFOM ETS- The AIRC Institute of Molecular Oncology Joint Research Laboratory, Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore, Karnataka, India
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Maeda A, Yamamoto R, Mizuno S, Miki S, Sakamoto Y, Kogata S, Toyama C, Sato K, Okamatsu C, Ando T, Iida M, Watsuji T, Sato T, Miyagawa S, Okuyama H, Takami A, Kodera Y. Efficacy of a 365 nm Ultraviolet A1 light Emitting Diode (UVA1-LED) in in vitro Extracorporeal Photopheresis. Photochem Photobiol 2022; 98:1229-1235. [PMID: 35238039 DOI: 10.1111/php.13613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 02/24/2022] [Accepted: 02/25/2022] [Indexed: 11/29/2022]
Abstract
Extracorporeal photochemotherapy (ECP) is one of the more effective cell therapies for graft-versus-host disease (GvHD). ECP is a widely recommended therapeutic approach for the treatment of chronic GvHD, particularly steroid-refractory GVHD. In recent years, the use of a light emitting diode (LED) in the clinic has attracted considerable interest. In this study, we examined the issue of whether an ultraviolet A1-light emitting diode (UVA1-LED) can be used as a light source in ECP. To compare the efficacy of ECP with conventional UVA lamp and a UVA1-LED, we established an in vitro ECP model. Treatment efficacy was evaluated by measuring the % apoptosis and the inhibition of T-cell proliferation. To investigate the effect of ECP on the innate immune reaction, THP-1 cells with a luciferase reporter gene driven by a NF-kB response element (THP-1 luc NF-kB) were treated with ECP. The LED-ECP induced apoptosis and inhibition of T-cell proliferation as efficiently as a conventional ECP. However, LED-ECP induced less innate immunity in THP-1. Since LED devices are more compact compared with conventional UVA irradiation devices, the use of a UVA1-LED in the treatment of ECP may be a better alternative to conventional ECP therapy.
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Affiliation(s)
- Akira Maeda
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Japan
- Department of Promotion for Blood and Marrow Transplantation, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Riho Yamamoto
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Japan
- Air Water Incorporated, Osaka, Japan
| | - Shohei Mizuno
- Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan
| | | | | | - Shuhei Kogata
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Chiyoshi Toyama
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kazuki Sato
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Chizu Okamatsu
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Takanori Ando
- Department of Promotion for Blood and Marrow Transplantation, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Minako Iida
- Department of Promotion for Blood and Marrow Transplantation, Aichi Medical University School of Medicine, Nagakute, Japan
| | | | - Toshinobu Sato
- Molecular Genetics, Institute of Life Science, Kurume University, Kurume, Japan
| | - Shuji Miyagawa
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Japan
- Meiji University International Institute for Bio-Resource Research, Kawasaki, Japan
| | - Hiroomi Okuyama
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Akiyoshi Takami
- Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yoshitaka Kodera
- Department of Promotion for Blood and Marrow Transplantation, Aichi Medical University School of Medicine, Nagakute, Japan
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50
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Chakraborty S, Khamaru P, Bhattacharyya A. Regulation of immune cell metabolism in health and disease: Special focus on T and B cell subsets. Cell Biol Int 2022; 46:1729-1746. [PMID: 35900141 DOI: 10.1002/cbin.11867] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 04/03/2022] [Accepted: 07/05/2022] [Indexed: 12/15/2022]
Abstract
Metabolism is a dynamic process and keeps changing from time to time according to the demand of a particular cell to meet its bio-energetic requirement. Different immune cells rely on distinct metabolic programs which allow the cell to balance its requirements for energy, molecular biosynthesis, and effector activity. In the aspect of infection and cancer immunology, effector T and B cells get exhausted and help tumor cells to evade immunosurveillance. On the other hand, T cells become hyperresponsive in the scenario of autoimmune diseases. In this article, we have explored the uniqueness and distinct metabolic features of key CD4+ T and B helper cell subsets, CD4+ T, B regulatory cell subsets and CD8+ T cells regarding health and disease. Th1 cells rely on glycolysis and glutaminolysis; inhibition of these metabolic pathways promotes Th1 cells in Treg population. However, Th2 cells are also dependent on glycolysis but an abundance of lactate within TME shifts their metabolic dependency to fatty acid metabolism. Th17 cells depend on HIF-1α mediated glycolysis, ablation of HIF-1α reduces Th17 cells but enhance Treg population. In contrast to effector T cells which are largely dependent on glycolysis for their differentiation and function, Treg cells mainly rely on FAO for their function. Therefore, it is of utmost importance to understand the metabolic fates of immune cells and how it facilitates their differentiation and function for different disease models. Targeting metabolic pathways to restore the functionality of immune cells in diseased conditions can lead to potent therapeutic measures.
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Affiliation(s)
- Sayan Chakraborty
- Immunology Laboratory, Department of Zoology, University of Calcutta, Kolkata, West Bengal, India
| | - Poulomi Khamaru
- Immunology Laboratory, Department of Zoology, University of Calcutta, Kolkata, West Bengal, India
| | - Arindam Bhattacharyya
- Immunology Laboratory, Department of Zoology, University of Calcutta, Kolkata, West Bengal, India
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