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1
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Roy P, Sharma S, Baranwal M. Computational Insight in the Identification of Non-Synonymous Single-Nucleotide Polymorphism Affecting the Structure and Function of Interleukin-4. Proteomics Clin Appl 2025; 19:e202400070. [PMID: 39648289 DOI: 10.1002/prca.202400070] [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: 07/13/2024] [Revised: 11/12/2024] [Accepted: 11/25/2024] [Indexed: 12/10/2024]
Abstract
BACKGROUND IL4 is a versatile cytokine essentially known for differentiation, proliferation and cell death in cells. Its dysregulation has been found to be associated with the development of inflammatory disorders. OBJECTIVE The goal of the current investigation is to identify and select non-synonymous single-nucleotide polymorphisms (nsSNPs) in the IL-4 gene by employing computational methods which may have a potential functional impact on the occurrence of disease. METHOD AND RESULT Six different nsSNPs were predicted to be deleterious based on the consensus of different algorithms: SIFT, Polyphen2 (Humdiv and HumVar), PredictSNP and SNP&GO. I-mutant and MuPro assessment revealed a decrease in the stability of these mutants except K150M. Modelling was then carried out to build the wild type along with its mutants, followed by superimposition of the wild type with mutants to evaluate the RMSD value, which lies between 0.26 and 0.34. Simulation results of mutant models, along with wild type, showed that four of the mutants (N113Y, A118G, R109W and K150M) deviated most and were unstable. A118G showed a significant deviation from the wild type, while V53A and C123R were stable. CONCLUSION The finding establishes the evidence that the identified six nsSNPs of IL-4 can be the new entrant presenting their candidature for genetic testing.
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Affiliation(s)
- Pratima Roy
- Department of Biotechnology, Thapar Institute of Engineering & Technology, Patiala, India
| | - Siddharth Sharma
- Department of Biotechnology, Thapar Institute of Engineering & Technology, Patiala, India
| | - Manoj Baranwal
- Department of Biotechnology, Thapar Institute of Engineering & Technology, Patiala, India
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2
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Liu R, Zhang J, Chen S, Xiao Y, Hu J, Zhou Z, Xie L. Intestinal mucosal immunity and type 1 diabetes: Non-negligible communication between gut and pancreas. Diabetes Obes Metab 2025; 27:1045-1064. [PMID: 39618164 PMCID: PMC11802406 DOI: 10.1111/dom.16101] [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: 07/28/2024] [Revised: 11/16/2024] [Accepted: 11/18/2024] [Indexed: 02/08/2025]
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by T cell-mediated pancreatic β cell loss, resulting in lifelong absolute insulin deficiency and hyperglycaemia. Environmental factors are recognized as a key contributor to the development of T1D, with the gut serving as a primary interface for environmental stimuli. Recent studies have revealed that the alterations in the intestinal microenvironment profoundly affect host immune responses, contributing to the aetiology and pathogenesis of T1D. However, the dominant intestinal immune cells and the underlying mechanisms remain incompletely elucidated. In this review, we provide an overview of the possible mechanisms of the intestinal mucosal system that underpin the pathogenesis of T1D, shedding light on the roles of both non-classical and classical immune cells in T1D. Our goal is to gain insights into how modulating these immune components may hold potential implications for T1D prevention and provide novel perspectives for immune-mediated therapy.
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Affiliation(s)
- Ruonan Liu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Jing Zhang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Si Chen
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life ScienceHunan Normal UniversityChangshaChina
| | - Yang Xiao
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Jingyi Hu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Lingxiang Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
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3
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Wyatt-Johnson SK, Afify R, Brutkiewicz RR. The immune system in neurological diseases: What innate-like T cells have to say. J Allergy Clin Immunol 2024; 153:913-923. [PMID: 38365015 PMCID: PMC10999338 DOI: 10.1016/j.jaci.2024.02.003] [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: 09/18/2023] [Revised: 01/26/2024] [Accepted: 02/13/2024] [Indexed: 02/18/2024]
Abstract
The immune system classically consists of 2 lines of defense, innate and adaptive, both of which interact with one another effectively to protect us against any pathogenic threats. Importantly, there is a diverse subset of cells known as innate-like T cells that act as a bridge between the innate and adaptive immune systems and are pivotal players in eliciting inflammatory immune responses. A growing body of evidence has demonstrated the regulatory impact of these innate-like T cells in central nervous system (CNS) diseases and that such immune cells can traffic into the brain in multiple pathological conditions, which can be typically attributed to the breakdown of the blood-brain barrier. However, until now, it has been poorly understood whether innate-like T cells have direct protective or causative properties, particularly in CNS diseases. Therefore, in this review, our attention is focused on discussing the critical roles of 3 unique subsets of unconventional T cells, namely, natural killer T cells, γδ T cells, and mucosal-associated invariant T cells, in the context of CNS diseases, disorders, and injuries and how the interplay of these immune cells modulates CNS pathology, in an attempt to gain a better understanding of their complex functions.
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Affiliation(s)
- Season K Wyatt-Johnson
- Department of Microbiology and Immunology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Ind
| | - Reham Afify
- Department of Microbiology and Immunology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Ind
| | - Randy R Brutkiewicz
- Department of Microbiology and Immunology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Ind.
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4
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Hebbandi Nanjundappa R, Shao K, Krishnamurthy P, Gershwin ME, Leung PSC, Sokke Umeshappa C. Invariant natural killer T cells in autoimmune cholangiopathies: Mechanistic insights and therapeutic implications. Autoimmun Rev 2024; 23:103485. [PMID: 38040101 DOI: 10.1016/j.autrev.2023.103485] [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: 11/07/2023] [Accepted: 11/23/2023] [Indexed: 12/03/2023]
Abstract
Invariant natural killer T cells (iNKT cells) constitute a specialized subset of lymphocytes that bridges innate and adaptive immunity through a combination of traits characteristic of both conventional T cells and innate immune cells. iNKT cells are characterized by their invariant T cell receptors and discerning recognition of lipid antigens, which are presented by the non-classical MHC molecule, CD1d. Within the hepatic milieu, iNKT cells hold heightened prominence, contributing significantly to the orchestration of organ homeostasis. Their unique positioning to interact with diverse cellular entities, ranging from epithelial constituents like hepatocytes and cholangiocytes to immunocytes including Kupffer cells, B cells, T cells, and dendritic cells, imparts them with potent immunoregulatory abilities. Emergering knowledge of liver iNKT cells subsets enable to explore their therapeutic potential in autoimmne liver diseases. This comprehensive review navigates the landscape of iNKT cell investigations in immune-mediated cholangiopathies, with a particular focus on primary biliary cholangitis and primary sclerosing cholangitis, across murine models and human subjects to unravel the intricate involvements of iNKT cells in liver autoimmunity. Additionally, we also highlight the prospectives of iNKT cells as therapeutic targets in cholangiopathies. Modulation of the equilibrium between regulatory and proinflammatory iNKT subsets can be defining determinant in the dynamics of hepatic autoimmunity. This discernment not only enriches our foundational comprehension but also lays the groundwork for pioneering strategies to navigate the multifaceted landscape of liver autoimmunity.
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Affiliation(s)
| | - Kun Shao
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116023, China
| | - Prasanna Krishnamurthy
- Department of Biomedical Engineering, Schools of Medicine and Engineering, University of Alabama at Birmingham, Birmingham, AL, USA
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA, United States.
| | - Patrick S C Leung
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA, United States
| | - Channakeshava Sokke Umeshappa
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada; Department of Pediatrics, IWK Research Center, Halifax, NS, Canada.
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5
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Yu X, Mai Y, Wei Y, Yu N, Gao T, Yang J. Therapeutic potential of tolerance-based peptide vaccines in autoimmune diseases. Int Immunopharmacol 2023; 116:109740. [PMID: 36696858 DOI: 10.1016/j.intimp.2023.109740] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 01/04/2023] [Accepted: 01/13/2023] [Indexed: 01/24/2023]
Abstract
Autoimmune diseases are caused by the dysfunction of the body's immune regulatory system, which leads to the recognition of self-antigens and the destruction of self-tissues and is mediated by immune cells such as T and B cells, and affects 5-10% of the population worldwide. Current treatments such as non-steroidal anti-inflammatory drugs and glucocorticoids can only relieve symptoms of the disease and are accompanied by serious side effects that affect patient quality of life. The recent rise in antigen-specific therapies, especially vaccines carrying autoantigenic peptides, promises to change this disadvantage, where research has increased dramatically in the last decade. This therapy established specific immune tolerance by delivering peptide fragments containing disease-specific self-antigen epitopes to suppress excessive immune responses, thereby exerting a therapeutic effect, with high safety and specificity. This article presents the latest progress on the treatment of autoimmune diseases with autoantigen peptide vaccines. It includes the construction of peptide vaccine delivery system, the mechanism of inducing immune tolerance and its application.
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Affiliation(s)
- Xueting Yu
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Yaping Mai
- School of Science and Technology Centers, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Yaya Wei
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Na Yu
- Department of Pharmaceutical Preparation, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Ting Gao
- Department of Pharmaceutical Preparation, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China.
| | - Jianhong Yang
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia, China.
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Nienhuis WA, Grutters JC. Potential therapeutic targets to prevent organ damage in chronic pulmonary sarcoidosis. Expert Opin Ther Targets 2021; 26:41-55. [PMID: 34949145 DOI: 10.1080/14728222.2022.2022123] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Sarcoidosis is a granulomatous inflammatory disease with high chances of reduced quality of life, irreversible organ damage, and reduced life expectancy when vital organs are involved. Any organ system can be affected, and the lungs are most often affected. There is no preventive strategy as the exact etiology is unknown, and complex immunogenetic and environmental factors determine disease susceptibility and phenotype. Present-day treatment options originated from clinical practice and are effective in many patients. However, a substantial percentage of patients suffer from unacceptable side effects or still develop refractory, threatening pulmonary or extrapulmonary disease. AREAS COVERED As non-caseating granulomas, the pathological hallmark of disease, are assigned to divergent activation and regulation of the immune system, targets in relation to the possible triggers of granuloma formation and their sequelae were searched and reviewed. EXPERT OPINION :The immunopathogenesis underlying sarcoidosis has been a dynamic field of study. Several recent new insights give way to promising new therapeutic targets, such as certain antigenic triggers (e.g. from Aspergillus nidulans), mTOR, JAK-STAT and PPARγ pathways, the NRP2 receptor and MMP-12, which await further exploration. Clinical and trigger related phenotyping, and molecular endotyping in sarcoidosis will likely hold the key for precision medicine in the future.
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Affiliation(s)
- W A Nienhuis
- ILD Center of Excellence, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands
| | - J C Grutters
- ILD Center of Excellence, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands.,Division of Hearth and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands
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Hsu CY, Chueh YS, Kuo ML, Lee PT, Hsiao HS, Huang JL, Lin SJ. Expansion of invariant natural killer T cells from systemic lupus erythematosus patients by alpha-Galactosylceramide and IL-15. PLoS One 2021; 16:e0261727. [PMID: 34936686 PMCID: PMC8694473 DOI: 10.1371/journal.pone.0261727] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 12/07/2021] [Indexed: 11/19/2022] Open
Abstract
CD1d-restricted invariant natural killer T cells (iNKT cells) may play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Interleukin (IL)-15 is a pro-inflammatory cytokine which is over-expressed in SLE patients. In the present study, we investigated the iNKT cell expansion of mononuclear cells (MNCs) from SLE patients following 10 days’ culture with α-galactosylceramide (α-Galcer) and /or IL-15. We sought to determine the phenotypic and functional characteristics of the expanded iNKT cells compared to healthy controls and correlated with disease activity. We observed that 1. The percentages of Vα24+/Vβ11+ iNKT cells following 10-day incubation was lower in SLE groups compared to controls; 2. The percentages and absolute numbers of Vα24+/Vβ11+ iNKT cells were expanded by α-galactosylceramide (α-Galcer), and further enhanced with IL-15 in SLE patient, but the effect of IL-15 was much lower than controls; 3.IL-15 +α-Galcer expanded CD3+/CD56+ NKT-like cells from SLE patients, especially with active disease 4. The CD161+ Vα24+/Vβ11+ iNKT cells in SLE were more responsive to α-Galcer stimulation than the CD161- counterpart; 5. IL-15 decreased apoptosis of α-Galcer activated SLE iNKT cells; 6. IL-15 enhanced CD69, CD1d and CD11a expression on α-Galcer treated iNKT cells; 7. The IL-4 production of iNKT cells was decreased in SLE patients compared to controls; 8. IL-15 increased IFN-γ and IL-4 production of SLE iNKT cells; 8. IL-15 failed to augment the ability of iNKT cells to aid NK-mediated K562 cytolysis in SLE patients; 9. CD161 positivity, granzyme B and perforin expression of α-Galcer+IL-15 expanded iNKT cells correlated with C3 levels in SLE patients. Taken together, our results demonstrated numeric and functional deficiency of iNKT cells and their response to IL-15 in SLE patients. Our finding may provide insight for using adoptive iNKT cell therapy in autoimmune diseases.
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Affiliation(s)
- Chien-Ya Hsu
- Division of Asthma, Allergy, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yu-Shan Chueh
- Division of Asthma, Allergy, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ming-Ling Kuo
- Division of Asthma, Allergy, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Center for Medical and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Pediatrics, New Taipei Municipal Tu Cheng Hospital, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
| | - Pei-Tzu Lee
- Division of Asthma, Allergy, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Hsiu-Shan Hsiao
- Division of Asthma, Allergy, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Jing-Long Huang
- Division of Asthma, Allergy, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Pediatrics, New Taipei Municipal Tu Cheng Hospital, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
- * E-mail: (SJL); (JLH)
| | - Syh-Jae Lin
- Division of Asthma, Allergy, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- * E-mail: (SJL); (JLH)
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8
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Lee HW, Shin J, Wilson BS, Oh JW. Peripheral immune tolerance by prolactin-induced protein originated from human invariant natural killer T cells. Bioengineered 2021; 12:461-475. [PMID: 33509033 PMCID: PMC8806214 DOI: 10.1080/21655979.2021.1875664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 01/02/2021] [Indexed: 11/23/2022] Open
Abstract
invariant natural killer T (iNKT) cells have been reported to regulate a diverse set of immunological responses. iNKT cell dysfunction in cytokine secretion is linked to the development of autoimmunity, an immune response against its own tissue. Interestingly, CD4+ iNKT cells preferentially secrete regulatory cytokines. Here we investigated what kind of secreting factors of it are involved in dendritic cell (DC) maturation to regulate immune responses. We found one of them, prolactin induced protein (PIP), from the supernatants of cultured CD4+ iNKT cells. It was validated using RT-quantitative real-time polymerase chain reaction (RT-qPCR) and western blot analysis. Subsequent analysis upon PIP treatment was performed using fluorescence-activated cell sorting (FACS) analysis. We identified PIP as one of strong candidates for inducing DC maturation, to similar level to lipopolysaccharide, an already known candidate molecule. Recombinant PIP recapitulated natural function, and induction of DC differentiation by both recombinant and purified PIP was blocked by anti-Toll-like receptor (TLR)2 antibody (Ab), but not by anti-TLR4/5 or anti-receptor Ab for advanced glycation end product Ab. Interestingly, PIP induced the differentiation of naïve T cells into CD4+ CD25+ Foxp3+ regulatory T cells and reduced the number of helper T (Th)1 and Th17 cells produced by Pam3CysSerLys4. Take in together, these results suggest that PIP is an important factor that mediates immunoregulation by iNKT cells through TLR2-mediated signaling.
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Affiliation(s)
- Hyeong-Woo Lee
- Department of Animal Science and Technology, Konkuk University, Seoul, Republic of Korea
- Speegenebio, Co., Ltd, Seongnam, Republic of Korea
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA
| | - Juhyun Shin
- Department of Stem Cell and Regenerative Biotechnology and Animal Resources Research Center, Konkuk University, Seoul, Republic of Korea
| | - Brian S. Wilson
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA
| | - Jae-Wook Oh
- Department of Stem Cell and Regenerative Biotechnology and Animal Resources Research Center, Konkuk University, Seoul, Republic of Korea
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9
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Iwaszko M, Biały S, Bogunia-Kubik K. Significance of Interleukin (IL)-4 and IL-13 in Inflammatory Arthritis. Cells 2021; 10:cells10113000. [PMID: 34831223 PMCID: PMC8616130 DOI: 10.3390/cells10113000] [Citation(s) in RCA: 144] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/26/2021] [Accepted: 10/30/2021] [Indexed: 12/12/2022] Open
Abstract
Interleukin (IL)-4 and IL-13 belong to the T helper 2 (Th2) cytokine family, along with IL-3, IL-5, and IL-9. These cytokines are key mediators of allergic inflammation. They have important immunomodulatory activities and exert influence on a wide variety of immune cells, such as B cells, eosinophils, basophils, monocytes, fibroblasts, endothelial cells, airway epithelial cells, smooth muscle cells, and keratinocytes. Recent studies have implicated IL-4 and IL-13 in the development of various autoimmune diseases. Additionally, these cytokines have emerged as potential players in pathogenesis of inflammatory arthritis. Recent findings suggest that the IL-4 and IL-13 might play a significant role in the downregulation of inflammatory processes underlying RA pathology, and beneficially modulate the course of the disease. This review summarizes the biological features of the IL-4 and IL-13 and provides current knowledge regarding the role of these cytokines in inflammatory arthritis.
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Gan J, Mao XR, Zheng SJ, Li JF. Invariant natural killer T cells: Not to be ignored in liver disease. J Dig Dis 2021; 22:136-142. [PMID: 33421264 DOI: 10.1111/1751-2980.12968] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 12/14/2020] [Accepted: 01/04/2021] [Indexed: 12/11/2022]
Abstract
The liver is an important immune organ. Hepatocellular injury can be caused by many factors, which further leads to chronic liver diseases by activating the immune system. Multiple immune cells, such as T lymphocytes, B lymphocytes, natural killer cells (NKs), natural killer T cells (NKTs), and γδT cells, accumulate and participate in the immune regulation of the liver. NKTs are an indispensable component of immune cells in the liver, and invariant natural killer T cells (iNKTs) are the main subpopulation of NKTs. iNKTs activated by glycolipid antigen presented on CD1d secrete a series of cytokines and also act on other immune cells through cell-to-cell contact. Studies on the relationship between iNKTs and liver immunity have provided clues to uncover the pathogenesis of liver diseases and develop a promising strategy for the diagnosis and treatment of liver diseases.
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Affiliation(s)
- Jian Gan
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu Province, China
| | - Xiao Rong Mao
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu Province, China
- Department of Infectious Disease, The First Hospital of Lanzhou University, Lanzhou, Gansu Province, China
| | - Su Jun Zheng
- Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Jun Feng Li
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu Province, China
- Department of Infectious Disease, The First Hospital of Lanzhou University, Lanzhou, Gansu Province, China
- Institute of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou, Gansu Province, China
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11
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Foray AP, Dietrich C, Pecquet C, Machavoine F, Chatenoud L, Leite-de-Moraes M. IL-4 and IL-17 Are Required for House Dust Mite-Driven Airway Hyperresponsiveness in Autoimmune Diabetes-Prone Non-Obese Diabetic Mice. Front Immunol 2021; 11:595003. [PMID: 33643284 PMCID: PMC7904896 DOI: 10.3389/fimmu.2020.595003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 12/29/2020] [Indexed: 12/27/2022] Open
Abstract
Allergic asthma is characterized by airway inflammation with a Th2-type cytokine profile, hyper-IgE production, mucus hypersecretion, and airway hyperreactivity (AHR). It is increasingly recognized that asthma is a heterogeneous disease implicating complex immune mechanisms resulting in distinct endotypes observed in patients. In this study, we showed that non-obese diabetic (NOD) mice, which spontaneously develop autoimmune diabetes, undergo more severe allergic asthma airway inflammation and AHR than pro-Th2 BALB/c mice upon house dust mite (HDM) sensitization and challenge. The use of IL-4-deficient NOD mice and the in vivo neutralization of IL-17 demonstrated that both IL-4 and IL-17 are responsible by the exacerbated airway inflammation and AHR observed in NOD mice. Overall, our findings indicate that autoimmune diabetes-prone NOD mice might become useful as a new HDM-induced asthma model to elucidate allergic dysimmune mechanisms involving Th2 and Th17 responses that could better mimic some asthmatic endoytpes.
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Affiliation(s)
- Anne-Perrine Foray
- Université de Paris, Paris, France.,Laboratory of Immunoregulation and Immunopathology, INEM (Institut Necker-Enfants Malades), CNRS UMR8253 and Inserm UMR1151, Paris, France
| | - Céline Dietrich
- Université de Paris, Paris, France.,Laboratory of Immunoregulation and Immunopathology, INEM (Institut Necker-Enfants Malades), CNRS UMR8253 and Inserm UMR1151, Paris, France
| | - Coralie Pecquet
- Université de Paris, Paris, France.,Laboratory of Immunoregulation and Immunopathology, INEM (Institut Necker-Enfants Malades), CNRS UMR8253 and Inserm UMR1151, Paris, France
| | - François Machavoine
- Université de Paris, Paris, France.,Laboratory of Immunoregulation and Immunopathology, INEM (Institut Necker-Enfants Malades), CNRS UMR8253 and Inserm UMR1151, Paris, France
| | - Lucienne Chatenoud
- Université de Paris, Paris, France.,Laboratory of Immunoregulation and Immunopathology, INEM (Institut Necker-Enfants Malades), CNRS UMR8253 and Inserm UMR1151, Paris, France
| | - Maria Leite-de-Moraes
- Université de Paris, Paris, France.,Laboratory of Immunoregulation and Immunopathology, INEM (Institut Necker-Enfants Malades), CNRS UMR8253 and Inserm UMR1151, Paris, France
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12
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Tootee A, Nikbin B, Ghahary A, Esfahani EN, Arjmand B, Aghayan H, Qorbani M, Larijani B. Immunopathology of Type 1 Diabetes and Immunomodulatory Effects of Stem Cells: A Narrative Review of the Literature. Endocr Metab Immune Disord Drug Targets 2021; 22:169-197. [PMID: 33538679 DOI: 10.2174/1871530321666210203212809] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 10/11/2020] [Accepted: 10/27/2020] [Indexed: 11/22/2022]
Abstract
Type 1 Diabetes (T1D) is a complex autoimmune disorder which occurs as a result of an intricate series of pathologic interactions between pancreatic β-cells and a wide range of components of both the innate and the adaptive immune systems. Stem-cell therapy, a recently-emerged potentially therapeutic option for curative treatment of diabetes, is demonstrated to cause significant alternations to both different immune cells such as macrophages, natural killer (NK) cells, dendritic cells, T cells, and B cells and non-cellular elements including serum cytokines and different components of the complement system. Although there exists overwhelming evidence indicating that the documented therapeutic effects of stem cells on patients with T1D is primarily due to their potential for immune regulation rather than pancreatic tissue regeneration, to date, the precise underlying mechanisms remain obscure. On the other hand, immune-mediated rejection of stem cells remains one of the main obstacles to regenerative medicine. Moreover, the consequences of efferocytosis of stem-cells by the recipients' lung-resident macrophages have recently emerged as a responsible mechanism for some immune-mediated therapeutic effects of stem-cells. This review focuses on the nature of the interactions amongst different compartments of the immune systems which are involved in the pathogenesis of T1D and provides explanation as to how stem cell-based interventions can influence immune system and maintain the physiologic equilibrium.
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Affiliation(s)
- Ali Tootee
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, . Iran
| | - Behrouz Nikbin
- Research Center of Molecular Immunology, Tehran University of Medical Sciences, Tehran, . Iran
| | - Aziz Ghahary
- British Columbia Professional Firefighters' Burn and Wound Healing Research Laboratory, Department of Surgery, Plastic Surgery, University of British Columbia, Vancouver, . Canada
| | - Ensieh Nasli Esfahani
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, . Iran
| | - Babak Arjmand
- Cell therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, . Iran
| | - Hamidreza Aghayan
- Cell therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, . Iran
| | - Mostafa Qorbani
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, . Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, . Iran
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13
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Suvas P, Liu L, Rao P, Steinle JJ, Suvas S. Systemic alterations in leukocyte subsets and the protective role of NKT cells in the mouse model of diabetic retinopathy. Exp Eye Res 2020; 200:108203. [PMID: 32890483 DOI: 10.1016/j.exer.2020.108203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 08/17/2020] [Accepted: 08/25/2020] [Indexed: 11/28/2022]
Abstract
The involvement of leukocytes in the pathophysiology of DR has mostly examined the role of monocytes and neutrophils with little emphasis on other immune cell types. In this study, we determined the systemic alterations in T cell subsets, myeloid cell types, NK cells, and NKT cells in the streptozotocin (STZ) mouse model of diabetic retinopathy (DR), and the role of NKT cells on retinal leukostasis and permeability changes. C57BL/6 J mice were made diabetic with 60 mg/kg dose of STZ given for 5-days. Flow cytometry assay measured the frequency of leukocyte subsets in the peripheral blood, spleen, and bone marrow of STZ- and vehicle-treated C57BL/6 J mice. Our results showed an increased proportion of memory CD8 T cells and interferon-gamma (IFN-γ) secreting CD8 T cells in the bone marrow of STZ-treated compared to control mice. Subsequently, increased production of inflammatory monocytes in the bone marrow and an enhanced frequency of CD11b + cells in the diabetic retina were seen in STZ-treated compared to control mice. The diabetic mice also exhibited a decrease in total NKT and CD4+NKT cells. A monoclonal antibody-based approach depleted NKT cells from STZ-treated mice, followed by measurements of retinal vascular permeability and leukostasis. The depletion of NKT cells in STZ-treated mice resulted in a significant increase in vascular permeability in the retinal tissue. Together, our results strongly imply the involvement of NKT cells in regulating the pathophysiology of the diabetic retina.
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Affiliation(s)
- Pratima Suvas
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, USA
| | - Li Liu
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, USA
| | - Pushpa Rao
- Department of Developmental Molecular and Chemical Biology, Tufts University School of Medicine, USA
| | - Jena J Steinle
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, USA.
| | - Susmit Suvas
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI, USA; Department of Biochemistry, Microbiology and Immunology, Wayne State University School of Medicine, Detroit, MI, USA.
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14
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Ye C, Low BE, Wiles MV, Brusko TM, Serreze DV, Driver JP. CD70 Inversely Regulates Regulatory T Cells and Invariant NKT Cells and Modulates Type 1 Diabetes in NOD Mice. THE JOURNAL OF IMMUNOLOGY 2020; 205:1763-1777. [PMID: 32868408 DOI: 10.4049/jimmunol.2000148] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 07/31/2020] [Indexed: 11/19/2022]
Abstract
The CD27-CD70 costimulatory pathway is essential for the full activation of T cells, but some studies show that blocking this pathway exacerbates certain autoimmune disorders. In this study, we report on the impact of CD27-CD70 signaling on disease progression in the NOD mouse model of type 1 diabetes (T1D). Specifically, our data demonstrate that CD70 ablation alters thymocyte selection and increases circulating T cell levels. CD27 signaling was particularly important for the thymic development and peripheral homeostasis of Foxp3+Helios+ regulatory T cells, which likely accounts for our finding that CD70-deficient NOD mice develop more-aggressive T1D onset. Interestingly, we found that CD27 signaling suppresses the thymic development and effector functions of T1D-protective invariant NKT cells. Thus, rather than providing costimulatory signals, the CD27-CD70 axis may represent a coinhibitory pathway for this immunoregulatory T cell population. Moreover, we showed that a CD27 agonist Ab reversed the effects of CD70 ablation, indicating that the phenotypes observed in CD70-deficient mice were likely due to a lack of CD27 signaling. Collectively, our results demonstrate that the CD27-CD70 costimulatory pathway regulates the differentiation program of multiple T cell subsets involved in T1D development and may be subject to therapeutic targeting.
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Affiliation(s)
- Cheng Ye
- Department of Animal Sciences, University of Florida, Gainesville, FL 32611
| | | | | | - Todd M Brusko
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL 32610
| | | | - John P Driver
- Department of Animal Sciences, University of Florida, Gainesville, FL 32611;
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15
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Sphingolipids in Type 1 Diabetes: Focus on Beta-Cells. Cells 2020; 9:cells9081835. [PMID: 32759843 PMCID: PMC7465050 DOI: 10.3390/cells9081835] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/01/2020] [Accepted: 08/03/2020] [Indexed: 12/28/2022] Open
Abstract
Type 1 diabetes (T1DM) is a chronic autoimmune disease, with a strong genetic background, leading to a gradual loss of pancreatic beta-cells, which secrete insulin and control glucose homeostasis. Patients with T1DM require life-long substitution with insulin and are at high risk for development of severe secondary complications. The incidence of T1DM has been continuously growing in the last decades, indicating an important contribution of environmental factors. Accumulating data indicates that sphingolipids may be crucially involved in T1DM development. The serum lipidome of T1DM patients is characterized by significantly altered sphingolipid composition compared to nondiabetic, healthy probands. Recently, several polymorphisms in the genes encoding the enzymatic machinery for sphingolipid production have been identified in T1DM individuals. Evidence gained from studies in rodent islets and beta-cells exposed to cytokines indicates dysregulation of the sphingolipid biosynthetic pathway and impaired function of several sphingolipids. Moreover, a number of glycosphingolipids have been suggested to act as beta-cell autoantigens. Studies in animal models of autoimmune diabetes, such as the Non Obese Diabetic (NOD) mouse and the LEW.1AR1-iddm (IDDM) rat, indicate a crucial role of sphingolipids in immune cell trafficking, islet infiltration and diabetes development. In this review, the up-to-date status on the findings about sphingolipids in T1DM will be provided, the under-investigated research areas will be identified and perspectives for future studies will be given.
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16
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Takahashi M, Kinugawa S, Takada S, Kakutani N, Furihata T, Sobirin MA, Fukushima A, Obata Y, Saito A, Ishimori N, Iwabuchi K, Tsutsui H. The disruption of invariant natural killer T cells exacerbates cardiac hypertrophy and failure caused by pressure overload in mice. Exp Physiol 2020; 105:489-501. [PMID: 31957919 DOI: 10.1113/ep087652] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 01/17/2020] [Indexed: 12/18/2022]
Abstract
NEW FINDINGS What is the central question of this study? We questioned whether the disruption of invariant natural killer T (iNKT) cells exacerbates left ventricular (LV) remodelling and heart failure after transverse aortic constriction in mice. What are the main findings and their importance? Pressure overload induced by transverse aortic constriction increased the infiltration of iNKT cells in mouse hearts. The disruption of iNKT cells exacerbated LV remodelling and hastened the transition from hypertrophy to heart failure, in association with the activation of mitogen-activated protein kinase signalling. Activation of iNKT cells modulated the immunological balance in this process and played a protective role against LV remodelling and failure. ABSTRACT Chronic inflammation is involved in the development of cardiac remodelling and heart failure (HF). Invariant natural killer T (iNKT) cells, a subset of T lymphocytes, have been shown to produce various cytokines and orchestrate tissue inflammation. The pathophysiological role of iNKT cells in HF caused by pressure overload has not been studied. In the present study, we investigated whether the disruption of iNKT cells affected this process in mice. Transverse aortic constriction (TAC) and a sham operation were performed in male C57BL/6J wild-type (WT) and iNKT cell-deficient Jα18 knockout (KO) mice. The infiltration of iNKT cells was increased after TAC. The disruption of iNKT cells exacerbated left ventricular (LV) remodelling and hastened the transition to HF after TAC. Histological examinations also revealed that the disruption of iNKT cells induced greater myocyte hypertrophy and a greater increase in interstitial fibrosis after TAC. The expressions of interleukin-10 and tumour necrosis factor-α mRNA and their ratio in the LV after TAC were decreased in the KO compared with WT mice, which might indicate that the disruption of iNKT cells leads to an imbalance between T-helper type 1 and type 2 cytokines. The phosphorylation of extracellular signal-regulated kinase was significantly increased in the KO mice. The disruption of iNKT cells exacerbated the development of cardiac remodelling and HF after TAC. The activation of iNKT cells might play a protective role against HF caused by pressure overload. Targeting the activation of iNKT cells might thus be a promising candidate as a new therapeutic strategy for HF.
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Affiliation(s)
- Masashige Takahashi
- Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Shintaro Kinugawa
- Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Shingo Takada
- Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Naoya Kakutani
- Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Takaaki Furihata
- Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | | | - Arata Fukushima
- Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Yoshikuni Obata
- Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Akimichi Saito
- Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Naoki Ishimori
- Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kazuya Iwabuchi
- Department of Immunobiology, Kitasato University School of Medicine, Kanagawa, Japan
| | - Hiroyuki Tsutsui
- Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
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17
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Stanfill B, Reehl S, Bramer L, Nakayasu ES, Rich SS, Metz TO, Rewers M, Webb-Robertson BJ. Extending Classification Algorithms to Case-Control Studies. Biomed Eng Comput Biol 2019; 10:1179597219858954. [PMID: 31320812 PMCID: PMC6630079 DOI: 10.1177/1179597219858954] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 04/26/2019] [Indexed: 12/16/2022] Open
Abstract
Classification is a common technique applied to 'omics data to build predictive models and identify potential markers of biomedical outcomes. Despite the prevalence of case-control studies, the number of classification methods available to analyze data generated by such studies is extremely limited. Conditional logistic regression is the most commonly used technique, but the associated modeling assumptions limit its ability to identify a large class of sufficiently complicated 'omic signatures. We propose a data preprocessing step which generalizes and makes any linear or nonlinear classification algorithm, even those typically not appropriate for matched design data, available to be used to model case-control data and identify relevant biomarkers in these study designs. We demonstrate on simulated case-control data that both the classification and variable selection accuracy of each method is improved after applying this processing step and that the proposed methods are comparable to or outperform existing variable selection methods. Finally, we demonstrate the impact of conditional classification algorithms on a large cohort study of children with islet autoimmunity.
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Affiliation(s)
- Bryan Stanfill
- Computing and Analytics Division, National Security Directorate, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Sarah Reehl
- Computing and Analytics Division, National Security Directorate, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Lisa Bramer
- Computing and Analytics Division, National Security Directorate, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Ernesto S Nakayasu
- Biological Sciences Division, Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Stephen S Rich
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Thomas O Metz
- Biological Sciences Division, Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Marian Rewers
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, USA
| | - Bobbie-Jo Webb-Robertson
- Biological Sciences Division, Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, WA, USA
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18
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Wu M, Lin Z, Ma S, Chen T, Jiang R, Wong WH. Simultaneous inference of phenotype-associated genes and relevant tissues from GWAS data via Bayesian integration of multiple tissue-specific gene networks. J Mol Cell Biol 2019; 9:436-452. [PMID: 29300920 DOI: 10.1093/jmcb/mjx059] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 12/20/2017] [Indexed: 02/07/2023] Open
Abstract
Although genome-wide association studies (GWAS) have successfully identified thousands of genomic loci associated with hundreds of complex traits in the past decade, the debate about such problems as missing heritability and weak interpretability has been appealing for effective computational methods to facilitate the advanced analysis of the vast volume of existing and anticipated genetic data. Towards this goal, gene-level integrative GWAS analysis with the assumption that genes associated with a phenotype tend to be enriched in biological gene sets or gene networks has recently attracted much attention, due to such advantages as straightforward interpretation, less multiple testing burdens, and robustness across studies. However, existing methods in this category usually exploit non-tissue-specific gene networks and thus lack the ability to utilize informative tissue-specific characteristics. To overcome this limitation, we proposed a Bayesian approach called SIGNET (Simultaneously Inference of GeNEs and Tissues) to integrate GWAS data and multiple tissue-specific gene networks for the simultaneous inference of phenotype-associated genes and relevant tissues. Through extensive simulation studies, we showed the effectiveness of our method in finding both associated genes and relevant tissues for a phenotype. In applications to real GWAS data of 14 complex phenotypes, we demonstrated the power of our method in both deciphering genetic basis and discovering biological insights of a phenotype. With this understanding, we expect to see SIGNET as a valuable tool for integrative GWAS analysis, thereby boosting the prevention, diagnosis, and treatment of human inherited diseases and eventually facilitating precision medicine.
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Affiliation(s)
- Mengmeng Wu
- Department of Computer Science, Tsinghua University, Beijing 100084, China.,Ministry of Education Key Laboratory of Bioinformatics and Bioinformatics Division, Tsinghua National Laboratory for Information Science and Technology, Beijing 100084, China.,Department of Statistics, Stanford University, CA 94305, USA
| | - Zhixiang Lin
- Department of Statistics, Stanford University, CA 94305, USA
| | - Shining Ma
- Department of Statistics, Stanford University, CA 94305, USA
| | - Ting Chen
- Department of Computer Science, Tsinghua University, Beijing 100084, China.,Ministry of Education Key Laboratory of Bioinformatics and Bioinformatics Division, Tsinghua National Laboratory for Information Science and Technology, Beijing 100084, China
| | - Rui Jiang
- Ministry of Education Key Laboratory of Bioinformatics and Bioinformatics Division, Tsinghua National Laboratory for Information Science and Technology, Beijing 100084, China.,Department of Automation, Tsinghua University, Beijing 100084, China
| | - Wing Hung Wong
- Department of Statistics, Stanford University, CA 94305, USA
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19
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Roles of Natural Killer T Cells and Natural Killer Cells in Kidney Injury. Int J Mol Sci 2019; 20:ijms20102487. [PMID: 31137499 PMCID: PMC6567827 DOI: 10.3390/ijms20102487] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Revised: 05/16/2019] [Accepted: 05/17/2019] [Indexed: 01/30/2023] Open
Abstract
Mouse natural killer T (NKT) cells and natural killer (NK) cells are innate immune cells that are highly abundant in the liver. In addition to their already-known antitumor and antimicrobial functions, their pathophysiological roles in the kidney have recently become evident. Under normal circumstances, the proportion of activated NKT cells in the kidney increases with age. Administration of a synthetic sphingoglycolipid ligand (alpha-galactosylceramide) further activates NKT cells, resulting in injury to renal vascular endothelial cells via the perforin-mediated pathway and tubular epithelial cells via the TNF-α/Fas ligand pathway, causing acute kidney injury (AKI) with hematuria. Activation of NKT cells by common bacterial DNA (CpG-ODN) also causes AKI. In addition, NKT cells together with B cells play significant roles in experimental lupus nephritis in NZB/NZW F1 mice through their Th2 immune responses. Mouse NK cells are also assumed to be involved in various renal diseases, and there may be complementary roles shared between NKT and NK cells. Human CD56+ T cells, a functional counterpart of mouse NKT cells, also damage renal cells through a mechanism similar to that of mice. A subpopulation of human CD56+ NK cells also exert strong cytotoxicity against renal cells and contribute to the progression of renal fibrosis.
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20
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Rakhshandehroo M, van Eijkeren RJ, Gabriel TL, de Haar C, Gijzel SMW, Hamers N, Ferraz MJ, Aerts JMFG, Schipper HS, van Eijk M, Boes M, Kalkhoven E. Adipocytes harbor a glucosylceramide biosynthesis pathway involved in iNKT cell activation. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1864:1157-1167. [PMID: 31051284 DOI: 10.1016/j.bbalip.2019.04.016] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 12/20/2018] [Accepted: 01/06/2019] [Indexed: 12/27/2022]
Abstract
BACKGROUND Natural killer T (NKT) cells in adipose tissue (AT) contribute to whole body energy homeostasis. RESULTS Inhibition of the glucosylceramide synthesis in adipocytes impairs iNKT cell activity. CONCLUSION Glucosylceramide biosynthesis pathway is important for endogenous lipid antigen activation of iNKT cells in adipocytes. SIGNIFICANCE Unraveling adipocyte-iNKT cell communication may help to fight obesity-induced AT dysfunction. Overproduction and/or accumulation of ceramide and ceramide metabolites, including glucosylceramides, can lead to insulin resistance. However, glucosylceramides also fulfill important physiological functions. They are presented by antigen presenting cells (APC) as endogenous lipid antigens via CD1d to activate a unique lymphocyte subspecies, the CD1d-restricted invariant (i) natural killer T (NKT) cells. Recently, adipocytes have emerged as lipid APC that can activate adipose tissue-resident iNKT cells and thereby contribute to whole body energy homeostasis. Here we investigate the role of the glucosylceramide biosynthesis pathway in the activation of iNKT cells by adipocytes. UDP-glucose ceramide glucosyltransferase (Ugcg), the first rate limiting step in the glucosylceramide biosynthesis pathway, was inhibited via chemical compounds and shRNA knockdown in vivo and in vitro. β-1,4-Galactosyltransferase (B4Galt) 5 and 6, enzymes that convert glucosylceramides into potentially inactive lactosylceramides, were subjected to shRNA knock down. Subsequently, (pre)adipocyte cell lines were tested in co-culture experiments with iNKT cells (IFNγ and IL4 secretion). Inhibition of Ugcg activity shows that it regulates presentation of a considerable fraction of lipid self-antigens in adipocytes. Furthermore, reduced expression levels of either B4Galt5 or -6, indicate that B4Galt5 is dominant in the production of cellular lactosylceramides, but that inhibition of either enzyme results in increased iNKT cell activation. Additionally, in vivo inhibition of Ugcg by the aminosugar AMP-DNM results in decreased iNKT cell effector function in adipose tissue. Inhibition of endogenous glucosylceramide production results in decreased iNKT cells activity and cytokine production, underscoring the role of this biosynthetic pathway in lipid self-antigen presentation by adipocytes.
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Affiliation(s)
- Maryam Rakhshandehroo
- Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Robert J van Eijkeren
- Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Tanit L Gabriel
- Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Colin de Haar
- Laboratory for Translational Immunology, University Medical Centre Utrecht, Utrecht, the Netherlands
| | - Sanne M W Gijzel
- Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Nicole Hamers
- Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Maria J Ferraz
- Leiden Institute of Chemistry, Department of Biochemistry, Leiden University, Leiden, the Netherlands
| | - Johannes M F G Aerts
- Leiden Institute of Chemistry, Department of Biochemistry, Leiden University, Leiden, the Netherlands
| | - Henk S Schipper
- Laboratory for Translational Immunology, University Medical Centre Utrecht, Utrecht, the Netherlands; Department of Pediatric Cardiology, Wilhelmina Children's Hospital, University Medical Center Utrecht, the Netherlands
| | - Marco van Eijk
- Leiden Institute of Chemistry, Department of Biochemistry, Leiden University, Leiden, the Netherlands
| | - Marianne Boes
- Laboratory for Translational Immunology, University Medical Centre Utrecht, Utrecht, the Netherlands; Department of Paediatric Immunology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Eric Kalkhoven
- Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
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21
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A natural killer T-cell subset that protects against airway hyperreactivity. J Allergy Clin Immunol 2019; 143:565-576.e7. [DOI: 10.1016/j.jaci.2018.03.022] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 01/31/2018] [Accepted: 03/19/2018] [Indexed: 12/25/2022]
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22
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Chen D, Liu H, Wang Y, Chen S, Liu J, Li W, Dou H, Hou W, Meng M. Study of the adoptive immunotherapy on rheumatoid arthritis with Thymus-derived invariant natural killer T cells. Int Immunopharmacol 2019; 67:427-440. [DOI: 10.1016/j.intimp.2018.12.040] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 11/20/2018] [Accepted: 12/14/2018] [Indexed: 12/15/2022]
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23
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Akimoto H, Fukuda-Kawaguchi E, Duramad O, Ishii Y, Tanabe K. A Novel Liposome Formulation Carrying Both an Insulin Peptide and a Ligand for Invariant Natural Killer T Cells Induces Accumulation of Regulatory T Cells to Islets in Nonobese Diabetic Mice. J Diabetes Res 2019; 2019:9430473. [PMID: 31781669 PMCID: PMC6855036 DOI: 10.1155/2019/9430473] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 10/03/2019] [Indexed: 12/27/2022] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of pancreatic β cells by autoantigen-reactive diabetogenic cells. Antigen-specific therapies using islet autoantigens for restoring immune tolerance have emerged as promising approaches for the treatment of T1D but have been unsuccessful in humans. Herein, we report that RGI-3100-iB, a novel liposomal formulation carrying both α-galactosylceramide (α-GalCer), which is a representative ligand for invariant natural killer T (iNKT) cells, and insulin B chain 9-23 peptide, which is an epitope for CD4+ T cells, could induce the accumulation of regulatory T cells (Tregs) in islets in a peptide-dependent manner, followed by the remarkable prevention of diabetes onset in nonobese diabetic (NOD) mice. While multiple administrations of a monotherapy using either α-GalCer or insulin B peptide in a liposomal formulation was confirmed to delay/prevent T1D in NOD mice, RGI-3100-iB synergistically enhanced the prevention effect of each monotherapy and alleviated insulitis in NOD mice. Immunopathological analysis showed that Foxp3+ Tregs accumulated in the islets in RGI-3100-iB-treated mice. Cotransfer of diabetogenic T cells and splenocytes of NOD mice treated with RGI-3100-iB, but not liposomal α-GalCer encapsulating an unrelated peptide, to NOD-SCID mice resulted in the prevention of diabetes and elevation of Foxp3 mRNA expression in the islets. These data indicate that the migration of insulin B-peptide-specific Tregs to islet of NOD mice that are involved in the suppression of pathogenic T cells related to diabetes onset and progression could be enhanced by the administration of liposomes containing α-GalCer and insulin B peptide.
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MESH Headings
- Adoptive Transfer
- Animals
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/prevention & control
- Disease Models, Animal
- Drug Compounding
- Female
- Forkhead Transcription Factors/metabolism
- Galactosylceramides/administration & dosage
- Hypoglycemic Agents/administration & dosage
- Insulin/administration & dosage
- Islets of Langerhans/drug effects
- Islets of Langerhans/immunology
- Islets of Langerhans/metabolism
- Liposomes
- Mice, Inbred NOD
- Mice, SCID
- Natural Killer T-Cells/drug effects
- Natural Killer T-Cells/immunology
- Natural Killer T-Cells/metabolism
- Peptide Fragments/administration & dosage
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- T-Lymphocytes, Regulatory/transplantation
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Affiliation(s)
- Hidetoshi Akimoto
- Research Division, REGiMMUNE Corporation, 35-3 Nihonbashi Hakozaki-cho, BRICK GATE 5F, Chuou-Ku, Tokyo 103-0015, Japan
| | - Emi Fukuda-Kawaguchi
- Research Division, REGiMMUNE Corporation, 35-3 Nihonbashi Hakozaki-cho, BRICK GATE 5F, Chuou-Ku, Tokyo 103-0015, Japan
| | - Omar Duramad
- Research Division, REGiMMUNE Inc, 820 Heinz Ave, Berkeley, CA 94710, USA
| | - Yasuyuki Ishii
- Research Division, REGiMMUNE Corporation, 35-3 Nihonbashi Hakozaki-cho, BRICK GATE 5F, Chuou-Ku, Tokyo 103-0015, Japan
| | - Kazunari Tanabe
- Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-Ku, Tokyo 162-8666, Japan
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24
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Terabe M, Berzofsky JA. Tissue-Specific Roles of NKT Cells in Tumor Immunity. Front Immunol 2018; 9:1838. [PMID: 30158927 PMCID: PMC6104122 DOI: 10.3389/fimmu.2018.01838] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 07/25/2018] [Indexed: 01/07/2023] Open
Abstract
NKT cells are an unusual population of T cells recognizing lipids presented by CD1d, a non-classical class-I-like molecule, rather than peptides presented by conventional MHC molecules. Type I NKT cells use a semi-invariant T cell receptor and almost all recognize a common prototype lipid, α-galactosylceramide (α-GalCer). Type II NKT cells are any lipid-specific CD1d-restricted T cells that use other receptors and generally don't recognize α-GalCer. They play important regulatory roles in immunity, including tumor immunity. In contrast to type I NKT cells that most have found to promote antitumor immunity, type II NKT cells suppress tumor immunity and the two subsets cross-regulate each other, forming an immunoregulatory axis. They also can promote other regulatory cells including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and can induce MDSCs to secrete TGF-β, one of the most immunosuppressive cytokines known. In some tumors, both Tregs and type II NKT cells can suppress immunosurveillance, and the balance between these is determined by a type I NKT cell. We have also seen that regulation of tumor immunity can depend on the tissue microenvironment, so the same tumor in the same animal in different tissues may be regulated by different cells, such as type II NKT cells in the lung vs Tregs in the skin. Also, the effector T cells that protect those sites when Tregs are removed do not always act between tissues even in the same animal. Thus, metastases may require different immunotherapy from primary tumors. Newly improved sulfatide-CD1d tetramers are starting to allow better characterization of the elusive type II NKT cells to better understand their function and control it to overcome immunosuppression.
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Affiliation(s)
- Masaki Terabe
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Jay A Berzofsky
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
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25
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Wang H, Hogquist KA. How Lipid-Specific T Cells Become Effectors: The Differentiation of iNKT Subsets. Front Immunol 2018; 9:1450. [PMID: 29997620 PMCID: PMC6028555 DOI: 10.3389/fimmu.2018.01450] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 06/12/2018] [Indexed: 12/24/2022] Open
Abstract
In contrast to peptide-recognizing T cells, invariant natural killer T (iNKT) cells express a semi-invariant T cell receptor that specifically recognizes self- or foreign-lipids presented by CD1d molecules. There are three major functionally distinct effector states for iNKT cells. Owning to these innate-like effector states, iNKT cells have been implicated in early protective immunity against pathogens. Yet, growing evidence suggests that iNKT cells play a role in tissue homeostasis as well. In this review, we discuss current knowledge about the underlying mechanisms that regulate the effector states of iNKT subsets, with a highlight on the roles of a variety of transcription factors and describe how each subset influences different facets of thymus homeostasis.
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Affiliation(s)
- Haiguang Wang
- Department of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota, Minneapolis, MN, United States
| | - Kristin A Hogquist
- Department of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota, Minneapolis, MN, United States
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26
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The Role of Invariant NKT in Autoimmune Liver Disease: Can Vitamin D Act as an Immunomodulator? Can J Gastroenterol Hepatol 2018; 2018:8197937. [PMID: 30046564 PMCID: PMC6038587 DOI: 10.1155/2018/8197937] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 05/16/2018] [Indexed: 12/18/2022] Open
Abstract
Natural killer T (NKT) cells are a distinct lineage of T cells which express both the T cell receptor (TCR) and natural killer (NK) cell markers. Invariant NKT (iNKT) cells bear an invariant TCR and recognize a small variety of glycolipid antigens presented by CD1d (nonclassical MHC-I). CD1d-restricted iNKT cells are regulators of immune responses and produce cytokines that may be proinflammatory (such as interferon-gamma (IFN-γ)) or anti-inflammatory (such as IL-4). iNKT cells also appear to play a role in B cell regulation and antibody production. Alpha-galactosylceramide (α-GalCer), a derivative of the marine sponge, is a potent stimulator of iNKT cells and has been proposed as a therapeutic iNKT cell activator. Invariant NKT cells have been implicated in the development and perpetuation of several autoimmune diseases such as multiple sclerosis and systemic lupus erythematosus (SLE). Animal models of SLE have shown abnormalities in iNKT cells numbers and function, and an inverse correlation between the frequency of NKT cells and IgG levels has also been observed. The role of iNKT cells in autoimmune liver disease (AiLD) has not been extensively studied. This review discusses the current data with regard to iNKT cells function in AiLD, in addition to providing an overview of iNKT cells function in other autoimmune conditions and animal models. We also discuss data regarding the immunomodulatory effects of vitamin D on iNKT cells, which may serve as a potential therapeutic target, given that deficiencies in vitamin D have been reported in various autoimmune disorders.
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Abstract
The inability to elicit strong and durable cellular responses is a major obstacle in the development of successful vaccines, in particular those against malaria. In this regard, the generation of novel adjuvants that will potently boost cell-mediated immunity induced by candidate vaccines is helpful. We and others have found a glycolipid, called α-galactosylceramide (α-GalCer), which could be presented on CD1d expressed by antigen-presenting cells (APCs) and stimulate natural killer T (NKT) cells. This triggers the activation/maturation of APCs, particularly dendritic cells (DCs). By activating NKT cells and subsequently DCs, α-GalCer has been shown to enhance adaptive immune responses, particularly of CD8
+ T cells, induced by the vaccines. More recently, we identified an analogue of α-GalCer, which can display a potent adjuvant activity in conjunction with malaria vaccines in mice and non-human primates. It is anticipated that CD1d-binding, NKT cell-stimulating glycolipids will be tested as adjuvants in humans in the near future.
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Affiliation(s)
- Jordana Grazziela Coelho-Dos-Reis
- Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.,Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY, USA
| | - Xiangming Li
- Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY, USA.,Sanofi, Cambridge, MA, USA
| | - Moriya Tsuji
- Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY, USA
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28
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Gannon M, Kulkarni RN, Tse HM, Mauvais-Jarvis F. Sex differences underlying pancreatic islet biology and its dysfunction. Mol Metab 2018; 15:82-91. [PMID: 29891438 PMCID: PMC6066785 DOI: 10.1016/j.molmet.2018.05.017] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 05/25/2018] [Indexed: 12/30/2022] Open
Abstract
Background The sex of an individual affects glucose homeostasis and the pathophysiology, incidence, and prevalence of diabetes as well as the response to therapy. Scope of the review This review focuses on clinical and experimental sex differences in islet cell biology and dysfunction during development and in adulthood in human and animal models. We discuss sex differences in β-cell and α-cell function, heterogeneity, and dysfunction. We cover sex differences in communication between gonads and islets and islet-cell immune interactions. Finally, we discuss sex differences in β-cell programming by nutrition and other environmental factors during pregnancy. Major conclusions Important sex differences exist in islet cell function and susceptibility to failure. These differences represent sex-related biological factors that can be harnessed for gender-based prevention of and therapy for diabetes.
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Affiliation(s)
- Maureen Gannon
- Department of Medicine, Vanderbilt University Medical Center, Nashville, USA; Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN, USA
| | - Rohit N Kulkarni
- Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, USA; Department of Medicine, Harvard Medical School, Boston, USA; Harvard Stem Cell Institute, Boston, MA, USA
| | - Hubert M Tse
- Department of Microbiology, Birmingham, USA; Comprehensive Diabetes Center, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA
| | - Franck Mauvais-Jarvis
- Department of Medicine, Section of Endocrinology and Metabolism, Tulane University Health Sciences Center School of Medicine, New Orleans, USA; Southeast Louisiana Veterans Healthcare System Medical Center, New Orleans, LA, USA.
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29
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Uchida T, Nakashima H, Yamagata A, Ito S, Ishikiriyama T, Nakashima M, Seki S, Kumagai H, Oshima N. Repeated administration of alpha-galactosylceramide ameliorates experimental lupus nephritis in mice. Sci Rep 2018; 8:8225. [PMID: 29844470 PMCID: PMC5974230 DOI: 10.1038/s41598-018-26470-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 05/14/2018] [Indexed: 01/20/2023] Open
Abstract
Lupus nephritis is a crucial complication of systemic lupus erythematosus. In this study, we investigated the roles of mouse natural killer T (NKT) cells in lupus nephritis. From 24 weeks of age, NZB/NZW F1 mice were injected with alpha-galactosylceramide (α-GalCer) or vehicle once a week for four weeks. In the α-GalCer group, the levels of proteinuria and blood urea nitrogen were significantly lower than those in the vehicle group. The histological evaluation showed a decrease in glomerular immune complex deposits and an alleviation of podocyte injury. The proportion of NKT cells in the mononuclear cell (MNC) fraction in the α-GalCer group was significantly decreased in the liver, kidney, and spleen. The proliferation and cytokine production in α-GalCer-stimulated liver MNCs were markedly diminished in the α-GalCer group (anergy). The IFN-γ production in liver MNCs stimulated by concanavalin A or an anti-CD3 antibody did not differ between the two groups, whereas the IL-4 production was significantly lower in the α-GalCer group. In addition, the IgM production in CpG-oligodeoxynucleotide-stimulated spleen MNCs was significantly lower in the α-GalCer group. These results suggest that α-GalCer suppressed Th2 immune responses in NKT cells and B cell function, thereby slowing the progression of lupus nephritis.
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Affiliation(s)
- Takahiro Uchida
- Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Saitama, Japan.
| | - Hiroyuki Nakashima
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Akira Yamagata
- Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Seigo Ito
- Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Takuya Ishikiriyama
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Masahiro Nakashima
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Shuhji Seki
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Hiroo Kumagai
- Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Naoki Oshima
- Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Saitama, Japan
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30
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Racine JJ, Stewart I, Ratiu J, Christianson G, Lowell E, Helm K, Allocco J, Maser RS, Chen YG, Lutz CM, Roopenian D, Schloss J, DiLorenzo TP, Serreze DV. Improved Murine MHC-Deficient HLA Transgenic NOD Mouse Models for Type 1 Diabetes Therapy Development. Diabetes 2018; 67:923-935. [PMID: 29472249 PMCID: PMC5909999 DOI: 10.2337/db17-1467] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 02/12/2018] [Indexed: 02/04/2023]
Abstract
Improved mouse models for type 1 diabetes (T1D) therapy development are needed. T1D susceptibility is restored to normally resistant NOD.β2m-/- mice transgenically expressing human disease-associated HLA-A*02:01 or HLA-B*39:06 class I molecules in place of their murine counterparts. T1D is dependent on pathogenic CD8+ T-cell responses mediated by these human class I variants. NOD.β2m-/--A2.1 mice were previously used to identify β-cell autoantigens presented by this human class I variant to pathogenic CD8+ T cells and for testing therapies to attenuate such effectors. However, NOD.β2m-/- mice also lack nonclassical MHC I family members, including FcRn, required for antigen presentation, and maintenance of serum IgG and albumin, precluding therapies dependent on these molecules. Hence, we used CRISPR/Cas9 to directly ablate the NOD H2-Kd and H2-Db classical class I variants either individually or in tandem (cMHCI-/-). Ablation of the H2-Ag7 class II variant in the latter stock created NOD mice totally lacking in classical murine MHC expression (cMHCI/II-/-). NOD-cMHCI-/- mice retained nonclassical MHC I molecule expression and FcRn activity. Transgenic expression of HLA-A2 or -B39 restored pathogenic CD8+ T-cell development and T1D susceptibility to NOD-cMHCI-/- mice. These next-generation HLA-humanized NOD models may provide improved platforms for T1D therapy development.
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31
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Van Kaer L, Wu L. Therapeutic Potential of Invariant Natural Killer T Cells in Autoimmunity. Front Immunol 2018; 9:519. [PMID: 29593743 PMCID: PMC5859017 DOI: 10.3389/fimmu.2018.00519] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 02/28/2018] [Indexed: 11/13/2022] Open
Abstract
Tolerance against self-antigens is regulated by a variety of cell types with immunoregulatory properties, such as CD1d-restricted invariant natural killer T (iNKT) cells. In many experimental models of autoimmunity, iNKT cells promote self-tolerance and protect against autoimmunity. These findings are supported by studies with patients suffering from autoimmune diseases. Based on these studies, the therapeutic potential of iNKT cells in autoimmunity has been explored. Many of these studies have been performed with the potent iNKT cell agonist KRN7000 or its structural variants. These findings have generated promising results in several autoimmune diseases, although mechanisms by which iNKT cells modulate autoimmunity remain incompletely understood. Here, we will review these preclinical studies and discuss the prospects for translating their findings to patients suffering from autoimmune diseases.
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Affiliation(s)
- Luc Van Kaer
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Lan Wu
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States
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32
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Gianchecchi E, Delfino DV, Fierabracci A. NK cells in autoimmune diseases: Linking innate and adaptive immune responses. Autoimmun Rev 2018; 17:142-154. [PMID: 29180124 DOI: 10.1016/j.autrev.2017.11.018] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The pathogenesis of autoimmunity remains to be fully elucidated, although the contribution of genetic and environmental factors is generally recognized. Despite autoimmune conditions are principally due to T and B lymphocytes, NK cells also appear to play a role in the promotion and/or maintenance of altered adaptive immune responses or in peripheral tolerance mechanisms. Although NK cells are components of the innate immune system, they shows characteristics of the adaptive immune system, such as the expansion of pathogen-specific cells, the generation of long-lasting "memory" cells able to persist upon cognate antigen encounter, and the possibility to induce an increased secondary recall response to re-challenge. Human NK cells are generally identified as CD56+CD3-, conversely CD56+CD3+ cells represent a mixed population of NK-like T (NK T) cells and antigen-experienced T cells showing the up-regulation of several NK cell markers. CD56dim constitute about 90% of NK cells in the peripheral blood, they are mature and involved in cytotoxicity responses; CD56bright instead are more immature, mostly involved in cytokine production, having only a limited role in cytolytic responses, keen to leave the blood vessels as the principal population observed in lymph nodes. NK cells have been identified also in non-lymphoid tissues since, in pathologic conditions, they can quickly reach the target organs. A cross-talk between NK with dendritic cells and T cells is established throughout different receptor-ligand bindings. Several studies support the correlation between NK cell number and/or functional alterations, such as a defective cytotoxic activity and several autoimmune conditions. Among the different autoimmune pathologies and even within the same disease, NK cell function is significantly different either promoting or even protecting against the onset of the autoimmune condition. In this Review, we discuss recent literature supporting the role played by NK cells, as a bridge between innate and adaptive immunity, in the onset of autoimmune diseases.
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Affiliation(s)
- Elena Gianchecchi
- Type 1 Diabetes Centre, Infectivology and Clinical Trials Research Department, Children's Hospital Bambino Gesù, Rome, Italy
| | | | - Alessandra Fierabracci
- Type 1 Diabetes Centre, Infectivology and Clinical Trials Research Department, Children's Hospital Bambino Gesù, Rome, Italy.
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33
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34
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Regulation of Humoral Immunity by CD1d-Restricted Natural Killer T Cells. Immunology 2018. [DOI: 10.1016/b978-0-12-809819-6.00005-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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35
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Kwon DI, Lee YJ. Lineage Differentiation Program of Invariant Natural Killer T Cells. Immune Netw 2017; 17:365-377. [PMID: 29302250 PMCID: PMC5746607 DOI: 10.4110/in.2017.17.6.365] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Revised: 10/27/2017] [Accepted: 11/02/2017] [Indexed: 02/07/2023] Open
Abstract
Invariant natural killer T (iNKT) cells are innate T cells restricted by CD1d molecules. They are positively selected in the thymic cortex and migrate to the medullary area, in which they differentiate into 3 different lineages. Promyelocytic leukemia zinc finger (PLZF) modulates this process, and PLZFhigh, PLZFintermediate, and PLZFlow iNKT cells are designated as NKT2, NKT17, and NKT1 cells, respectively. Analogous to conventional helper CD4 T cells, each subset expresses distinct combinations of transcription factors and produces different cytokines. In lymphoid organs, iNKT subsets have unique localizations, which determine their cytokine responses upon antigenic challenge. The lineage differentiation programs of iNKT cells are differentially regulated in various mice strains in a cell-intrinsic manner, and BALB/c mice contain a high frequency of NKT2 cells. In the thymic medulla, steady state IL-4 from NKT2 cells directly conditions CD8 T cells to become memory-like cells expressing Eomesodermin, which function as premade memory effectors. The genetic signature of iNKT cells is more similar to that of γδ T cells and innate lymphoid cells (ILCs) than of conventional helper T cells, suggesting that ILCs and innate T cells share common developmental programs.
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Affiliation(s)
- Dong-Il Kwon
- Academy of Immunology and Microbiology, Institute for Basic Science, Pohang 37673, Korea.,Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 37673, Korea
| | - You Jeong Lee
- Academy of Immunology and Microbiology, Institute for Basic Science, Pohang 37673, Korea.,Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 37673, Korea
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36
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Schrumpf E, Jiang X, Zeissig S, Pollheimer MJ, Anmarkrud JA, Tan C, Exley MA, Karlsen TH, Blumberg RS, Melum E. The role of natural killer T cells in a mouse model with spontaneous bile duct inflammation. Physiol Rep 2017; 5:5/4/e13117. [PMID: 28219981 PMCID: PMC5328767 DOI: 10.14814/phy2.13117] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Revised: 12/01/2016] [Accepted: 12/13/2016] [Indexed: 12/15/2022] Open
Abstract
Natural killer T (NKT) cells are activated by lipid antigens presented by CD1d molecules and represent a major lymphocyte subset of the liver. NODc3c4 mice spontaneously develop biliary inflammation in extra- and intrahepatic bile ducts. We demonstrated by flow cytometry that invariant NKT (iNKT) cells were more abundant in the thymus, spleen, and liver of NODc3c4 mice compared to NOD mice. iNKT cells in NODc3c4 mice displayed an activated phenotype. Further, NOD and NODCd1d-/- mice were irradiated and injected with NODc3c4 bone marrow, and injection of NODc3c4 bone marrow resulted in biliary infiltrates independently of CD1d expression in recipient mice. Activation or blocking of NKT cells with α-galactosylceramide or anti-CD1d antibody injections did not affect the biliary phenotype of NODc3c4 mice. NODc3c4.Cd1d-/- mice were generated by crossing NODCd1d-/- mice onto a NODc3c4 background. NODc3c4.Cd1d-/- and NODc3c4 mice developed the same extent of biliary disease. This study demonstrates that iNKT cells are more abundant and activated in the NODc3c4 model. The portal inflammation of NODc3c4 mice can be transferred to irradiated recipients, which suggests an immune-driven disease. Our findings imply that NKT cells can potentially participate in the biliary inflammation, but are not the primary drivers of disease in NODc3c4 mice.
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Affiliation(s)
- Elisabeth Schrumpf
- Norwegian PSC Research Center, Division of Surgery, Inflammatory Diseases and Transplantation Oslo University Hospital, Rikshospitalet, Oslo, Norway.,K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Xiaojun Jiang
- Norwegian PSC Research Center, Division of Surgery, Inflammatory Diseases and Transplantation Oslo University Hospital, Rikshospitalet, Oslo, Norway.,K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Sebastian Zeissig
- Department of Medicine 1, University Medical Center Dresden Technical University Dresden, Dresden, Germany.,Center for Regenerative Therapies (CRTD), Technical University Dresden, Dresden, Germany
| | - Marion J Pollheimer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Research Unit for Experimental and Molecular Hepatology, Graz, Austria.,Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Jarl Andreas Anmarkrud
- Norwegian PSC Research Center, Division of Surgery, Inflammatory Diseases and Transplantation Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Corey Tan
- Norwegian PSC Research Center, Division of Surgery, Inflammatory Diseases and Transplantation Oslo University Hospital, Rikshospitalet, Oslo, Norway.,K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Mark A Exley
- Manchester Collaborative Centre for Inflammation Research (MCCIR), Faculty of Medical & Human Sciences, University of Manchester, Manchester, United Kingdom.,Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Tom H Karlsen
- Norwegian PSC Research Center, Division of Surgery, Inflammatory Diseases and Transplantation Oslo University Hospital, Rikshospitalet, Oslo, Norway.,K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation Oslo University Hospital, Rikshospitalet, Oslo, Norway.,Section of Gastroenterology, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Richard S Blumberg
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Espen Melum
- Norwegian PSC Research Center, Division of Surgery, Inflammatory Diseases and Transplantation Oslo University Hospital, Rikshospitalet, Oslo, Norway .,K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation Oslo University Hospital, Rikshospitalet, Oslo, Norway.,Section of Gastroenterology, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
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HDAC4 is expressed on multiple T cell lineages but dispensable for their development and function. Oncotarget 2017; 8:17562-17572. [PMID: 28177888 PMCID: PMC5392269 DOI: 10.18632/oncotarget.15077] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 01/11/2017] [Indexed: 01/08/2023] Open
Abstract
Histone deacetylation, reciprocally mediated by histone deacetylases (HDAC) and acetyltransferases, represents one major form of post-translational modification. Previous research indicates that HDACs play an essential regulatory role in the development of various immune cells. However, the specific function of individual HDACs remains largely unexplored. HDAC4, a member of class II HDACs, profoundly investigated in the nervous system, while the expression profile and function of HDAC4 in T cells are barely known. For the first time, we report here that HDAC4 is expressed in the multiple T cell lineages. Using T-cell-specific HDAC4-deficient mice, we discovered that lack of HDAC4 did not alter the frequencies of conventional T cells, invariant NKT (iNKT) cells or regulatory T cells within both the thymus and secondary lymphoid organs. Moreover, conventional T cells and iNKT cells from wild-type and HDAC4-deficient mice displayed no significant difference in cytokine production. In conclusion, our results imply that under steady stage, HDAC4 is not required for the development and function of multiple T cell lineages, including conventional T cells and iNKT cells.
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38
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Bézie S, Usal C, Guillonneau C. In Vitro and In Vivo Assessment of T, B and Myeloid Cells Suppressive Activity and Humoral Responses from Transplant Recipients. J Vis Exp 2017. [PMID: 28829428 DOI: 10.3791/55510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
The main concern in transplantation is to achieve specific tolerance through induction of regulatory cells. The understanding of tolerance mechanisms requires reliable models. Here, we describe models of tolerance to cardiac allograft in rat, induced by blockade of costimulation signals or by upregulation of immunoregulatory molecules through gene transfer. Each of these models allowed in vivo generation of regulatory cells such as regulatory T cells (Tregs), regulatory B cells (Bregs) or regulatory myeloid cells (RegMCs). In this manuscript, we describe two complementary protocols that have been used to identify and define in vitro and in vivo regulatory cell activity to determine their responsibility in tolerance induction and maintenance. First, an in vitro suppressive assay allowed rapid identification of cells with suppressive capacity on effector immune responses in a dose dependent manner, and can be used for further analysis such as cytokine measurement or cytotoxicity. Second, the adoptive transfer of cells from a tolerant treated recipient to a newly irradiated grafted recipient, highlighted the tolerogenic properties of these cells in controlling graft directed immune responses and/or converting new regulatory cells (termed infectious tolerance). These methods are not restricted to cells with known phenotypic markers and can be extended to any cell population. Furthermore, donor directed allospecificity of regulatory cells (an important goal in the field) can be assessed by using third party donor cells or graft either in vitro or in vivo. Finally, to determine the specific tolerogenic capacity of these regulatory cells, we provide protocols to assess the humoral anti-donor antibody responses and the capacity of the recipient to develop humoral responses against new or former known antigens. The models of tolerance described can be used to further characterize regulatory cells, to identify new biomarkers, and immunoregulatory molecules, and are adaptable to other transplantation models or autoimmune diseases in rodent or human.
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Affiliation(s)
- Séverine Bézie
- Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes
| | - Claire Usal
- Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes
| | - Carole Guillonneau
- Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes;
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Ukah TK, Cattin-Roy AN, Chen W, Miller MM, Barik S, Zaghouani H. On the Role IL-4/IL-13 Heteroreceptor Plays in Regulation of Type 1 Diabetes. THE JOURNAL OF IMMUNOLOGY 2017. [PMID: 28646042 DOI: 10.4049/jimmunol.1700410] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Type 1 diabetes (T1D) manifests when the insulin-producing pancreatic β cells are destroyed as a consequence of an inflammatory process initiated by lymphocytes of the immune system. The NOD mouse develops T1D spontaneously and serves as an animal model for human T1D. The IL-4Rα/IL-13Rα1 heteroreceptor (HR) serves both IL-4 and IL-13 cytokines, which are believed to function as anti-inflammatory cytokines in T1D. However, whether the HR provides a responsive element to environmental (i.e., physiologic) IL-4/IL-13 in the regulation of peripheral tolerance and the development of T1D has yet to be defined. In this study, NOD mice deficient for the HR have been generated by means of IL-13Rα1 gene disruption and used to determine whether such deficiency affects the development of T1D. Surprisingly, the findings indicate that NOD mice lacking the HR (13R-/-) display resistance to T1D as the rise in blood glucose level and islet inflammation were significantly delayed in these HR-deficient relative to HR-sufficient (13R+/+) mice. In fact, the frequency and spleen-to-pancreas dynamics of both Th1 and Th17 cells were affected in 13R-/- mice. This is likely due to an increase in the frequency of mTGFβ+Foxp3int regulatory T cells and the persistence of CD206+ macrophages in the pancreas as both types of cells confer resistance to T1D upon transfer to 13R+/+ mice. These findings reveal new insights as to the role environmental IL-4/IL-13 and the HR play in peripheral tolerance and the development of T1D.
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Affiliation(s)
- Tobechukwu K Ukah
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212
| | - Alexis N Cattin-Roy
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212
| | - Weirong Chen
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212
| | - Mindy M Miller
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212
| | - Subhasis Barik
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212
| | - Habib Zaghouani
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212; .,Department of Neurology, University of Missouri School of Medicine, Columbia, MO 65212; and.,Department of Child Health, University of Missouri School of Medicine, Columbia, MO 65212
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40
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Belo R, Santarém N, Pereira C, Pérez-Cabezas B, Macedo F, Leite-de-Moraes M, Cordeiro-da-Silva A. Leishmania infantum Exoproducts Inhibit Human Invariant NKT Cell Expansion and Activation. Front Immunol 2017; 8:710. [PMID: 28674535 PMCID: PMC5474685 DOI: 10.3389/fimmu.2017.00710] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 06/01/2017] [Indexed: 01/28/2023] Open
Abstract
Leishmania infantum is one of the major parasite species associated with visceral leishmaniasis, a severe form of the disease that can become lethal if untreated. This obligate intracellular parasite has developed diverse strategies to escape the host immune response, such as exoproducts (Exo) carrying a wide range of molecules, including parasite virulence factors, which are potentially implicated in early stages of infection. Herein, we report that L. infantum Exo and its two fractions composed of extracellular vesicles (EVs) and vesicle-depleted-exoproducts (VDEs) inhibit human peripheral blood invariant natural killer T (iNKT) cell expansion in response to their specific ligand, the glycolipid α-GalactosylCeramide (α-GalCer), as well as their capacity to promptly produce IL-4 and IFNγ. Using plate-bound CD1d and α-GalCer, we found that Exo, EV, and VDE fractions reduced iNKT cell activation in a dose-dependent manner, suggesting that they prevented α-GalCer presentation by CD1d molecules. This direct effect on CD1d was confirmed by the observation that CD1d:α-GalCer complex formation was impaired in the presence of Exo, EV, and VDE fractions. Furthermore, lipid extracts from the three compounds mimicked the inhibition of iNKT cell activation. These lipid components of L. infantum exoproducts, including EV and VDE fractions, might compete for CD1-binding sites, thus blocking iNKT cell activation. Overall, our results provide evidence for a novel strategy through which L. infantum can evade immune responses of mammalian host cells by preventing iNKT lymphocytes from recognizing glycolipids in a TCR-dependent manner.
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Affiliation(s)
- Renata Belo
- Parasite Disease Group, Institute for Molecular and Cell Biology (IBMC), Institute for Investigation and Innovation in Health (i3S), Porto, Portugal.,Laboratory of Immunoregulation and Immunopathology, Institut Necker-Enfants Malades, CNRS UMR 8253 and INSERM UMR 1151, Paris, France.,Université Paris Descartes Sorbonne Paris Cité, Paris, France
| | - Nuno Santarém
- Parasite Disease Group, Institute for Molecular and Cell Biology (IBMC), Institute for Investigation and Innovation in Health (i3S), Porto, Portugal
| | - Cátia Pereira
- Cell Activation and Gene Expression, Institute for Molecular and Cell Biology (IBMC), Institute for Investigation and Innovation in Health (i3S), Porto, Portugal
| | - Begoña Pérez-Cabezas
- Parasite Disease Group, Institute for Molecular and Cell Biology (IBMC), Institute for Investigation and Innovation in Health (i3S), Porto, Portugal
| | - Fátima Macedo
- Cell Activation and Gene Expression, Institute for Molecular and Cell Biology (IBMC), Institute for Investigation and Innovation in Health (i3S), Porto, Portugal.,Department of Medical Science, Aveiro University, Aveiro, Portugal
| | - Maria Leite-de-Moraes
- Laboratory of Immunoregulation and Immunopathology, Institut Necker-Enfants Malades, CNRS UMR 8253 and INSERM UMR 1151, Paris, France.,Université Paris Descartes Sorbonne Paris Cité, Paris, France
| | - Anabela Cordeiro-da-Silva
- Parasite Disease Group, Institute for Molecular and Cell Biology (IBMC), Institute for Investigation and Innovation in Health (i3S), Porto, Portugal.,Faculty of Pharmacy, Department of Biological Sciences, University of Porto, Porto, Portugal
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41
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Tocheva AS, Mansour S, Holt TGH, Jones S, Chancellor A, Sanderson JP, Eren E, Elliott TJ, Holt RIG, Gadola SD. The Clonal Invariant NKT Cell Repertoire in People with Type 1 Diabetes Is Characterized by a Loss of Clones Expressing High-Affinity TCRs. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2017; 198:1452-1459. [PMID: 28062695 DOI: 10.4049/jimmunol.1600255] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 12/02/2016] [Indexed: 02/11/2024]
Abstract
Invariant NKT (iNKT) cells in healthy people express iNKT-TCRs with widely varying affinities for CD1d, suggesting different roles for high- and low-affinity iNKT clones in immune regulation. However, the functional implications of this heterogeneity have not yet been determined. Functionally aberrant iNKT responses have been previously demonstrated in different autoimmune diseases, including human type 1 diabetes, but their relationship to changes in the iNKT clonal repertoire have not been addressed. In this study, we directly compared the clonal iNKT repertoire of people with recent onset type 1 diabetes and age- and gender-matched healthy controls with regard to iNKT-TCR affinity and cytokine production. Our results demonstrate a selective loss of clones expressing high-affinity iNKT-TCRs from the iNKT repertoire of people with type 1 diabetes. Furthermore, this bias in the clonal iNKT repertoire in type 1 diabetes was associated with increased GM-CSF, IL-4, and IL-13 cytokine secretion among Ag-stimulated low-affinity iNKT clones. Thus, qualitative changes of the clonal iNKT repertoire with the potential to affect the regulatory function of this highly conserved T cell population are already established at the early stages in type 1 diabetes. These findings may inform future rationales for the development of iNKT-based therapies aiming to restore immune tolerance in type 1 diabetes.
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Affiliation(s)
- Anna S Tocheva
- Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton National Health Service Foundation Trust, Southampton SO17 1BJ, United Kingdom;
- Department of Medicine, New York University School of Medicine, New York, NY 10016
| | - Salah Mansour
- Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton National Health Service Foundation Trust, Southampton SO17 1BJ, United Kingdom
- Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom
| | - Tristan G H Holt
- Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton National Health Service Foundation Trust, Southampton SO17 1BJ, United Kingdom
| | - Samuel Jones
- Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton National Health Service Foundation Trust, Southampton SO17 1BJ, United Kingdom
| | - Andrew Chancellor
- Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton National Health Service Foundation Trust, Southampton SO17 1BJ, United Kingdom
| | | | - Efrem Eren
- Department of Clinical Immunology, University Hospital Southampton National Health Service Foundation Trust, Southampton SO17 1BJ, United Kingdom
| | - Tim J Elliott
- Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom
| | - Richard I G Holt
- Human Development and Health, Faculty of Medicine, University of Southampton, University Hospital Southampton National Health Service Foundation Trust, Southampton SO17 1BJ, United Kingdom; and
| | - Stephan D Gadola
- Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, University Hospital Southampton National Health Service Foundation Trust, Southampton SO17 1BJ, United Kingdom;
- Translational medicine, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland
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42
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Lee HW, Jie HB, Bollyky PL, Sarracino D, Kim TS, Wilson BS. Role of dendritic cell maturation factors produced by human invariant NKT cells in immune tolerance. J Leukoc Biol 2016; 101:989-1003. [PMID: 27837018 DOI: 10.1189/jlb.1a0416-164rrr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Revised: 10/04/2016] [Accepted: 10/27/2016] [Indexed: 01/12/2023] Open
Abstract
In this study, we used the culture supernatant of iNKT cells to identify human myeloid DC maturation factors produced by human CD4+ iNKT cells. S100A8 had a strong maturation effect. Notably, the recombinant S100A8 protein displayed properties of DC maturation functioning, and the induction of DC differentiation by both the purified and the recombinant protein were blocked by anti-S100A8 and anti-TLR-4 mAbs. DC differentiation induced by anti-major histocompatibility complex class II/CD1d Ab, S100A8, or both was qualitatively indistinguishable from that induced by the coculture of DCs and iNKT cells or via culture supplementation with supernatants from activated CD4+ iNKT cells. S100A8 also induced CD4+/CD25+/Foxp3+ Treg cells from naïve T cells. S100A8 may contribute to DC differentiation by elevating transcription factors or activating transcription factor-2, heat shock factor-1, or both, in mature DCs. S100A8 is a novel candidate iNKT cell-dependent DC maturation factor.
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Affiliation(s)
- Hyeong-Woo Lee
- Departments of Tropical Medicine and Parasitology, Inha University School of Medicine, Incheon, Republic of Korea.,Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida
| | - Hyun Bae Jie
- OncoMed Pharmaceuticals, Inc., Redwood City, California
| | - Paul L Bollyky
- Division of Infectious Diseases, Stanford University Medical Center, Stanford, California; and
| | - David Sarracino
- Thermo Fisher Scientific Biomarkers Research Initiatives in Mass Spectrometry (BRIMS) Center, Cambridge, Massachusetts
| | - Tong-Soo Kim
- Departments of Tropical Medicine and Parasitology, Inha University School of Medicine, Incheon, Republic of Korea;
| | - Brian S Wilson
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida;
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43
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Affiliation(s)
- Isabelle Nel
- INSERM U1016 and Centre National de la Recherche Scientifique UMR8104, Institut Cochin, and Laboratoire d'Excellence INFLAMEX, Université Paris Descartes, Université Sorbonne Paris Cité, Paris, France
| | - Agnes Lehuen
- INSERM U1016 and Centre National de la Recherche Scientifique UMR8104, Institut Cochin, and Laboratoire d'Excellence INFLAMEX, Université Paris Descartes, Université Sorbonne Paris Cité, Paris, France
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44
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Michel ML, Lenoir C, Massot B, Diem S, Pasquier B, Sawa S, Rignault-Bricard R, Lehuen A, Eberl G, Veillette A, Leite-de-Moraes M, Latour S. SLAM-associated protein favors the development of iNKT2 over iNKT17 cells. Eur J Immunol 2016; 46:2162-74. [PMID: 27338553 DOI: 10.1002/eji.201646313] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Revised: 05/11/2016] [Accepted: 06/20/2016] [Indexed: 11/09/2022]
Abstract
Invariant NKT (iNKT) cells differentiate in the thymus into three distinct lineages defined by their cytokine and transcription factor expression. Signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) is essential for early stages of iNKT cell development, but its role during terminal differentiation of iNKT1, iNKT2, or iNKT17 cells remains unclear. Taking advantage of SAP-deficient mice expressing a Vα14-Jα18 TCRα transgene, we found that SAP is critical not only for IL-4 production but also for the terminal differentiation of IL-4-producing iNKT2 cells. Furthermore, without SAP, the IL-17 producing subset is expanded, while IFN-γ-producing iNKT1 differentiation is only moderately compromised. Lack of SAP reduced the expression of the transcription factors GATA-3 and promyelocytic leukemia zinc finger, but enhanced the levels of retinoic acid receptor-related orphan receptor γt. In the absence of SAP, lineage commitment was actually shifted toward the emergence of iNKT17 over iNKT2 cells. Collectively, our data unveil a new critical regulatory function for SAP in thymic iNKT cell fate decisions.
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Affiliation(s)
- Marie-Laure Michel
- Laboratory of Immunoregulation and Immunopathology, Institut Necker-Enfants Malades, CNRS UMR 8253 and INSERM UMR 1151, Paris, France.,Université Paris Descartes Sorbonne Paris Cité, Paris, France
| | - Christelle Lenoir
- Laboratory of Lymphocyte Activation and EBV Susceptibility, INSERM UMR 1163, Institut des Maladies Génétiques, Hôpital Necker-Enfants Malades, Paris, France
| | - Bérangère Massot
- Laboratory of Immunoregulation and Immunopathology, Institut Necker-Enfants Malades, CNRS UMR 8253 and INSERM UMR 1151, Paris, France.,Université Paris Descartes Sorbonne Paris Cité, Paris, France
| | - Séverine Diem
- Laboratory of Immunoregulation and Immunopathology, Institut Necker-Enfants Malades, CNRS UMR 8253 and INSERM UMR 1151, Paris, France.,Université Paris Descartes Sorbonne Paris Cité, Paris, France
| | - Benoit Pasquier
- Laboratory of Lymphocyte Activation and EBV Susceptibility, INSERM UMR 1163, Institut des Maladies Génétiques, Hôpital Necker-Enfants Malades, Paris, France
| | - Shinichiro Sawa
- Lymphoid Tissue Development Unit, Institut Pasteur, Paris, France
| | - Rachel Rignault-Bricard
- Laboratory of Immunoregulation and Immunopathology, Institut Necker-Enfants Malades, CNRS UMR 8253 and INSERM UMR 1151, Paris, France.,Institut Imagine, Université Paris Descartes Sorbonne Paris Cité, Paris, France
| | - Agnès Lehuen
- Hôpital Cochin-St. Vincent de Paul, INSERM UMR 986, Paris, France
| | - Gérard Eberl
- Lymphoid Tissue Development Unit, Institut Pasteur, Paris, France
| | - André Veillette
- Laboratory of Molecular Oncology, Clinical Research Institute of Montréal, Québec, Canada
| | - Maria Leite-de-Moraes
- Laboratory of Immunoregulation and Immunopathology, Institut Necker-Enfants Malades, CNRS UMR 8253 and INSERM UMR 1151, Paris, France.,Université Paris Descartes Sorbonne Paris Cité, Paris, France
| | - Sylvain Latour
- Laboratory of Lymphocyte Activation and EBV Susceptibility, INSERM UMR 1163, Institut des Maladies Génétiques, Hôpital Necker-Enfants Malades, Paris, France. .,Institut Imagine, Université Paris Descartes Sorbonne Paris Cité, Paris, France.
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Tard C, Rouxel O, Lehuen A. Regulatory role of natural killer T cells in diabetes. Biomed J 2016; 38:484-95. [PMID: 27013448 PMCID: PMC6138260 DOI: 10.1016/j.bj.2015.04.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Accepted: 04/24/2015] [Indexed: 01/02/2023] Open
Abstract
Type 1 and type 2 diabetes are growing public health problems. Despite having different pathophysiologies, both diseases are associated with defects in immune regulation. Invariant natural killer T (iNKT) cells are innate-like T cells that recognize glycolipids presented by CD1d. These cells not only play a key role in the defense against pathogens, but also exert potent immunoregulatory functions. The regulatory role of iNKT cells in the prevention of type 1 diabetes has been demonstrated in murine models and analyzed in diabetic patients. The decreased frequency of iNKT cells in non-obese diabetic mice initially suggested the regulatory role of this cell subset. Increasing the frequency or the activation of iNKT cells with agonists protects non-obese diabetic mice from the development of diabetes. Several mechanisms mediate iNKT regulatory functions. They can rapidly produce immunoregulatory cytokines, interleukin (IL)-4 and IL-10. They induce tolerogenic dendritic cells, thereby inducing the anergy of autoreactive anti-islet T cells and increasing the frequency of T regulatory cells (Treg cells). Synthetic agonists are able to activate iNKT cells and represent potential therapeutic treatment in order to prevent type 1 diabetes. Growing evidence points to a role of immune system in glucose intolerance and type 2 diabetes. iNKT cells are resident cells of adipose tissue and their local and systemic frequencies are reduced in obese patients, suggesting their involvement in local and systemic inflammation during obesity. With the discovery of potential continuity between type 1 and type 2 diabetes in some patients, the role of iNKT cells in these diseases deserves further investigation.
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Affiliation(s)
- Celine Tard
- Laboratory "Immunology of Diabetes", U1016 INSERM-Institut Cochin, Paris, France; CNRS UMR8104, Paris, France; Laboratoire d'Excellence INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; DHU Authors, Hôpital Cochin, 75014, Paris, France
| | - Ophelie Rouxel
- Laboratory "Immunology of Diabetes", U1016 INSERM-Institut Cochin, Paris, France; CNRS UMR8104, Paris, France; Laboratoire d'Excellence INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; DHU Authors, Hôpital Cochin, 75014, Paris, France
| | - Agnes Lehuen
- Laboratory "Immunology of Diabetes", U1016 INSERM-Institut Cochin, Paris, France; CNRS UMR8104, Paris, France; Laboratoire d'Excellence INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; DHU Authors, Hôpital Cochin, 75014, Paris, France.
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46
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Gourdy P, Bourgeois EA, Levescot A, Pham L, Riant E, Ahui ML, Damotte D, Gombert JM, Bayard F, Ohlsson C, Arnal JF, Herbelin A. Estrogen Therapy Delays Autoimmune Diabetes and Promotes the Protective Efficiency of Natural Killer T-Cell Activation in Female Nonobese Diabetic Mice. Endocrinology 2016; 157:258-67. [PMID: 26485613 DOI: 10.1210/en.2015-1313] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Therapeutic strategies focused on restoring immune tolerance remain the main avenue to prevent type 1 diabetes (T1D). Because estrogens potentiate FoxP3+ regulatory T cells (Treg) and invariant natural killer T (iNKT) cells, two regulatory lymphocyte populations that are functionally deficient in nonobese diabetic (NOD) mice, we investigated whether estradiol (E2) therapy influences the course of T1D in this model. To this end, female NOD mice were sc implanted with E2- or placebo-delivering pellets to explore the course of spontaneous and cyclophosphamide-induced diabetes. Treg-depleted and iNKT-cell-deficient (Jα18(-/-)) NOD mice were used to assess the respective involvement of these lymphocyte populations in E2 effects. Early E2 administration (from 4 wk of age) was found to preserve NOD mice from both spontaneous and cyclophosphamide-induced diabetes, and a complete protection was also observed throughout treatment when E2 treatment was initiated after the onset of insulitis (from 12 wk of age). This delayed E2 treatment remained fully effective in Treg-depleted mice but failed to entirely protect Jα18(-/-) mice. Accordingly, E2 administration was shown to restore the cytokine production of iNKT cells in response to in vivo challenge with the cognate ligand α-galactosylceramide. Finally, transient E2 administration potentiated the previously described protective action of α-galactosylceramide treatment in NOD females. This study provides original evidence that E2 therapy strongly protects NOD mice from T1D and reveals the estrogen/iNKT cell axis as a new effective target to counteract diabetes onset at the stage of insulitis. Estrogen-based therapy should thus be considered for T1D prevention.
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MESH Headings
- Animals
- Autoimmune Diseases/drug therapy
- Autoimmune Diseases/immunology
- Autoimmune Diseases/metabolism
- Autoimmune Diseases/prevention & control
- Cytokines/blood
- Cytokines/metabolism
- Diabetes Mellitus, Type 1/drug therapy
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/prevention & control
- Drug Implants
- Estradiol/administration & dosage
- Estradiol/therapeutic use
- Estrogen Replacement Therapy
- Estrogens/administration & dosage
- Estrogens/therapeutic use
- Female
- Galactosylceramides/agonists
- Galactosylceramides/pharmacology
- Galactosylceramides/therapeutic use
- Immune Tolerance/drug effects
- Killer Cells, Natural/drug effects
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Lymphocyte Activation/drug effects
- Lymphocyte Depletion/adverse effects
- Mice, Inbred C57BL
- Mice, Inbred NOD
- Mice, Mutant Strains
- Ovariectomy/adverse effects
- Prediabetic State/drug therapy
- Prediabetic State/immunology
- Prediabetic State/metabolism
- Prediabetic State/prevention & control
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
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Affiliation(s)
- Pierre Gourdy
- INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden
| | - Elvire A Bourgeois
- INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden
| | - Anaïs Levescot
- INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden
| | - Linh Pham
- INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden
| | - Elodie Riant
- INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden
| | - Marie-Louise Ahui
- INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden
| | - Diane Damotte
- INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden
| | - Jean-Marc Gombert
- INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden
| | - Francis Bayard
- INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden
| | - Claes Ohlsson
- INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden
| | - Jean-François Arnal
- INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden
| | - André Herbelin
- INSERM Unité 1048 (P.G., E.R., F.B., J.-F.A.), Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Toulouse University (P.G., J.-F.A.), 31059 Toulouse, France; Department of Diabetology (P.G.), Toulouse University Hospital, 31403 Toulouse, France; Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147 (E.A.B., L.P., M.-L.A.), Necker Hospital, 75015 Paris, France; Paris Descartes University, Necker Hospital (E.A.B., L.P., M.-L.A., A.H.), 75014 Paris, France; INSERM Unité 1082 (A.L., A.H.), 86022 Poitiers, France; Paris-Sud-11 University (A.L.), 91405 Orsay, France; Department of Anatomy and Cytology (A.L., D.D.), Hôtel Dieu, 49033 Paris, France; Laboratory of Immunology (J.-M.G.), Poitiers, and Poitiers University (J.-M.G., A.H.), 86000 Poitiers, France; Centre Hospitalo-Universitaire de Poitiers (J.-M.G., A.H.), 86021 Poitiers, France; and Centre for Bone and Arthritis Research (C.O.), University of Gothenburg, S-405 30 Gothenburg, Sweden
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Staphylococcus enterotoxin B-induced T cells can efficaciously protect against type 1 diabetes in non-obese diabetic mice. Cent Eur J Immunol 2015; 40:292-9. [PMID: 26648772 PMCID: PMC4655378 DOI: 10.5114/ceji.2015.54589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 05/26/2015] [Indexed: 11/17/2022] Open
Abstract
Type 1 diabetes (T1D), an autoimmune disease, can be protected against by natural killer T (NKT) cells. Several attempts demonstrate that NKT cells also can be produced by inducing with Staphylococcus enterotoxin B (SEB) in addition to its classical activated antigen α-galactosylceramide. Here, we examined a potential usage of SEB-induced T (SEB-T) cells for the treatment of T1D. We established the immunophenotypes of SEB-T cells via flow cytometry, and in consequence, enriched in CD8+NKT cells after SEB stimulated. A high level of transforming growth factor β (TGF-β), detected by RT-PCR and ELISA, was first observed to be expressed and secreted by these SEB-T cells. Mixed lymphocyte reactions indicated that SEB-T cells could not produce a response to mitogens and allogeneic lymphocyte, and can inhibit lymphocytes response to mitogens. In an animal model, our data indicated that infusion of SEB-T cells in non-obese diabetic mice was well tolerated and could ameliorate hyperglycemia and maintain the blood glucose nearly on normal level until sacrifice. Strikingly, infusion of SEB-T cells resulted in an increase in the serum TGF-β level. These data raise the possibility that SEB-T cells can protect against T1D, which is associated with NKT cells generated in these SEB-induced cells.
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Schrumpf E, Tan C, Karlsen TH, Sponheim J, Björkström NK, Sundnes O, Alfsnes K, Kaser A, Jefferson DM, Ueno Y, Eide TJ, Haraldsen G, Zeissig S, Exley MA, Blumberg RS, Melum E. The biliary epithelium presents antigens to and activates natural killer T cells. Hepatology 2015; 62:1249-59. [PMID: 25855031 PMCID: PMC4589438 DOI: 10.1002/hep.27840] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Accepted: 04/07/2015] [Indexed: 02/02/2023]
Abstract
UNLABELLED Cholangiocytes express antigen-presenting molecules, but it has been unclear whether they can present antigens. Natural killer T (NKT) cells respond to lipid antigens presented by the major histocompatibility complex class I-like molecule CD1d and are abundant in the liver. We investigated whether cholangiocytes express CD1d and present lipid antigens to NKT cells and how CD1d expression varies in healthy and diseased bile ducts. Murine and human cholangiocyte cell lines as well as human primary cholangiocytes expressed CD1d as determined by flow cytometry and western blotting. Murine cholangiocyte cell lines were able to present both exogenous and endogenous lipid antigens to invariant and noninvariant NKT cell hybridomas and primary NKT cells in a CD1d-dependent manner. A human cholangiocyte cell line, cholangiocarcinoma cell lines, and human primary cholangiocytes also presented exogenous CD1d-restricted antigens to invariant NKT cell clones. CD1d expression was down-regulated in the biliary epithelium of patients with late primary sclerosing cholangitis, primary biliary cirrhosis, and alcoholic cirrhosis compared to healthy controls. CONCLUSIONS Cholangiocytes express CD1d and present antigens to NKT cells and CD1d expression is down-regulated in diseased biliary epithelium, findings which show that the biliary epithelium can activate an important lymphocyte subset of the liver. This is a potentially important immune pathway in the biliary system, which may be capable of regulating inflammation in the context of biliary disease.
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Affiliation(s)
- Elisabeth Schrumpf
- Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Corey Tan
- Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Tom H. Karlsen
- Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Jon Sponheim
- K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Section of Gastroenterology, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Laboratory of Immunohistochemistry and Immunopathology, Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Niklas K. Björkström
- Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
- Liver Immunology Laboratory, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Olav Sundnes
- Laboratory of Immunohistochemistry and Immunopathology, Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- K.G. Jebsen Inflammation Research Centre, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Kristian Alfsnes
- Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Arthur Kaser
- Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - Douglas M. Jefferson
- Department of Integrative Physiology and Pathobiology, Sackler School, Tufts University School of Medicine, Boston, MA, USA
| | - Yoshiyuki Ueno
- Division of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Tor J. Eide
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Guttorm Haraldsen
- Laboratory of Immunohistochemistry and Immunopathology, Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- K.G. Jebsen Inflammation Research Centre, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Sebastian Zeissig
- Department of Internal Medicine, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Mark A. Exley
- Manchester Collaborative Centre for Inflammation Research (MCCIR), Faculty of Medical & Human Sciences, University of Manchester, Manchester, UK
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Richard S. Blumberg
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Espen Melum
- Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
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Gottschalk C, Mettke E, Kurts C. The Role of Invariant Natural Killer T Cells in Dendritic Cell Licensing, Cross-Priming, and Memory CD8(+) T Cell Generation. Front Immunol 2015; 6:379. [PMID: 26284065 PMCID: PMC4517377 DOI: 10.3389/fimmu.2015.00379] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Accepted: 07/11/2015] [Indexed: 12/23/2022] Open
Abstract
New vaccination strategies focus on achieving CD8+ T cell (CTL) immunity rather than on induction of protective antibody responses. While the requirement of CD4+ T (Th) cell help in dendritic cell (DC) activation and licensing, and in CTL memory induction has been described in several disease models, CTL responses may occur in a Th cell help-independent manner. Invariant natural killer T cells (iNKT cells) can substitute for Th cell help and license DC as well. iNKT cells produce a broad spectrum of Th1 and Th2 cytokines, thereby inducing a similar set of costimulatory molecules and cytokines in DC. This form of licensing differs from Th cell help by inducing other chemokines, while Th cell-licensed DCs produce CCR5 ligands, iNKT cell-licensed DCs produce CCL17, which attracts CCR4+ CD8+ T cells for subsequent activation. It has recently been shown that iNKT cells do not only enhance immune responses against bacterial pathogens or parasites but also play a role in viral infections. The inclusion of iNKT cell ligands in influenza virus vaccines enhanced memory CTL generation and protective immunity in a mouse model. This review will focus on the role of iNKT cells in the cross-talk with cross-priming DC and memory CD8+ T cell formation.
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Affiliation(s)
- Catherine Gottschalk
- Institute of Experimental Immunology, Rheinische Friedrich-Wilhelms-University of Bonn , Bonn , Germany
| | - Elisabeth Mettke
- Institute of Experimental Immunology, Rheinische Friedrich-Wilhelms-University of Bonn , Bonn , Germany
| | - Christian Kurts
- Institute of Experimental Immunology, Rheinische Friedrich-Wilhelms-University of Bonn , Bonn , Germany
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Magalhaes I, Kiaf B, Lehuen A. iNKT and MAIT Cell Alterations in Diabetes. Front Immunol 2015; 6:341. [PMID: 26191063 PMCID: PMC4489333 DOI: 10.3389/fimmu.2015.00341] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Accepted: 06/18/2015] [Indexed: 12/29/2022] Open
Abstract
Type 1 diabetes (T1D) and type 2 diabetes (T2D) are multifactorial diseases with different etiologies in which chronic inflammation takes place. Defects in invariant natural killer T (iNKT) cell populations have been reported in both T1D and T2D patients, mouse models and our recent study revealed mucosal-associated invariant T (MAIT) cell defects in T2D and obese patients. Regarding iNKT cells many studies in non-obese diabetic mice demonstrated their protective role against T1D whereas their potential role in human T1D is still under debate. Studies in mouse models and patients suggest that iNKT cells present in adipose tissue (AT) could exert a regulatory role against obesity and associated metabolic disorders, such as T2D. Scarce data are yet available on MAIT cells; however, we recently described MAIT cell abnormalities in the blood and ATs from obese and T2D patients. These data show that a link between MAIT cells and metabolic disorders pave the way for further investigations on MAIT cells in T1D and T2D in humans and mouse models. Furthermore, we hypothesize that the gut microbiota alterations associated with T1D and T2D could modulate iNKT and MAIT cell frequency and functions. The potential role of iNKT and MAIT cells in the regulation of metabolic pathways and their cross-talk with microbiota represent exciting new lines of research.
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Affiliation(s)
- Isabelle Magalhaes
- INSERM U1016, Institut Cochin , Paris , France ; UMR8104, CNRS , Paris , France ; Laboratoire d'Excellence INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité , Paris , France
| | - Badr Kiaf
- INSERM U1016, Institut Cochin , Paris , France ; UMR8104, CNRS , Paris , France ; Laboratoire d'Excellence INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité , Paris , France
| | - Agnès Lehuen
- INSERM U1016, Institut Cochin , Paris , France ; UMR8104, CNRS , Paris , France ; Laboratoire d'Excellence INFLAMEX, Université Paris Descartes, Sorbonne Paris Cité , Paris , France ; Département de Diabétologie, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris , Paris , France
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