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Yao Z, Sun L, Gao Y, Su Y, He B, Ge Y, Yang C, Jia X, Jiao A, Sun C, Zhang B. The m 6A demethylase FTO controls Th1 differentiation and immunity against infections. Mol Immunol 2025; 183:172-181. [PMID: 40378511 DOI: 10.1016/j.molimm.2025.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2025] [Revised: 05/05/2025] [Accepted: 05/05/2025] [Indexed: 05/19/2025]
Abstract
Antigen-specific effector CD4+ T cells are critical for defense against exogenous pathogens. However, the epigenetic mechanisms underlying CD4+ T cell immune responses, particularly RNA modifications, remain incompletely understood. In this study, we employed a T cell-specific deletion of the fat mass and obesity-associated protein (FTO), a key N6-methyladenosine (m6A) demethylase, to elucidate its role in CD4+ T cell mediated immunity. Our findings demonstrate that FTO is essential for maintaining CD4+ T cell immune responses and protective functions. Specifically, FTO deficiency restricts the expansion of CD4+ T helper (Th)1 effector cells following antigen challenge and results in decreased expression of T-bet and IFN-γ in Th1 cells. Additionally, FTO deficient CD4+ T cells exhibit impaired pathogen elimination. Collectively, our study reveals a novel epigenetic regulatory mechanism in supporting CD4+ T cell differentiation, providing new insights into the post-transcriptional regulation of CD4+ T cell immunity and highlighting the potential for therapeutic strategies.
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Affiliation(s)
- Zhihong Yao
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Faculty of Clinical Medicine, Hanzhong Vocational and Technical College, Hanzhong 723002, China
| | - Lina Sun
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, China; Key Laboratory for ImmunoHealth of Shaanxi Province, Xi'an, Shannxi 710061, China
| | - Yang Gao
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Department of Kidney Transplantation, Hospital of Nephropathy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China; Institute of Organ Transplantation, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Yanhong Su
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, China; Key Laboratory for ImmunoHealth of Shaanxi Province, Xi'an, Shannxi 710061, China
| | - Boxiao He
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, China; Key Laboratory for ImmunoHealth of Shaanxi Province, Xi'an, Shannxi 710061, China
| | - Yao Ge
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Chen Yang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Xiaoxuan Jia
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Anjun Jiao
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, China; Key Laboratory for ImmunoHealth of Shaanxi Province, Xi'an, Shannxi 710061, China
| | - Chenming Sun
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, China; Key Laboratory for ImmunoHealth of Shaanxi Province, Xi'an, Shannxi 710061, China
| | - Baojun Zhang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Institute of Infection and Immunity, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, China; Key Laboratory for ImmunoHealth of Shaanxi Province, Xi'an, Shannxi 710061, China.
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2
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Kolland D, Kuhlmann M, de Almeida GP, Köhler A, Arifovic A, von Strempel A, Pourjam M, Bolsega S, Wurmser C, Steiger K, Basic M, Neuhaus K, Schmidt-Weber CB, Stecher B, Zehn D, Ohnmacht C. A specific microbial consortium enhances Th1 immunity, improves LCMV viral clearance but aggravates LCMV disease pathology in mice. Nat Commun 2025; 16:3902. [PMID: 40274773 PMCID: PMC12022176 DOI: 10.1038/s41467-025-59073-x] [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: 02/07/2024] [Accepted: 04/10/2025] [Indexed: 04/26/2025] Open
Abstract
Anti-viral immunity can vary tremendously from individual to individual but mechanistic understanding is still scarce. Here, we show that a defined, low complex bacterial community (OMM12) but not the general absence of microbes in germ-free mice leads to a more potent immune response compared to the microbiome of specific-pathogen-free (SPF) mice after a systemic viral infection with LCMV Clone-13. Consequently, gnotobiotic mice colonized with OMM12 have more severe LCMV-induced disease pathology but also enhance viral clearance in the intestinal tract. Mechanistically, single-cell RNA sequencing analysis of adoptively transferred virus-specific T helper cells and endogenous T helper cells in the intestinal tract reveal a stronger pro-inflammatory Th1 profile and a more vigorous expansion in OMM12 than SPF mice. Altogether, our work highlights the causative function of the intestinal microbiome for shaping adaptive anti-viral immunity with implications for vaccination strategies and anti-cancer treatment regimens.
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Affiliation(s)
- Daphne Kolland
- Center of Allergy and Environment (ZAUM), Technical University and Helmholtz Center, Munich, Germany
| | - Miriam Kuhlmann
- Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Gustavo P de Almeida
- Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
- Center for Infection Prevention (ZIP), School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Amelie Köhler
- Center of Allergy and Environment (ZAUM), Technical University and Helmholtz Center, Munich, Germany
| | - Anela Arifovic
- Center of Allergy and Environment (ZAUM), Technical University and Helmholtz Center, Munich, Germany
| | - Alexandra von Strempel
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Faculty of Medicine, LMU, Munich, Germany
| | - Mohsen Pourjam
- Core Facility Microbiome ZIEL - Institute for Food & Health, Technical University of Munich, Freising, Germany
| | - Silvia Bolsega
- Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany
| | - Christine Wurmser
- Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
- Center for Infection Prevention (ZIP), School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Katja Steiger
- Institute of Pathology, School of Medicine and Health, Technical University Munich, Munich, Germany
| | - Marijana Basic
- Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany
| | - Klaus Neuhaus
- Core Facility Microbiome ZIEL - Institute for Food & Health, Technical University of Munich, Freising, Germany
| | - Carsten B Schmidt-Weber
- Center of Allergy and Environment (ZAUM), Technical University and Helmholtz Center, Munich, Germany
- Member of the German Center of Lung Research (DZL), Partner Site Munich, Munich, Germany
| | - Bärbel Stecher
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Faculty of Medicine, LMU, Munich, Germany
- German Center for Infection Research (DZIF), partner site LMU, Munich, Germany
| | - Dietmar Zehn
- Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.
- Center for Infection Prevention (ZIP), School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.
| | - Caspar Ohnmacht
- Center of Allergy and Environment (ZAUM), Technical University and Helmholtz Center, Munich, Germany.
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3
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Perkins B, Novis CL, Baessler A, Sircy LM, Thomas MM, Harrison-Chau M, Richens AW, Fuchs B, Nguyen NX, Flint K, Strobelt BM, Varley KE, Hale JS. Dnmt3a-dependent de novo DNA methylation enforces lineage commitment and preserves functionality of memory Th1 and Tfh cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.12.03.623450. [PMID: 39677644 PMCID: PMC11642886 DOI: 10.1101/2024.12.03.623450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Following acute viral infection, naïve CD4+ T cells differentiate into T follicular helper (Tfh) and T helper 1 (Th1) cells that generate long-lived memory cells. However, it is unclear how memory Tfh and Th1 cells maintain their lineage commitment. We demonstrate that Tfh and Th1 lineages acquire distinct Dnmt3a-dependent de novo DNA methylation programs that are preserved into memory. Dnmt3a deletion impairs lineage commitment and functionality of memory Th1 and Tfh cells, resulting in aberrant Runx1 upregulation that represses germinal center Tfh cell differentiation. In contrast, transient pharmacological DNA methyltransferase inhibition during priming impairs repression of Tfh-associated genes while properly silencing Runx1, and results in enhanced Tfh cell functionality in primary and secondary responses to viral infections. Together, these findings demonstrate that Dnmt3a-mediated epigenetic programing is required to enforce T helper lineage commitment and preserve Tfh and Th1-specific functions during the recall response to infection, and reveal novel strategies to improve long-lived adaptive immunity against infectious diseases.
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Affiliation(s)
- Bryant Perkins
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112
| | - Camille L. Novis
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112
| | - Andrew Baessler
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112
| | - Linda M. Sircy
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112
| | - Monyca M. Thomas
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112
| | - Malia Harrison-Chau
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112
| | - Andrew W. Richens
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112
| | - Bryce Fuchs
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112
| | - Nguyen X. Nguyen
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112
| | - Kaitlyn Flint
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112
| | - Brittany M. Strobelt
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112
| | - Katherine E. Varley
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - J. Scott Hale
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112
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4
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Sasaki E, Asanuma H, Momose H, Maeyama JI, Moriyama S, Nagata N, Suzuki T, Hamaguchi I, Hasegawa H, Takahashi Y. Calboxyvinyl polymer adjuvant enhances respiratory iga responses through mucosal and systemic administration. NPJ Vaccines 2025; 10:28. [PMID: 39934182 PMCID: PMC11814125 DOI: 10.1038/s41541-025-01086-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 02/04/2025] [Indexed: 02/13/2025] Open
Abstract
Adjuvants play a crucial role in enhancing vaccine efficacy. Although several adjuvants have been approved, there remains a demand for safer and more effective adjuvants for nasal vaccines. Here, we identified calboxyvinyl polymer (CVP) as a superior mucosal vaccine adjuvant from pharmaceutical base materials using our screening systems; single nasal vaccination of the CVP-combined influenza split vaccine-induced antigen-specific IgA and IgG antibodies and provided protection against lethal influenza virus infection. Furthermore, nasal vaccination with CVP-combined severe acute respiratory syndrome coronavirus 2 antigen protected against the virus and stimulated the production of highly cross-reactive IgG antibodies against variants XBB1.5 and JN.1. Intriguingly, intramuscular vaccination of the CVP-combined vaccine also elicited the production of IgA antibodies in both nasal wash and bronchoalveolar lavage fluid in mice and cynomolgus monkeys. CVP therefore offers superior adjuvanticity to existing adjuvants and is anticipated to be a safe and effective adjuvant for mucosal vaccines.
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Affiliation(s)
- Eita Sasaki
- Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku, Tokyo, Japan.
- Center for Influenza and Respiratory Virus Research, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashi-Murayama, Tokyo, Japan.
| | - Hideki Asanuma
- Center for Influenza and Respiratory Virus Research, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashi-Murayama, Tokyo, Japan
| | - Haruka Momose
- Research Center for Biological Products in the Next Generation, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashi-Murayama, Tokyo, Japan
| | - Jun-Ichi Maeyama
- Research Center for Biological Products in the Next Generation, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashi-Murayama, Tokyo, Japan
| | - Saya Moriyama
- Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku, Tokyo, Japan
| | - Noriyo Nagata
- Department of Pathology, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashi-Murayama, Tokyo, Japan
| | - Tadaki Suzuki
- Department of Pathology, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashi-Murayama, Tokyo, Japan
| | - Isao Hamaguchi
- Research Center for Biological Products in the Next Generation, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashi-Murayama, Tokyo, Japan
- Department of Clinical Laboratory, Subaru Health Insurance Society Ota Memorial Hospital, 455-1, Oshima-cho, Ota, Gumma, Japan
| | - Hideki Hasegawa
- Center for Influenza and Respiratory Virus Research, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashi-Murayama, Tokyo, Japan
| | - Yoshimasa Takahashi
- Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku, Tokyo, Japan
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5
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Setia M, Suvas PK, Rana M, Chakraborty A, Suvas S. Herpes stromal keratitis erodes the establishment of tissue-resident memory T cell pool in HSV-1 infected corneas. Mucosal Immunol 2025; 18:188-204. [PMID: 39581232 PMCID: PMC11891946 DOI: 10.1016/j.mucimm.2024.11.003] [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: 09/09/2024] [Revised: 11/13/2024] [Accepted: 11/17/2024] [Indexed: 11/26/2024]
Abstract
The recurrent herpes simplex virus-1 (HSV-1) infection of the cornea can cause the development of herpes stromal keratitis (HSK). This chronic immunoinflammatory condition is a major cause of infection-induced vision loss. The previous episodes of HSK increase the risk of future recurrences in the same cornea. However, not all HSV-1 infected corneas that shed infectious virus at the ocular surface develop HSK, suggesting that corneal HSV-1 infection may cause an establishment of protective immunity in HSV-1 infected corneas. However, upon recurrent corneal HSV-1 infection, the established protective immunity can get compromised, resulting in the development of HSK. In this study, we compared the quantity and quality of tissue-resident memory T (TRM) cells in HSV-1 infected corneas that did or did not develop HSK. Our results showed the predominance of TRM cell in the epithelium than in stroma of HSV-1 infected corneas. Furthermore, HSV-1 infected non-HSK corneas exhibited more CD4 and CD8 TRM cells than HSK corneas. The TRM cells in non-HSK than in HSK corneas were more effective in clearing the infectious virus upon secondary corneal HSV-1 infection. Our results demonstrate the differential quantity and quality of TRM cells in HSV-1 infected corneas that did or did not develop HSK.
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Affiliation(s)
- Mizumi Setia
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, United States; Vaccine and Infectious Diseases Division, Fred Hutch Cancer Research Center, Seattle, Washington, United States
| | - Pratima Krishna Suvas
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, United States
| | - Mashidur Rana
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, United States
| | - Anish Chakraborty
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, United States
| | - Susmit Suvas
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, United States.
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6
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Osum KC, Becker SH, Krueger PD, Mitchell JS, Hong SW, Magill IR, Jenkins MK. A minority of Th1 and Tfh effector cells express survival genes shared by memory cell progeny that require IL-7 or TCR signaling to persist. Cell Rep 2025; 44:115111. [PMID: 39723889 PMCID: PMC12009130 DOI: 10.1016/j.celrep.2024.115111] [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: 12/08/2023] [Revised: 10/24/2024] [Accepted: 12/03/2024] [Indexed: 12/28/2024] Open
Abstract
It is not clear how CD4+ memory T cells are formed from a much larger pool of earlier effector cells. We found that transient systemic bacterial infection rapidly generates several antigen-specific T helper (Th)1 and T follicular helper (Tfh) cell populations with different tissue residence behaviors. Although most cells of all varieties had transcriptomes indicative of cell stress and death at the peak of the response, some had already acquired a memory cell signature characterized by expression of genes involved in cell survival. Each Th1 and Tfh cell type was maintained long term by interleukin (IL)-7, except germinal center Tfh cells, which depended on a T cell antigen receptor (TCR) signal. The results indicate that acute infection induces rapid differentiation of Th1 and Tfh cells, a minority of which quickly adopt the gene expression profile of memory cells and survive by signals from the IL-7 receptor or TCR.
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Affiliation(s)
- Kevin C Osum
- Department of Microbiology and Immunology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Samuel H Becker
- Department of Microbiology and Immunology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Peter D Krueger
- Department of Microbiology and Immunology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Jason S Mitchell
- Department of Microbiology and Immunology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Sung-Wook Hong
- Department of Microbiology and Immunology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Department of Biotechnology, Yonsei University, Seoul, South Korea
| | - Ian R Magill
- Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
| | - Marc K Jenkins
- Department of Microbiology and Immunology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
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7
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Le PM, Mattapallil MJ, Caspi RR, Stepp MA, Menko AS. Immunoregulatory Properties of Immune Cells that Associate with the Lens Capsule Surface during Acute and Resolution Phases of Experimental Autoimmune Uveitis. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:2194-2211. [PMID: 39159867 PMCID: PMC11627221 DOI: 10.1016/j.ajpath.2024.07.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 06/07/2024] [Accepted: 07/31/2024] [Indexed: 08/21/2024]
Abstract
Inflammation in the eye is tightly regulated to prevent vision impairment and irreversible blindness. Emerging evidence shows that immune cells are specifically recruited to the lens capsule in response to autoimmune uveitis, yet the potential that they have a role in regulating this inflammatory disease remained unexplored. Here, an immunolocalization approach combined with high-resolution confocal microscopy was used to investigate whether the immune cells that become stably associated with the lens capsule in the eyes of C57BL/6J mice with experimental autoimmune uveitis (EAU) have an immunoregulatory phenotype. These studies revealed that during the acute phase of uveitis, at day 18 after disease induction, the immune cells specifically recruited to the lens capsule, such as regulatory T cells [forkhead box P3 (FoxP3)+CD4+] and M2 macrophages (CD68+ arginase 1+IL-10+), included those with putative anti-inflammatory, proresolution roles. The frequency of these lens capsule-associated immunomodulatory phenotypes increased at day 35 after induction, during the resolution phase of EAU inflammation. At this later stage of resolution, most of the macrophages expressed CD206, a mannose receptor responsible for removing inflammatory molecules, in addition to arginase 1 and IL-10. These results suggest a previously unknown role for the lens as a site for recruitment of immune cells whose role is to suppress inflammation, promote resolution, and maintain remission of EAU.
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Affiliation(s)
- Phuong M Le
- Department of Pathology and Genomic Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Mary J Mattapallil
- Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland
| | - Rachel R Caspi
- Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland
| | - Mary Ann Stepp
- Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia; Department of Ophthalmology, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia
| | - A Sue Menko
- Department of Pathology and Genomic Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Ophthalmology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
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8
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Mitchell JS, Spanier JA, Dwyer AJ, Knutson TP, Alkhatib MH, Qian G, Weno ME, Chen Y, Shaheen ZR, Tucker CG, Kangas TO, Morales MS, Silva N, Kaisho T, Farrar MA, Fife BT. CD4 + T cells reactive to a hybrid peptide from insulin-chromogranin A adopt a distinct effector fate and are pathogenic in autoimmune diabetes. Immunity 2024; 57:2399-2415.e8. [PMID: 39214091 DOI: 10.1016/j.immuni.2024.07.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 06/04/2024] [Accepted: 07/30/2024] [Indexed: 09/04/2024]
Abstract
T cell-mediated islet destruction is a hallmark of autoimmune diabetes. Here, we examined the dynamics and pathogenicity of CD4+ T cell responses to four different insulin-derived epitopes during diabetes initiation in non-obese diabetic (NOD) mice. Single-cell RNA sequencing of tetramer-sorted CD4+ T cells from the pancreas revealed that islet-antigen-specific T cells adopted a wide variety of fates and required XCR1+ dendritic cells for their activation. Hybrid-insulin C-chromogranin A (InsC-ChgA)-specific CD4+ T cells skewed toward a distinct T helper type 1 (Th1) effector phenotype, whereas the majority of insulin B chain and hybrid-insulin C-islet amyloid polypeptide-specific CD4+ T cells exhibited a regulatory phenotype and early or weak Th1 phenotype, respectively. InsC-ChgA-specific CD4+ T cells were uniquely pathogenic upon transfer, and an anti-InsC-ChgA:IAg7 antibody prevented spontaneous diabetes. Our findings highlight the heterogeneity of T cell responses to insulin-derived epitopes in diabetes and argue for the feasibility of antigen-specific therapies that blunts the response of pathogenic CD4+ T cells causing autoimmunity.
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Affiliation(s)
- Jason S Mitchell
- Center for Immunology, University of Minnesota, Minneapolis, MN, USA
| | - Justin A Spanier
- Center for Immunology, University of Minnesota, Minneapolis, MN, USA; Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, USA; Center for Autoimmune Disease Research, University of Minnesota, Minneapolis, MN, USA
| | - Alexander J Dwyer
- Center for Immunology, University of Minnesota, Minneapolis, MN, USA; Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, USA
| | - Todd P Knutson
- Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, USA
| | - Mohannad H Alkhatib
- Center for Immunology, University of Minnesota, Minneapolis, MN, USA; Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, USA
| | - Gina Qian
- Center for Immunology, University of Minnesota, Minneapolis, MN, USA; Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, USA
| | - Matthew E Weno
- Center for Immunology, University of Minnesota, Minneapolis, MN, USA; Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, USA
| | - Yixin Chen
- Center for Immunology, University of Minnesota, Minneapolis, MN, USA; Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, USA
| | - Zachary R Shaheen
- Center for Immunology, University of Minnesota, Minneapolis, MN, USA; Department of Pediatrics, Division of Pediatric Rheumatology, Allergy, & Immunology, University of Minnesota, Minneapolis, MN, USA
| | - Christopher G Tucker
- Center for Immunology, University of Minnesota, Minneapolis, MN, USA; Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, USA
| | - Takashi O Kangas
- Center for Immunology, University of Minnesota, Minneapolis, MN, USA; Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, USA
| | - Milagros Silva Morales
- Center for Immunology, University of Minnesota, Minneapolis, MN, USA; Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, USA
| | - Nubia Silva
- Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, USA
| | - Tsuneyasu Kaisho
- Department of Immunology Institute for Advanced Medicine, Wakayama Medical University, Wakayama, Japan
| | - Michael A Farrar
- Center for Immunology, University of Minnesota, Minneapolis, MN, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
| | - Brian T Fife
- Center for Immunology, University of Minnesota, Minneapolis, MN, USA; Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota, Minneapolis, MN, USA; Center for Autoimmune Disease Research, University of Minnesota, Minneapolis, MN, USA.
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9
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Dong L, Choi H, Budhu S, Schulze I, Verma S, Mangarin LM, Estrada Nevarro V, Mehanna N, Khan JF, Venkatesh D, Thach D, Rosen N, Wolchok JD, Merghoub T. Intermittent MEK Inhibition with GITR Costimulation Rescues T-cell Function for Increased Efficacy with CTLA-4 Blockade in Solid Tumor Models. Cancer Immunol Res 2024; 12:1392-1408. [PMID: 38885362 DOI: 10.1158/2326-6066.cir-23-0729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 03/14/2024] [Accepted: 06/14/2024] [Indexed: 06/20/2024]
Abstract
MEK inhibitors (MEKi) have shown limited success as a treatment for MAPK/ERK pathway-dependent cancers due to various resistance mechanisms tumor cells can employ. CH5126766 (CKI27) is an inhibitor that binds to MEK and prevents release of RAF, reducing the relief of negative feedback commonly observed with other MEKis. We observed that CKI27 increased MHC expression in tumor cells and improved T cell-mediated killing. Yet, CKI27 also decreased T-cell proliferation, activation, and cytolytic activity by inhibiting the MAPK/ERK pathway that is activated downstream of T-cell receptor signaling. Therefore, we aimed to balance the positive and negative immunomodulatory effects of MEKis for optimal combination with immunotherapy. Intermittent administration of CKI27 allowed T cells to partially recover and costimulation via GITR and OX-40 agonist antibodies completely alleviated inhibition of function. In Kras mutant lung and colon tumor mouse models, intermittent CKI27 and anti-GITR significantly decreased tumor growth and prolonged survival when further combined with CTLA-4 immune checkpoint blockade. Moreover, this triple combination increased CD8+ and CD4+ T-cell proliferation, activation, and effector/memory subsets in the tumor-draining lymph nodes and tumors and led to intratumoral regulatory T-cell destabilization. These data, collectively, will allow for more informed decisions when optimizing combination regimens by overcoming resistance, reducing toxicity, and generating long-term immune responses.
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Affiliation(s)
- Lauren Dong
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Hyejin Choi
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Sadna Budhu
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Isabell Schulze
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Svena Verma
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Levi M Mangarin
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Valeria Estrada Nevarro
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Nezar Mehanna
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Jonathan F Khan
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Divya Venkatesh
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Daniel Thach
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Neal Rosen
- Department of Medicine, Memorial Hospital, Memorial Sloan Kettering Cancer Center, New York, New York
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jedd D Wolchok
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
| | - Taha Merghoub
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York
- Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, New York
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, New York
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10
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Lang HP, Osum KC, Friedenberg SG. A review of CD4 + T cell differentiation and diversity in dogs. Vet Immunol Immunopathol 2024; 275:110816. [PMID: 39173398 PMCID: PMC11421293 DOI: 10.1016/j.vetimm.2024.110816] [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: 06/19/2024] [Revised: 08/12/2024] [Accepted: 08/13/2024] [Indexed: 08/24/2024]
Abstract
CD4+ T cells are an integral component of the adaptive immune response, carrying out many functions to combat a diverse range of pathogenic challenges. These cells exhibit remarkable plasticity, differentiating into specialized subsets such as T helper type 1 (TH1), TH2, TH9, TH17, TH22, regulatory T cells (Tregs), and follicular T helper (TFH) cells. Each subset is capable of addressing a distinct immunological need ranging from pathogen eradication to regulation of immune homeostasis. As the immune response subsides, CD4+ T cells rest down into long-lived memory phenotypes-including central memory (TCM), effector memory (TEM), resident memory (TRM), and terminally differentiated effector memory cells (TEMRA) that are localized to facilitate a swift and potent response upon antigen re-encounter. This capacity for long-term immunological memory and rapid reactivation upon secondary exposure highlights the role CD4+ T cells play in sustaining both adaptive defense mechanisms and maintenance. Decades of mouse, human, and to a lesser extent, pig T cell research has provided the framework for understanding the role of CD4+ T cells in immune responses, but these model systems do not always mimic each other. Although our understanding of pig immunology is not as extensive as mouse or human research, we have gained valuable insight by studying this model. More akin to pigs, our understanding of CD4+ T cells in dogs is much less complete. This disparity exists in part because canine immunologists depend on paradigms from mouse and human studies to characterize CD4+ T cells in dogs, with a fraction of available lineage-defining antibody markers. Despite this, every major CD4+ T cell subset has been described to some extent in dogs. These subsets have been studied in various contexts, including in vitro stimulation, homeostatic conditions, and across a range of disease states. Canine CD4+ T cells have been categorized according to lineage-defining characteristics, trafficking patterns, and what cytokines they produce upon stimulation. This review addresses our current understanding of canine CD4+ T cells from a comparative perspective by highlighting both the similarities and differences from mouse, human, and pig CD4+ T cell biology. We also discuss knowledge gaps in our current understanding of CD4+ T cells in dogs that could provide direction for future studies in the field.
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Affiliation(s)
- Haeree P Lang
- Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA.
| | - Kevin C Osum
- Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA.
| | - Steven G Friedenberg
- Center for Immunology, University of Minnesota, Minneapolis, MN 55414, USA; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA.
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11
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Becker SH, Ronayne CE, Bold TD, Jenkins MK. CD4 + T cells recruit, then engage macrophages in cognate interactions to clear Mycobacterium tuberculosis from the lungs. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.22.609198. [PMID: 39229103 PMCID: PMC11370583 DOI: 10.1101/2024.08.22.609198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
IFN-γ-producing CD4 + T cells are required for protection against lethal Mycobacterium tuberculosis ( Mtb ) infections. However, the ability of CD4 + T cells to suppress Mtb growth cannot be fully explained by IFN-γ or other known T cell products. In this study, we show that CD4 + T cell-derived IFN-γ promoted the recruitment of monocyte-derived macrophages (MDMs) to the lungs of Mtb -infected mice. Although the recruited MDMs became quickly and preferentially infected with Mtb , CD4 + T cells rapidly disinfected the MDMs. Clearance of Mtb from MDMs was not explained by IFN-γ, but rather by MHCII-mediated cognate interactions with CD4 + T cells. These interactions promoted MDM expression of glycolysis genes essential for Mtb control. Thus, by recruiting MDMs, CD4 + T cells initiate a cycle of bacterial phagocytosis, Mtb antigen presentation and disinfection in an attempt to clear the bacteria from the lungs.
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12
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Wiesheu R, Edwards SC, Hedley A, Hall H, Tosolini M, Fares da Silva MGF, Sumaria N, Castenmiller SM, Wardak L, Optaczy Y, Lynn A, Hill DG, Hayes AJ, Hay J, Kilbey A, Shaw R, Whyte D, Walsh PJ, Michie AM, Graham GJ, Manoharan A, Halsey C, Blyth K, Wolkers MC, Miller C, Pennington DJ, Jones GW, Fournie JJ, Bekiaris V, Coffelt SB. IL-27 maintains cytotoxic Ly6C + γδ T cells that arise from immature precursors. EMBO J 2024; 43:2878-2907. [PMID: 38816652 PMCID: PMC11251046 DOI: 10.1038/s44318-024-00133-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 04/19/2024] [Accepted: 05/03/2024] [Indexed: 06/01/2024] Open
Abstract
In mice, γδ-T lymphocytes that express the co-stimulatory molecule, CD27, are committed to the IFNγ-producing lineage during thymic development. In the periphery, these cells play a critical role in host defense and anti-tumor immunity. Unlike αβ-T cells that rely on MHC-presented peptides to drive their terminal differentiation, it is unclear whether MHC-unrestricted γδ-T cells undergo further functional maturation after exiting the thymus. Here, we provide evidence of phenotypic and functional diversity within peripheral IFNγ-producing γδ T cells. We found that CD27+ Ly6C- cells convert into CD27+Ly6C+ cells, and these CD27+Ly6C+ cells control cancer progression in mice, while the CD27+Ly6C- cells cannot. The gene signatures of these two subsets were highly analogous to human immature and mature γδ-T cells, indicative of conservation across species. We show that IL-27 supports the cytotoxic phenotype and function of mouse CD27+Ly6C+ cells and human Vδ2+ cells, while IL-27 is dispensable for mouse CD27+Ly6C- cell and human Vδ1+ cell functions. These data reveal increased complexity within IFNγ-producing γδ-T cells, comprising immature and terminally differentiated subsets, that offer new insights into unconventional T-cell biology.
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MESH Headings
- Animals
- Mice
- Antigens, Ly/metabolism
- Antigens, Ly/genetics
- Tumor Necrosis Factor Receptor Superfamily, Member 7/metabolism
- Tumor Necrosis Factor Receptor Superfamily, Member 7/genetics
- Tumor Necrosis Factor Receptor Superfamily, Member 7/immunology
- Humans
- Receptors, Antigen, T-Cell, gamma-delta/metabolism
- Receptors, Antigen, T-Cell, gamma-delta/immunology
- Receptors, Antigen, T-Cell, gamma-delta/genetics
- Interferon-gamma/metabolism
- Interferon-gamma/immunology
- Interleukin-27/metabolism
- Interleukin-27/genetics
- Cell Differentiation/immunology
- Mice, Inbred C57BL
- T-Lymphocytes, Cytotoxic/immunology
- T-Lymphocytes, Cytotoxic/metabolism
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Affiliation(s)
- Robert Wiesheu
- School of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Sarah C Edwards
- School of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Ann Hedley
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Holly Hall
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Marie Tosolini
- Cancer Research Centre of Toulouse, University of Toulouse, Toulouse, France
| | | | - Nital Sumaria
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Suzanne M Castenmiller
- Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Department Of Hematopoiesis, Sanquin Research, Amsterdam, The Netherlands
- Oncode Institute, Utrecht, The Netherlands
| | - Leyma Wardak
- Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Department Of Hematopoiesis, Sanquin Research, Amsterdam, The Netherlands
- Oncode Institute, Utrecht, The Netherlands
| | | | - Amy Lynn
- School of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - David G Hill
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
| | - Alan J Hayes
- School of Infection & Immunity, University of Glasgow, Glasgow, UK
| | - Jodie Hay
- School of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Anna Kilbey
- School of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Robin Shaw
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Declan Whyte
- Cancer Research UK Scotland Institute, Glasgow, UK
| | | | - Alison M Michie
- School of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Gerard J Graham
- School of Infection & Immunity, University of Glasgow, Glasgow, UK
| | - Anand Manoharan
- School of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Christina Halsey
- School of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Karen Blyth
- School of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Monika C Wolkers
- Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Department Of Hematopoiesis, Sanquin Research, Amsterdam, The Netherlands
- Oncode Institute, Utrecht, The Netherlands
| | - Crispin Miller
- School of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Daniel J Pennington
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Gareth W Jones
- School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK
| | | | - Vasileios Bekiaris
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Seth B Coffelt
- School of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
- Cancer Research UK Scotland Institute, Glasgow, UK.
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13
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Hegazy AN, Peine C, Niesen D, Panse I, Vainshtein Y, Kommer C, Zhang Q, Brunner TM, Peine M, Fröhlich A, Ishaque N, Marek RM, Zhu J, Höfer T, Löhning M. Plasticity and lineage commitment of individual T H1 cells are determined by stable T-bet expression quantities. SCIENCE ADVANCES 2024; 10:eadk2693. [PMID: 38838155 PMCID: PMC11152138 DOI: 10.1126/sciadv.adk2693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 05/01/2024] [Indexed: 06/07/2024]
Abstract
T helper 1 (TH1) cell identity is defined by the expression of the lineage-specifying transcription factor T-bet. Here, we examine the influence of T-bet expression heterogeneity on subset plasticity by leveraging cell sorting of distinct in vivo-differentiated TH1 cells based on their quantitative expression of T-bet and interferon-γ. Heterogeneous T-bet expression states were regulated by virus-induced type I interferons and were stably maintained even after secondary viral infection. Exposed to alternative differentiation signals, the sorted subpopulations exhibited graded levels of plasticity, particularly toward the TH2 lineage: T-bet quantities were inversely correlated with the ability to express the TH2 lineage-specifying transcription factor GATA-3 and TH2 cytokines. Reprogramed TH1 cells acquired graded mixed TH1 + TH2 phenotypes with a hybrid epigenetic landscape. Continuous presence of T-bet in differentiated TH1 cells was essential to ensure TH1 cell stability. Thus, innate cytokine signals regulate TH1 cell plasticity via an individual cell-intrinsic rheostat to enable T cell subset adaptation to subsequent challenges.
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Affiliation(s)
- Ahmed N. Hegazy
- Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medical Department of Gastroenterology, Infectious Diseases and Rheumatology, 12203 Berlin, Germany
- German Rheumatism Research Center (DRFZ), a Leibniz Institute, Inflammatory Mechanisms, 10117 Berlin, Germany
- Berlin Institute of Health (BIH) at Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Caroline Peine
- Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, 10117 Berlin, Germany
- German Rheumatism Research Center (DRFZ), a Leibniz Institute, Pitzer Laboratory of Osteoarthritis Research, 10117 Berlin, Germany
| | - Dominik Niesen
- Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, 10117 Berlin, Germany
- German Rheumatism Research Center (DRFZ), a Leibniz Institute, Pitzer Laboratory of Osteoarthritis Research, 10117 Berlin, Germany
| | - Isabel Panse
- Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, 10117 Berlin, Germany
- German Rheumatism Research Center (DRFZ), a Leibniz Institute, Pitzer Laboratory of Osteoarthritis Research, 10117 Berlin, Germany
| | - Yevhen Vainshtein
- German Cancer Research Center (DKFZ), Division of Theoretical Systems Biology, 69120 Heidelberg, Germany
- University of Heidelberg, Bioquant Center, 69120 Heidelberg, Germany
| | - Christoph Kommer
- German Cancer Research Center (DKFZ), Division of Theoretical Systems Biology, 69120 Heidelberg, Germany
- University of Heidelberg, Bioquant Center, 69120 Heidelberg, Germany
| | - Qin Zhang
- German Cancer Research Center (DKFZ), Division of Theoretical Systems Biology, 69120 Heidelberg, Germany
- University of Heidelberg, Bioquant Center, 69120 Heidelberg, Germany
| | - Tobias M. Brunner
- Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, 10117 Berlin, Germany
- German Rheumatism Research Center (DRFZ), a Leibniz Institute, Pitzer Laboratory of Osteoarthritis Research, 10117 Berlin, Germany
| | - Michael Peine
- Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, 10117 Berlin, Germany
- German Rheumatism Research Center (DRFZ), a Leibniz Institute, Pitzer Laboratory of Osteoarthritis Research, 10117 Berlin, Germany
| | - Anja Fröhlich
- Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, 10117 Berlin, Germany
- German Rheumatism Research Center (DRFZ), a Leibniz Institute, Pitzer Laboratory of Osteoarthritis Research, 10117 Berlin, Germany
| | - Naveed Ishaque
- German Cancer Research Center (DKFZ), Division of Theoretical Systems Biology, 69120 Heidelberg, Germany
- University of Heidelberg, Bioquant Center, 69120 Heidelberg, Germany
| | - Roman M. Marek
- Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, 10117 Berlin, Germany
- German Rheumatism Research Center (DRFZ), a Leibniz Institute, Pitzer Laboratory of Osteoarthritis Research, 10117 Berlin, Germany
| | - Jinfang Zhu
- National Institute of Allergy and Infectious Diseases, Laboratory of Immune System Biology, National Institutes of Health, Bethesda, MD 20892, USA
| | - Thomas Höfer
- German Cancer Research Center (DKFZ), Division of Theoretical Systems Biology, 69120 Heidelberg, Germany
- University of Heidelberg, Bioquant Center, 69120 Heidelberg, Germany
| | - Max Löhning
- Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Experimental Immunology and Osteoarthritis Research, Department of Rheumatology and Clinical Immunology, 10117 Berlin, Germany
- German Rheumatism Research Center (DRFZ), a Leibniz Institute, Pitzer Laboratory of Osteoarthritis Research, 10117 Berlin, Germany
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14
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Kim Y, Saini U, Kim D, Hernandez-Aguirre I, Hedberg J, Martin A, Mo X, Cripe TP, Markert J, Cassady KA, Dhital R. Enhanced IL-12 transgene expression improves oncolytic viroimmunotherapy. Front Immunol 2024; 15:1375413. [PMID: 38895115 PMCID: PMC11184146 DOI: 10.3389/fimmu.2024.1375413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 05/20/2024] [Indexed: 06/21/2024] Open
Abstract
Introduction Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with unacceptably low cure rates occurring often in patients with neurofibromatosis 1 defects. To investigate oncolytic Herpes Simplex Virus (oHSV) as an immunotherapeutic approach, we compared viral replication, functional activity, and immune response between unarmed and interleukin 12 (IL-12)-armed oncolytic viruses in virus-permissive (B109) and -resistant (67C-4) murine MPNSTs. Methods This study compared two attenuated IL-12-oHSVs with γ134.5 gene deletions (Δγ134.5) and the same transgene expression cassette. The primary difference in the IL-12-oHSVs was in their ability to counter the translational arrest response in infected cells. Unlike M002 (Δγ134.5, mIL-12), C002 (Δγ134.5, mIL-12, IRS1) expresses an HCMV IRS1 gene and evades dsRNA activated translational arrest in infected cells. Results and discussion Our results show that oHSV replication and gene expression results in vitro were not predictive of oHSV direct oncolytic activity in vivo. Tumors that supported viral replication in cell culture studies resisted viral replication by both oHSVs and restricted M002 transgene expression in vivo. Furthermore, two IL-12-oHSVs with equivalent transcriptional activity differed in IL-12 protein production in vivo, and the differences in IL-12 protein levels were reflected in immune infiltrate activity changes as well as tumor growth suppression differences between the IL-12-oHSVs. C002-treated tumors exhibited sustained IL-12 production with improved dendritic cells, monocyte-macrophage activity (MHCII, CD80/CD86 upregulation) and a polyfunctional Th1-cell response in the tumor infiltrates. Conclusion These results suggest that transgene protein production differences between oHSVs in vivo, in addition to replication differences, can impact OV-therapeutic activity.
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Affiliation(s)
- Yeaseul Kim
- Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
| | - Uksha Saini
- Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
| | - Doyeon Kim
- Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
| | - Ilse Hernandez-Aguirre
- Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
- Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, United States
- College of Medicine, The Ohio State University, Columbus, OH, United States
| | - Jack Hedberg
- Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
- Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, United States
- College of Medicine, The Ohio State University, Columbus, OH, United States
| | - Alexia Martin
- Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
- Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, United States
- College of Medicine, The Ohio State University, Columbus, OH, United States
| | - Xiaokui Mo
- Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, United States
| | - Timothy P. Cripe
- Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, United States
| | - James Markert
- Department of Neurosurgery, The University of Alabama at Birmingham, Birmingham, AL, United States
| | - Kevin A. Cassady
- Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, United States
- Department of Pediatrics, Division of Pediatric Infectious Diseases, Nationwide Children’s Hospital, Columbus, OH, United States
| | - Ravi Dhital
- Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
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15
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Finn CM, McKinstry KK. Ex Pluribus Unum: The CD4 T Cell Response against Influenza A Virus. Cells 2024; 13:639. [PMID: 38607077 PMCID: PMC11012043 DOI: 10.3390/cells13070639] [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: 02/26/2024] [Revised: 04/01/2024] [Accepted: 04/03/2024] [Indexed: 04/13/2024] Open
Abstract
Current Influenza A virus (IAV) vaccines, which primarily aim to generate neutralizing antibodies against the major surface proteins of specific IAV strains predicted to circulate during the annual 'flu' season, are suboptimal and are characterized by relatively low annual vaccine efficacy. One approach to improve protection is for vaccines to also target the priming of virus-specific T cells that can protect against IAV even in the absence of preexisting neutralizing antibodies. CD4 T cells represent a particularly attractive target as they help to promote responses by other innate and adaptive lymphocyte populations and can also directly mediate potent effector functions. Studies in murine models of IAV infection have been instrumental in moving this goal forward. Here, we will review these findings, focusing on distinct subsets of CD4 T cell effectors that have been shown to impact outcomes. This body of work suggests that a major challenge for next-generation vaccines will be to prime a CD4 T cell population with the same spectrum of functional diversity generated by IAV infection. This goal is encapsulated well by the motto 'ex pluribus unum': that an optimal CD4 T cell response comprises many individual specialized subsets responding together.
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Affiliation(s)
| | - K. Kai McKinstry
- Immunity and Pathogenesis Division, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA;
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16
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Sun W, Hughes EP, Kim H, Perovanovic J, Charley KR, Perkins B, Du J, Ibarra A, Syage AR, Hale JS, Williams MA, Tantin D. OCA-B/Pou2af1 is sufficient to promote CD4 + T cell memory and prospectively identifies memory precursors. Proc Natl Acad Sci U S A 2024; 121:e2309153121. [PMID: 38386711 PMCID: PMC10907311 DOI: 10.1073/pnas.2309153121] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 01/12/2024] [Indexed: 02/24/2024] Open
Abstract
The molecular mechanisms leading to the establishment of immunological memory are inadequately understood, limiting the development of effective vaccines and durable antitumor immune therapies. Here, we show that ectopic OCA-B expression is sufficient to improve antiviral memory recall responses, while having minimal effects on primary effector responses. At peak viral response, short-lived effector T cell populations are expanded but show increased Gadd45b and Socs2 expression, while memory precursor effector cells show increased expression of Bcl2, Il7r, and Tcf7 on a per-cell basis. Using an OCA-B mCherry reporter mouse line, we observe high OCA-B expression in CD4+ central memory T cells. We show that early in viral infection, endogenously elevated OCA-B expression prospectively identifies memory precursor cells with increased survival capability and memory recall potential. Cumulatively, the results demonstrate that OCA-B is both necessary and sufficient to promote CD4 T cell memory in vivo and can be used to prospectively identify memory precursor cells.
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Affiliation(s)
- Wenxiang Sun
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT84112
- Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT84112
| | - Erik P. Hughes
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT84112
- Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT84112
| | - Heejoo Kim
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT84112
- Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT84112
| | - Jelena Perovanovic
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT84112
- Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT84112
| | - Krystal R. Charley
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT84112
- Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT84112
| | - Bryant Perkins
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT84112
| | - Junhong Du
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT84112
- Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT84112
| | - Andrea Ibarra
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT84112
- Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT84112
| | - Amber R. Syage
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT84112
- Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT84112
| | - J. Scott Hale
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT84112
| | - Matthew A. Williams
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT84112
- Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT84112
| | - Dean Tantin
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT84112
- Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT84112
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17
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Raineri D, Abreu H, Vilardo B, Kustrimovic N, Venegoni C, Cappellano G, Chiocchetti A. Deep Flow Cytometry Unveils Distinct Immune Cell Subsets in Inducible T Cell Co-Stimulator Ligand (ICOSL)- and ICOS-Knockout Mice during Experimental Autoimmune Encephalomyelitis. Int J Mol Sci 2024; 25:2509. [PMID: 38473756 DOI: 10.3390/ijms25052509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 02/10/2024] [Accepted: 02/16/2024] [Indexed: 03/14/2024] Open
Abstract
The inducible T cell co-stimulator ligand (ICOSL), expressed by antigen presenting cells, binds to the inducible T cell co-stimulator (ICOS) on activated T cells. Improper function of the ICOS/ICOSL pathway has been implicated in several autoimmune diseases, including multiple sclerosis (MS). Previous studies showed that ICOS-knockout (KO) mice exhibit severe experimental autoimmune encephalomyelitis (EAE), the animal model of MS, but data on ICOSL deficiency are not available. In our study, we explored the impact of both ICOS and ICOSL deficiencies on MOG35-55 -induced EAE and its associated immune cell dynamics by employing ICOSL-KO and ICOS-KO mice with a C57BL/6J background. During EAE resolution, MOG-driven cytokine levels and the immunophenotype of splenocytes were evaluated by ELISA and multiparametric flow cytometry, respectively. We found that both KO mice exhibited an overlapping and more severe EAE compared to C57BL/6J mice, corroborated by a reduction in memory/regulatory T cell subsets and interleukin (IL-)17 levels. It is noteworthy that an unsupervised analysis showed that ICOSL deficiency modifies the immune response in an original way, by affecting T central and effector memory (TCM, TEM), long-lived CD4+ TEM cells, and macrophages, compared to ICOS-KO and C57BL/6J mice, suggesting a role for other binding partners to ICOSL in EAE development, which deserves further study.
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Affiliation(s)
- Davide Raineri
- Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, University of Eastern Piedmont, 28100 Novara, Italy
- Center for Translational Research on Autoimmune and Allergic Disease-CAAD, University of Eastern Piedmont, 28100 Novara, Italy
| | - Hugo Abreu
- Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, University of Eastern Piedmont, 28100 Novara, Italy
- Center for Translational Research on Autoimmune and Allergic Disease-CAAD, University of Eastern Piedmont, 28100 Novara, Italy
| | - Beatrice Vilardo
- Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, University of Eastern Piedmont, 28100 Novara, Italy
- Center for Translational Research on Autoimmune and Allergic Disease-CAAD, University of Eastern Piedmont, 28100 Novara, Italy
| | - Natasa Kustrimovic
- Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, University of Eastern Piedmont, 28100 Novara, Italy
- Center for Translational Research on Autoimmune and Allergic Disease-CAAD, University of Eastern Piedmont, 28100 Novara, Italy
| | - Chiara Venegoni
- Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, University of Eastern Piedmont, 28100 Novara, Italy
- Center for Translational Research on Autoimmune and Allergic Disease-CAAD, University of Eastern Piedmont, 28100 Novara, Italy
| | - Giuseppe Cappellano
- Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, University of Eastern Piedmont, 28100 Novara, Italy
- Center for Translational Research on Autoimmune and Allergic Disease-CAAD, University of Eastern Piedmont, 28100 Novara, Italy
| | - Annalisa Chiocchetti
- Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases-IRCAD, University of Eastern Piedmont, 28100 Novara, Italy
- Center for Translational Research on Autoimmune and Allergic Disease-CAAD, University of Eastern Piedmont, 28100 Novara, Italy
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18
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Charley KR, Ramstead AG, Matous JG, Kumaki Y, Sircy LM, Hale JS, Williams MA. Effector-Phase IL-2 Signals Drive Th1 Effector and Memory Responses Dependently and Independently of TCF-1. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:586-595. [PMID: 38149929 PMCID: PMC10872735 DOI: 10.4049/jimmunol.2300570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 12/03/2023] [Indexed: 12/28/2023]
Abstract
Following viral infection, CD4+ T cell differentiation is tightly regulated by cytokines and TCR signals. Although most activated CD4+ T cells express IL-2Rα after lymphocytic choriomeningtis virus infection, by day 3 postinfection, only half of activated T cells maintain expression. IL-2Rα at this time point distinguishes precursors for terminally differentiated Th1 cells (IL-2Rαhi) from precursors for Tfh cells and memory T cells (IL-2Rαlo) and is linked to strong TCR signals. In this study, we test whether TCR-dependent IL-2 links the TCR to CD4+ T cell differentiation. We employ a mixture of anti-IL-2 Abs to neutralize IL-2 throughout the primary CD4+ T cell response to lymphocytic choriomeningitis virus infection in mice or only after the establishment of lineage-committed effector cells (day 3 postinfection). We report that IL-2 signals drive the formation of Th1 precursor cells in the early stages of the immune response and sustain Th1 responses during its later stages (after day 3). Effector-stage IL-2 also shapes the composition and function of resulting CD4+ memory T cells. Although IL-2 has been shown previously to drive Th1 differentiation by reducing the activity of the transcriptional repressor TCF-1, we found that sustained IL-2 signals were still required to drive optimal Th1 differentiation even in the absence of TCF-1. Therefore, we concluded that IL-2 plays a central role throughout the effector phase in regulating the balance between Th1 and Tfh effector and memory cells via mechanisms that are both dependent and independent of its role in modulating TCF-1 activity.
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Affiliation(s)
- Krystal R. Charley
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84112
- Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah 84112
| | - Andrew G. Ramstead
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84112
- Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah 84112
| | - Joseph G. Matous
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84112
- Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah 84112
| | - Yohichi Kumaki
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84112
- Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah 84112
| | - Linda M. Sircy
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84112
| | - J. Scott Hale
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84112
| | - Matthew A. Williams
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84112
- Huntsman Cancer Institute, University of Utah Health, Salt Lake City, Utah 84112
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19
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Sun R, Lei C, Xu Z, Gu X, Huang L, Chen L, Tan Y, Peng M, Yaddanapudi K, Siskind L, Kong M, Mitchell R, Yan J, Deng Z. Neutral ceramidase regulates breast cancer progression by metabolic programming of TREM2-associated macrophages. Nat Commun 2024; 15:966. [PMID: 38302493 PMCID: PMC10834982 DOI: 10.1038/s41467-024-45084-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 01/15/2024] [Indexed: 02/03/2024] Open
Abstract
The tumor microenvironment is reprogrammed by cancer cells and participates in all stages of tumor progression. Neutral ceramidase is a key regulator of ceramide, the central intermediate in sphingolipid metabolism. The contribution of neutral ceramidase to the reprogramming of the tumor microenvironment is not well understood. Here, we find that deletion of neutral ceramidase in multiple breast cancer models in female mice accelerates tumor growth. Our result show that Ly6C+CD39+ tumor-infiltrating CD8 T cells are enriched in the tumor microenvironment and display an exhausted phenotype. Deletion of myeloid neutral ceramidase in vivo and in vitro induces exhaustion in tumor-infiltrating Ly6C+CD39+CD8+ T cells. Mechanistically, myeloid neutral ceramidase is required for the generation of lipid droplets and for the induction of lipolysis, which generate fatty acids for fatty-acid oxidation and orchestrate macrophage metabolism. Metabolite ceramide leads to reprogramming of macrophages toward immune suppressive TREM2+ tumor associated macrophages, which promote CD8 T cells exhaustion.
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Affiliation(s)
- Rui Sun
- Department of Surgery, Division of Immunotherapy, University of Louisville, Louisville, KY, USA
- Brown Cancer Center, University of Louisville, Louisville, KY, KY40202, USA
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, P. R. China
| | - Chao Lei
- Department of Surgery, Division of Immunotherapy, University of Louisville, Louisville, KY, USA
- Brown Cancer Center, University of Louisville, Louisville, KY, KY40202, USA
| | - Zhishan Xu
- Department of Surgery, Division of Immunotherapy, University of Louisville, Louisville, KY, USA
- Brown Cancer Center, University of Louisville, Louisville, KY, KY40202, USA
| | - Xuemei Gu
- Brown Cancer Center, University of Louisville, Louisville, KY, KY40202, USA
| | - Liu Huang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, P.R. China
| | - Liang Chen
- Department of Surgery, Division of Immunotherapy, University of Louisville, Louisville, KY, USA
- Brown Cancer Center, University of Louisville, Louisville, KY, KY40202, USA
| | - Yi Tan
- Department of Pediatrics and Pediatric Research Institute, University of Louisville, Louisville, KY, USA
| | - Min Peng
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, P. R. China
| | - Kavitha Yaddanapudi
- Department of Surgery, Division of Immunotherapy, University of Louisville, Louisville, KY, USA
- Brown Cancer Center, University of Louisville, Louisville, KY, KY40202, USA
| | - Leah Siskind
- Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY, 40202, USA
| | - Maiying Kong
- Brown Cancer Center, University of Louisville, Louisville, KY, KY40202, USA
- Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, KY, USA
| | - Robert Mitchell
- Department of Surgery, Division of Immunotherapy, University of Louisville, Louisville, KY, USA
- Brown Cancer Center, University of Louisville, Louisville, KY, KY40202, USA
| | - Jun Yan
- Department of Surgery, Division of Immunotherapy, University of Louisville, Louisville, KY, USA
- Brown Cancer Center, University of Louisville, Louisville, KY, KY40202, USA
| | - Zhongbin Deng
- Department of Surgery, Division of Immunotherapy, University of Louisville, Louisville, KY, USA.
- Brown Cancer Center, University of Louisville, Louisville, KY, KY40202, USA.
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20
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Macalinao ML, Inoue SI, Tsogtsaikhan S, Matsumoto H, Bayarsaikhan G, Jian JY, Kimura K, Yasumizu Y, Inoue T, Yoshida H, Hafalla J, Kimura D, Yui K. IL-27 produced during acute malaria infection regulates Plasmodium-specific memory CD4 + T cells. EMBO Mol Med 2023; 15:e17713. [PMID: 37855243 DOI: 10.15252/emmm.202317713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 09/27/2023] [Accepted: 09/28/2023] [Indexed: 10/20/2023] Open
Abstract
Malaria infection elicits both protective and pathogenic immune responses, and IL-27 is a critical cytokine that regulate effector responses during infection. Here, we identified a critical window of CD4+ T cell responses that is targeted by IL-27. Neutralization of IL-27 during acute infection with Plasmodium chabaudi expanded specific CD4+ T cells, which were maintained at high levels thereafter. In the chronic phase, Plasmodium-specific CD4+ T cells in IL-27-neutralized mice consisted mainly of CD127+ KLRG1- and CD127- KLRG1+ subpopulations that displayed distinct cytokine production, proliferative capacity, and are maintained in a manner independent of active infection. Single-cell RNA-seq analysis revealed that these CD4+ T cell subsets formed independent clusters that express unique Th1-type genes. These IL-27-neutralized mice exhibited enhanced cellular and humoral immune responses and protection. These findings demonstrate that IL-27, which is produced during the acute phase of malaria infection, inhibits the development of unique Th1 memory precursor CD4+ T cells, suggesting potential implications for the development of vaccines and other strategic interventions.
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Affiliation(s)
- Maria Lourdes Macalinao
- School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan
- Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK
| | - Shin-Ichi Inoue
- Division of Immunology, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Sanjaadorj Tsogtsaikhan
- Division of Immunology, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Hirotaka Matsumoto
- School of Information and Data Sciences, Nagasaki University, Nagasaki, Japan
| | - Ganchimeg Bayarsaikhan
- Division of Immunology, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Jiun-Yu Jian
- Division of Immunology, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Kazumi Kimura
- Division of Immunology, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Yoshiaki Yasumizu
- Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, Japan
| | - Tsuyoshi Inoue
- Department of Physiology of Visceral Function and Body Fluid, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Hiroki Yoshida
- Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan
| | - Julius Hafalla
- Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK
| | - Daisuke Kimura
- Division of Immunology, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Katsuyuki Yui
- School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan
- Division of Immunology, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
- Shionogi Global Infectious Diseases Division, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan
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21
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Sandner L, Alteneder M, Rica R, Woller B, Sala E, Frey T, Tosevska A, Zhu C, Madern M, Khan M, Hoffmann P, Schebesta A, Taniuchi I, Bonelli M, Schmetterer K, Iannacone M, Kuka M, Ellmeier W, Sakaguchi S, Herbst R, Boucheron N. The guanine nucleotide exchange factor Rin-like controls Tfh cell differentiation via CD28 signaling. J Exp Med 2023; 220:e20221466. [PMID: 37703004 PMCID: PMC10499045 DOI: 10.1084/jem.20221466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 06/07/2023] [Accepted: 08/21/2023] [Indexed: 09/14/2023] Open
Abstract
T follicular helper (Tfh) cells are essential for the development of germinal center B cells and high-affinity antibody-producing B cells in humans and mice. Here, we identify the guanine nucleotide exchange factor (GEF) Rin-like (Rinl) as a negative regulator of Tfh generation. Loss of Rinl leads to an increase of Tfh in aging, upon in vivo immunization and acute LCMV Armstrong infection in mice, and in human CD4+ T cell in vitro cultures. Mechanistically, adoptive transfer experiments using WT and Rinl-KO naïve CD4+ T cells unraveled T cell-intrinsic GEF-dependent functions of Rinl. Further, Rinl regulates CD28 internalization and signaling, thereby shaping CD4+ T cell activation and differentiation. Thus, our results identify the GEF Rinl as a negative regulator of global Tfh differentiation in an immunological context and species-independent manner, and furthermore, connect Rinl with CD28 internalization and signaling pathways in CD4+ T cells, demonstrating for the first time the importance of endocytic processes for Tfh differentiation.
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Affiliation(s)
- Lisa Sandner
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Marlis Alteneder
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Ramona Rica
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Barbara Woller
- Center for Brain Research, Medical University of Vienna, Vienna, Austria
| | - Eleonora Sala
- School of Medicine, Vita-Salute San Raffaele University and Division of Immunology, Transplantation, and Infectious Diseases, Istituto di Ricovero e Cura a Carettere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy
| | - Tobias Frey
- Department of Laboratory Medicine, Klinisches Institut für Labormedizin (KILM), Anna Spiegel Research Building, Medical University of Vienna, Vienna, Austria
| | - Anela Tosevska
- Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria
| | - Ci Zhu
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Moritz Madern
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Matarr Khan
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Pol Hoffmann
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Alexandra Schebesta
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Ichiro Taniuchi
- Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
| | - Michael Bonelli
- Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria
| | - Klaus Schmetterer
- Department of Laboratory Medicine, Klinisches Institut für Labormedizin (KILM), Anna Spiegel Research Building, Medical University of Vienna, Vienna, Austria
| | - Matteo Iannacone
- School of Medicine, Vita-Salute San Raffaele University and Division of Immunology, Transplantation, and Infectious Diseases, Istituto di Ricovero e Cura a Carettere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy
- Experimental Imaging Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy
| | - Mirela Kuka
- School of Medicine, Vita-Salute San Raffaele University and Division of Immunology, Transplantation, and Infectious Diseases, Istituto di Ricovero e Cura a Carettere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy
| | - Wilfried Ellmeier
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Shinya Sakaguchi
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Ruth Herbst
- Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Nicole Boucheron
- Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
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22
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Zaini A, Dalit L, Sheikh AA, Zhang Y, Thiele D, Runting J, Rodrigues G, Ng J, Bramhall M, Scheer S, Hailes L, Groom JR, Good-Jacobson KL, Zaph C. Heterogeneous Tfh cell populations that develop during enteric helminth infection predict the quality of type 2 protective response. Mucosal Immunol 2023; 16:642-657. [PMID: 37392971 DOI: 10.1016/j.mucimm.2023.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 06/19/2023] [Accepted: 06/24/2023] [Indexed: 07/03/2023]
Abstract
T follicular helper (Tfh) cells are an important component of germinal center (GC)-mediated humoral immunity. Yet, how a chronic type 1 versus protective type 2 helminth infection modulates Tfh-GC responses remains poorly understood. Here, we employ the helminth Trichuris muris model and demonstrate that Tfh cell phenotypes and GC are differentially regulated in acute versus chronic infection. The latter failed to induce Tfh-GC B cell responses, with Tfh cells expressing Τ-bet and interferon-γ. In contrast, interleukin-4-producing Tfh cells dominate responses to an acute, resolving infection. Heightened expression and increased chromatin accessibility of T helper (Th)1- and Th2 cell-associated genes are observed in chronic and acute induced Tfh cells, respectively. Blockade of the Th1 cell response by T-cell-intrinsic T-bet deletion promoted Tfh cell expansion during chronic infection, pointing to a correlation between a robust Tfh cell response and protective immunity to parasites. Finally, blockade of Tfh-GC interactions impaired type 2 immunity, revealing the critical protective role of GC-dependent Th2-like Tfh cell responses during acute infection. Collectively, these results provide new insights into the protective roles of Tfh-GC responses and identify distinct transcriptional and epigenetic features of Tfh cells that emerge during resolving or chronic T. muris infection.
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Affiliation(s)
- Aidil Zaini
- Immunity Program, Monash Biomedicine Discovery Institute, Clayton, Australia; Department of Biochemistry and Molecular Biology, Clayton, Australia; Department of Immunology and Pathology, Central Clinical School, Monash University, The Alfred Centre, Melbourne, Australia
| | - Lennard Dalit
- Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
| | - Amania A Sheikh
- Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
| | - Yan Zhang
- Immunity Program, Monash Biomedicine Discovery Institute, Clayton, Australia; Department of Biochemistry and Molecular Biology, Clayton, Australia
| | - Daniel Thiele
- Immunity Program, Monash Biomedicine Discovery Institute, Clayton, Australia; Department of Microbiology, Monash University, Clayton, Australia
| | - Jessica Runting
- Immunity Program, Monash Biomedicine Discovery Institute, Clayton, Australia; Department of Biochemistry and Molecular Biology, Clayton, Australia
| | - Grace Rodrigues
- Immunity Program, Monash Biomedicine Discovery Institute, Clayton, Australia; Department of Biochemistry and Molecular Biology, Clayton, Australia
| | - Judy Ng
- Immunity Program, Monash Biomedicine Discovery Institute, Clayton, Australia; Department of Biochemistry and Molecular Biology, Clayton, Australia
| | - Michael Bramhall
- Immunity Program, Monash Biomedicine Discovery Institute, Clayton, Australia; Department of Biochemistry and Molecular Biology, Clayton, Australia; Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia
| | - Sebastian Scheer
- Immunity Program, Monash Biomedicine Discovery Institute, Clayton, Australia; Department of Biochemistry and Molecular Biology, Clayton, Australia
| | - Lauren Hailes
- Immunity Program, Monash Biomedicine Discovery Institute, Clayton, Australia; Department of Biochemistry and Molecular Biology, Clayton, Australia
| | - Joanna R Groom
- Division of Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
| | - Kim L Good-Jacobson
- Immunity Program, Monash Biomedicine Discovery Institute, Clayton, Australia; Department of Biochemistry and Molecular Biology, Clayton, Australia.
| | - Colby Zaph
- Immunity Program, Monash Biomedicine Discovery Institute, Clayton, Australia; Department of Biochemistry and Molecular Biology, Clayton, Australia.
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23
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Cui C, Craft J, Joshi NS. T follicular helper cells in cancer, tertiary lymphoid structures, and beyond. Semin Immunol 2023; 69:101797. [PMID: 37343412 DOI: 10.1016/j.smim.2023.101797] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 06/09/2023] [Accepted: 06/15/2023] [Indexed: 06/23/2023]
Abstract
With the emergence and success of checkpoint blockade immunotherapy, immuno-oncology has primarily focused on CD8 T cells, whose cytotoxic programs directly target tumor cells. However, the limited response rate of current immunotherapy regimens has prompted investigation into other types of tumor-infiltrating immune cells, such as CD4 T cells and B cells, and how they interact with CD8 T cells in a coordinated network. Recent studies have demonstrated the potential therapeutic benefits of CD4 T follicular helper (TFH) cells and B cells in cancer, highlighting the important role of their crosstalk and interactions with other immune cell components in the tumor microenvironment. These interactions also occur in tumor-associated tertiary lymphoid structures (TLS), which resemble secondary lymphoid organs (SLOs) with orchestrated vascular, chemokine, and cellular infrastructures that support the developmental pathways of functional immune cells. In this review, we discuss recent breakthroughs on TFH biology and T cell-B cell interactions in tumor immunology, and their potential as novel therapeutic targets to advance cancer treatment.
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Affiliation(s)
- Can Cui
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Joseph Craft
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Internal Medicine (Rheumatology, Allergy and Immunology), Yale University School of Medicine, New Haven, CT 06520, USA.
| | - Nikhil S Joshi
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
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24
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Zhou P, Cao C, Ji T, Zheng T, Dai Y, Liu M, Jiang J, Sun D, Bai Z, Lu X, Gong F. Longitudinal analysis of memory Tfh cells and antibody response following CoronaVac vaccination. JCI Insight 2023; 8:e168437. [PMID: 37384407 PMCID: PMC10445683 DOI: 10.1172/jci.insight.168437] [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: 01/03/2023] [Accepted: 06/28/2023] [Indexed: 07/01/2023] Open
Abstract
The inactivated vaccine CoronaVac is one of the most widely used COVID-19 vaccines globally. However, the longitudinal evolution of the immune response induced by CoronaVac remains elusive compared with other vaccine platforms. Here, we recruited 88 healthy individuals who received 3 doses of CoronaVac vaccine. We longitudinally evaluated their polyclonal and antigen-specific CD4+ T cells and neutralizing antibody response after receiving each dose of vaccine for over 300 days. Both the second and third doses of vaccine induced robust spike-specific neutralizing antibodies, with a third vaccine further increasing the overall magnitude of antibody response and neutralization against Omicron sublineages B.1.1.529, BA.2, BA.4/BA.5, and BA.2.75.2. Spike-specific CD4+ T cells and circulating T follicular helper (cTfh) cells were markedly increased by the second and third dose of CoronaVac vaccine, accompanied by altered composition of functional cTfh cell subsets with distinct effector and memory potential. Additionally, cTfh cells were positively correlated with neutralizing antibody titers. Our results suggest that CoronaVac vaccine-induced spike-specific T cells are capable of supporting humoral immunity for long-term immune protection.
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Affiliation(s)
- Pengcheng Zhou
- Department of Laboratory Medicine, Affiliated Hospital of Jiangnan University, Wuxi, China
- The University of Queensland Diamantina Institute, Brisbane, Queensland, Australia
| | - Cheng Cao
- Department of Laboratory Medicine, Affiliated Hospital of Jiangnan University, Wuxi, China
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Tuo Ji
- Department of Laboratory Medicine, Affiliated Hospital of Jiangnan University, Wuxi, China
- Department of Central Laboratory, The Second People’s Hospital of Lianyungang City (Cancer Hospital of Lianyungang), Lianyungang, China
| | - Ting Zheng
- Hospital for Special Surgery, Weill Cornell Medical College, New York, New York, USA
| | - Yaping Dai
- Department of Laboratory Medicine, The Fifth People’s Hospital of Wuxi, Wuxi, China
| | - Min Liu
- School of Biotechnology, Jiangnan University, Wuxi, China
| | - Junfeng Jiang
- Department of Laboratory Medicine, Affiliated Hospital of Jiangnan University, Wuxi, China
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Daoqi Sun
- Department of Laboratory Medicine, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Zhonghu Bai
- School of Biotechnology, Jiangnan University, Wuxi, China
| | - Xiaojie Lu
- Department of Laboratory Medicine, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Fang Gong
- Department of Laboratory Medicine, Affiliated Hospital of Jiangnan University, Wuxi, China
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25
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Brandi J, Wiethe C, Riehn M, Jacobs T. OMIP-93: A 41-color high parameter panel to characterize various co-inhibitory molecules and their ligands in the lymphoid and myeloid compartment in mice. Cytometry A 2023; 103:624-630. [PMID: 37219006 DOI: 10.1002/cyto.a.24740] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 03/03/2023] [Accepted: 05/04/2023] [Indexed: 05/24/2023]
Abstract
This 41-color panel has been designed to characterize both the lymphoid and the myeloid compartments in mice. The number of immune cells isolated from organs is often low, whilst an increasing number of factors need to be analyzed to gain a deeper understanding of the complexity of an immune response. With a focus on T cells, their activation and differentiation status, as well as their expression of several co-inhibitory and effector molecules, this panel also allows the analysis of ligands to these co-inhibitory molecules on antigen-presenting cells. This panel enables deep phenotypic characterization of CD4+ and CD8+ T cells, regulatory T cells, γδ T cells, NK T cells, B cells, NK cells, monocytes, macrophages, dendritic cells, and neutrophils. Whilst previous panels have focused on these topics individually, this is the first panel to enable simultaneous analysis of these compartments, thus enabling a comprehensive analysis with a limited number of immune cells/sample size. This panel is designed to analyze and compare the immune response in different mouse models of infectious diseases, but can also be extended to other disease models, for example tumors or autoimmune diseases. Here, we apply this panel to C57BL/6 mice infected with Plasmodium berghei ANKA, a mouse model of cerebral malaria.
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Affiliation(s)
- Johannes Brandi
- Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Carsten Wiethe
- Marketing and Scientific Application, BioLegend Inc, San Diego, California, USA
| | - Mathias Riehn
- Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Thomas Jacobs
- Protozoa Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
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26
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Depew CE, Nguyen AT, Franke MC, Calderon J, Sciammas R, McSorley SJ. Cutting Edge: Optimal Formation of Hepatic Tissue-Resident Memory CD4 T Cells Requires T-bet Regulation of CD18. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 211:180-185. [PMID: 37283516 PMCID: PMC10330511 DOI: 10.4049/jimmunol.2300017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 05/15/2023] [Indexed: 06/08/2023]
Abstract
CD4 tissue-resident memory T cells (TRMs) allow robust protection of barrier surfaces against pathogens. We investigated the role of T-bet in the formation of liver CD4 TRMs using mouse models. T-bet-deficient CD4 T cells did not efficiently form liver TRMs when compared with wild-type (WT). In addition, ectopic expression of T-bet enhanced the formation of liver CD4 TRMs, but only when in competition with WT CD4 T cells. Liver TRMs also expressed higher levels of CD18, which was T-bet dependent. The WT competitive advantage was blocked by Ab neutralization of CD18. Taken together, our data show that activated CD4 T cells compete for entry to liver niches via T-bet-induced expression of CD18, allowing TRM precursors to access subsequent hepatic maturation signals. These findings uncover an essential role for T-bet in liver TRM CD4 formation and suggest targeted enhancement of this pathway could increase the efficacy of vaccines that require hepatic TRMs.
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Affiliation(s)
- Claire E Depew
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA
| | - Alana T Nguyen
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA
| | - Marissa C Franke
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA
| | - Jesica Calderon
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA
| | - Roger Sciammas
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA
| | - Stephen J McSorley
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA
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27
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Zhu F, McMonigle RJ, Schroeder AR, Xia X, Figge D, Greer BD, González-Avalos E, Sialer DO, Wang YH, Chandler KM, Getzler AJ, Brown ER, Xiao C, Kutsch O, Harada Y, Pipkin ME, Hu H. Spatiotemporal resolution of germinal center Tfh cell differentiation and divergence from central memory CD4 + T cell fate. Nat Commun 2023; 14:3611. [PMID: 37330549 PMCID: PMC10276816 DOI: 10.1038/s41467-023-39299-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 05/27/2023] [Indexed: 06/19/2023] Open
Abstract
Follicular helper T (Tfh) cells are essential for germinal center (GC) B cell responses. However, it is not clear which PD-1+CXCR5+Bcl6+CD4+ T cells will differentiate into PD-1hiCXCR5hiBcl6hi GC-Tfh cells and how GC-Tfh cell differentiation is regulated. Here, we report that the sustained Tigit expression in PD-1+CXCR5+CD4+ T cells marks the precursor Tfh (pre-Tfh) to GC-Tfh transition, whereas Tigit-PD-1+CXCR5+CD4+ T cells upregulate IL-7Rα to become CXCR5+CD4+ T memory cells with or without CCR7. We demonstrate that pre-Tfh cells undergo substantial further differentiation at the transcriptome and chromatin accessibility levels to become GC-Tfh cells. The transcription factor c-Maf appears critical in governing the pre-Tfh to GC-Tfh transition, and we identify Plekho1 as a stage-specific downstream factor regulating the GC-Tfh competitive fitness. In summary, our work identifies an important marker and regulatory mechanism of PD-1+CXCR5+CD4+ T cells during their developmental choice between memory T cell fate and GC-Tfh cell differentiation.
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Affiliation(s)
- Fangming Zhu
- Department of Microbiology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Ryan J McMonigle
- Department of Microbiology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Andrew R Schroeder
- Department of Microbiology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Xianyou Xia
- Department of Microbiology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - David Figge
- Department of Pathology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Braxton D Greer
- Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Edahí González-Avalos
- Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, 92037, USA
| | - Diego O Sialer
- Department of Microbiology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Yin-Hu Wang
- Department of Microbiology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Kelly M Chandler
- Department of Microbiology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Adam J Getzler
- Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, 33458, USA
| | - Emily R Brown
- Department of Microbiology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Changchun Xiao
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Olaf Kutsch
- Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Yohsuke Harada
- Faculty of Pharmaceutical Sciences, Tokyo, University of Science, Chiba, 278-8510, Japan
| | - Matthew E Pipkin
- Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, 33458, USA
| | - Hui Hu
- Department of Microbiology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
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28
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Abstract
Specialized subpopulations of CD4+ T cells survey major histocompatibility complex class II-peptide complexes to control phagosomal infections, help B cells, regulate tissue homeostasis and repair or perform immune regulation. Memory CD4+ T cells are positioned throughout the body and not only protect the tissues from reinfection and cancer, but also participate in allergy, autoimmunity, graft rejection and chronic inflammation. Here we provide updates on our understanding of the longevity, functional heterogeneity, differentiation, plasticity, migration and human immunodeficiency virus reservoirs as well as key technological advances that are facilitating the characterization of memory CD4+ T cell biology.
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Affiliation(s)
- Marco Künzli
- Center for Immunology, Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN, USA
| | - David Masopust
- Center for Immunology, Department of Microbiology and Immunology, University of Minnesota, Minneapolis, MN, USA.
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29
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Harbour JC, Abdelbary M, Schell JB, Fancher SP, McLean JJ, Nappi TJ, Liu S, Nice TJ, Xia Z, Früh K, Nolz JC. T helper 1 effector memory CD4 + T cells protect the skin from poxvirus infection. Cell Rep 2023; 42:112407. [PMID: 37083328 PMCID: PMC10281076 DOI: 10.1016/j.celrep.2023.112407] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 03/15/2023] [Accepted: 04/04/2023] [Indexed: 04/22/2023] Open
Abstract
Poxvirus infections of the skin are a recent emerging public health concern, yet the mechanisms that mediate protective immunity against these viral infections remain largely unknown. Here, we show that T helper 1 (Th1) memory CD4+ T cells are necessary and sufficient to provide complete and broad protection against poxvirus skin infections, whereas memory CD8+ T cells are dispensable. Core 2 O-glycan-synthesizing Th1 effector memory CD4+ T cells rapidly infiltrate the poxvirus-infected skin microenvironment and produce interferon γ (IFNγ) in an antigen-dependent manner, causing global changes in gene expression to promote anti-viral immunity. Keratinocytes express IFN-stimulated genes, upregulate both major histocompatibility complex (MHC) class I and MHC class II antigen presentation in an IFNγ-dependent manner, and require IFNγ receptor (IFNγR) signaling and MHC class II expression for memory CD4+ T cells to protect the skin from poxvirus infection. Thus, Th1 effector memory CD4+ T cells exhibit potent anti-viral activity within the skin, and keratinocytes are the key targets of IFNγ necessary for preventing poxvirus infection of the epidermis.
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Affiliation(s)
- Jake C Harbour
- Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, USA
| | - Mahmoud Abdelbary
- Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, USA
| | - John B Schell
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, USA
| | - Samantha P Fancher
- Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, USA
| | - Jack J McLean
- Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, USA
| | - Taylen J Nappi
- Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, USA
| | - Susan Liu
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA
| | - Timothy J Nice
- Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, USA
| | - Zheng Xia
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA
| | - Klaus Früh
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, USA
| | - Jeffrey C Nolz
- Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, USA; Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR, USA; Department of Dermatology, Oregon Health & Science University, Portland, OR, USA.
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30
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Nguyen QP, Takehara KK, Deng TZ, O’Shea S, Heeg M, Omilusik KD, Milner JJ, Quon S, Pipkin ME, Choi J, Crotty S, Goldrath AW. Transcriptional programming of CD4 + T RM differentiation in viral infection balances effector- and memory-associated gene expression. Sci Immunol 2023; 8:eabq7486. [PMID: 37172104 PMCID: PMC10350289 DOI: 10.1126/sciimmunol.abq7486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 04/19/2023] [Indexed: 05/14/2023]
Abstract
After resolution of infection, T cells differentiate into long-lived memory cells that recirculate through secondary lymphoid organs or establish residence in tissues. In contrast to CD8+ tissue-resident memory T cells (TRM), the developmental origins and transcriptional regulation of CD4+ TRM remain largely undefined. Here, we investigated the phenotypic, functional, and transcriptional profiles of CD4+ TRM in the small intestine (SI) responding to acute viral infection, revealing a shared gene expression program and chromatin accessibility profile with circulating TH1 and the progressive acquisition of a mature TRM program. Single-cell RNA sequencing identified heterogeneity among established CD4+ TRM, which were predominantly located in the lamina propria, and revealed a population of cells that coexpressed both effector- and memory-associated genes, including the transcriptional regulators Blimp1, Id2, and Bcl6. TH1-associated Blimp1 and Id2 and TFH-associated Bcl6 were required for early TRM formation and development of a mature TRM population in the SI. These results demonstrate a developmental relationship between TH1 effector cells and the establishment of early TRM, as well as highlighted differences in CD4+ versus CD8+ TRM populations, providing insights into the mechanisms underlying the origins, differentiation, and persistence of CD4+ TRM in response to viral infection.
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Affiliation(s)
- Quynh P Nguyen
- School of Biological Sciences, Department of Molecular Biology, University of California, San Diego, La Jolla, CA
| | - Kennidy K Takehara
- School of Biological Sciences, Department of Molecular Biology, University of California, San Diego, La Jolla, CA
| | - Tianda Z Deng
- School of Biological Sciences, Department of Molecular Biology, University of California, San Diego, La Jolla, CA
| | - Shannon O’Shea
- School of Biological Sciences, Department of Molecular Biology, University of California, San Diego, La Jolla, CA
| | - Maximilian Heeg
- School of Biological Sciences, Department of Molecular Biology, University of California, San Diego, La Jolla, CA
| | - Kyla D Omilusik
- School of Biological Sciences, Department of Molecular Biology, University of California, San Diego, La Jolla, CA
| | - J Justin Milner
- School of Biological Sciences, Department of Molecular Biology, University of California, San Diego, La Jolla, CA
| | - Sara Quon
- School of Biological Sciences, Department of Molecular Biology, University of California, San Diego, La Jolla, CA
| | - Matthew E Pipkin
- Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida
| | - Jinyong Choi
- Department of Microbiology, College of Medicine, The Catholic University of Korea
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA
| | - Shane Crotty
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA
- Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA
| | - Ananda W Goldrath
- School of Biological Sciences, Department of Molecular Biology, University of California, San Diego, La Jolla, CA
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31
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Finn CM, Dhume K, Prokop E, Strutt TM, McKinstry KK. STAT1 Controls the Functionality of Influenza-Primed CD4 T Cells but Therapeutic STAT4 Engagement Maximizes Their Antiviral Impact. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 210:1292-1304. [PMID: 36961447 PMCID: PMC10121883 DOI: 10.4049/jimmunol.2200407] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 02/22/2023] [Indexed: 03/25/2023]
Abstract
It is generally accepted that influenza A virus (IAV) infection promotes a Th1-like CD4 T cell response and that this effector program underlies its protective impact. Canonical Th1 polarization requires cytokine-mediated activation of the transcription factors STAT1 and STAT4 that synergize to maximize the induction of the "master regulator" Th1 transcription factor, T-bet. Here, we determine the individual requirements for these transcription factors in directing the Th1 imprint primed by influenza infection in mice by tracking virus-specific wild-type or T-bet-deficient CD4 T cells in which STAT1 or STAT4 is knocked out. We find that STAT1 is required to protect influenza-primed CD4 T cells from NK cell-mediated deletion and for their expression of hallmark Th1 attributes. STAT1 is also required to prevent type I IFN signals from inhibiting the induction of the Th17 master regulator, Rorγt, in Th17-prone T-bet-/- cells responding to IAV. In contrast, STAT4 expression does not appreciably impact the phenotypic or functional attributes of wild-type or T-bet-/- CD4 T cell responses. However, cytokine-mediated STAT4 activation in virus-specific CD4 T cells enhances their Th1 identity in a T-bet-dependent manner, indicating that influenza infection does not promote maximal Th1 induction. Finally, we show that the T-bet-dependent protective capacity of CD4 T cell effectors against IAV is optimized by engaging both STAT1 and STAT4 during Th1 priming, with important implications for vaccine strategies aiming to generate T cell immunity.
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Affiliation(s)
- Caroline M. Finn
- Burnett School of Biomedical Sciences, Division of Immunity and Pathogenesis, College of Medicine, University of Central Florida, Orlando, FL, USA
| | - Kunal Dhume
- Burnett School of Biomedical Sciences, Division of Immunity and Pathogenesis, College of Medicine, University of Central Florida, Orlando, FL, USA
| | - Emily Prokop
- Burnett School of Biomedical Sciences, Division of Immunity and Pathogenesis, College of Medicine, University of Central Florida, Orlando, FL, USA
| | - Tara M. Strutt
- Burnett School of Biomedical Sciences, Division of Immunity and Pathogenesis, College of Medicine, University of Central Florida, Orlando, FL, USA
| | - K. Kai McKinstry
- Burnett School of Biomedical Sciences, Division of Immunity and Pathogenesis, College of Medicine, University of Central Florida, Orlando, FL, USA
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32
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Seth A, Yokokura Y, Choi JY, Shyer JA, Vidyarthi A, Craft J. AP-1-independent NFAT signaling maintains follicular T cell function in infection and autoimmunity. J Exp Med 2023; 220:e20211110. [PMID: 36820828 PMCID: PMC9998660 DOI: 10.1084/jem.20211110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 09/05/2022] [Accepted: 02/01/2023] [Indexed: 02/24/2023] Open
Abstract
Coordinated gene expression programs enable development and function of T cell subsets. Follicular helper T (Tfh) cells coordinate humoral immune responses by providing selective and instructive cues to germinal center B cells. Here, we show that AP-1-independent NFAT gene expression, a program associated with hyporesponsive T cell states like anergy or exhaustion, is also a distinguishing feature of Tfh cells. NFAT signaling in Tfh cells, maintained by NFAT2 autoamplification, is required for their survival. ICOS signaling upregulates Bcl6 and induces an AP-1-independent NFAT program in primary T cells. Using lupus-prone mice, we demonstrate that genetic disruption or pharmacologic inhibition of NFAT signaling specifically impacts Tfh cell maintenance and leads to amelioration of autoantibody production and renal injury. Our data provide important conceptual and therapeutic insights into the signaling mechanisms that regulate Tfh cell development and function.
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Affiliation(s)
- Abhinav Seth
- Department of Internal Medicine, Section of Rheumatology, Allergy and Immunology, School of Medicine, Yale University, New Haven, CT, USA
| | - Yoshiyuki Yokokura
- Department of Internal Medicine, Section of Rheumatology, Allergy and Immunology, School of Medicine, Yale University, New Haven, CT, USA
| | - Jin-Young Choi
- Department of Internal Medicine, Section of Rheumatology, Allergy and Immunology, School of Medicine, Yale University, New Haven, CT, USA
| | - Justin A. Shyer
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA
| | - Aurobind Vidyarthi
- Department of Internal Medicine, Section of Rheumatology, Allergy and Immunology, School of Medicine, Yale University, New Haven, CT, USA
| | - Joe Craft
- Department of Internal Medicine, Section of Rheumatology, Allergy and Immunology, School of Medicine, Yale University, New Haven, CT, USA
- Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA
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33
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Gocher-Demske AM, Cui J, Szymczak-Workman AL, Vignali KM, Latini JN, Pieklo GP, Kimball JC, Avery L, Cipolla EM, Huckestein BR, Hedden L, Meisel M, Alcorn JF, Kane LP, Workman CJ, Vignali DAA. IFNγ-induction of T H1-like regulatory T cells controls antiviral responses. Nat Immunol 2023; 24:841-854. [PMID: 36928412 PMCID: PMC10224582 DOI: 10.1038/s41590-023-01453-w] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 02/06/2023] [Indexed: 03/18/2023]
Abstract
Regulatory T (Treg) cells are an immunosuppressive population that are required to maintain peripheral tolerance and prevent tissue damage from immunopathology, via anti-inflammatory cytokines, inhibitor receptors and metabolic disruption. Here we show that Treg cells acquire an effector-like state, yet remain stable and functional, when exposed to interferon gamma (IFNγ) during infection with lymphocytic choriomeningitis and influenza A virus. Treg cell-restricted deletion of the IFNγ receptor (encoded by Ifngr1), but not the interleukin 12 (IL12) receptor (encoded by Il12rb2), prevented TH1-like polarization (decreased expression of T-bet, CXC motif chemokine receptor 3 and IFNγ) and promoted TH2-like polarization (increased expression of GATA-3, CCR4 and IL4). TH1-like Treg cells limited CD8+ T cell effector function, proliferation and memory formation during acute and chronic infection. These findings provide fundamental insights into how Treg cells sense inflammatory cues from the environment (such as IFNγ) during viral infection to provide guidance to the effector immune response. This regulatory circuit prevents prolonged immunoinflammatory responses and shapes the quality and quantity of the memory T cell response.
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Affiliation(s)
- Angela M Gocher-Demske
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Jian Cui
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | | | - Kate M Vignali
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Julianna N Latini
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Gwen P Pieklo
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Jesse C Kimball
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Lyndsay Avery
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Program in Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA
| | - Ellyse M Cipolla
- Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
- Program in Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Brydie R Huckestein
- Program in Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA
- Program in Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Lee Hedden
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Marlies Meisel
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - John F Alcorn
- Program in Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA
| | - Lawrence P Kane
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Creg J Workman
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Dario A A Vignali
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
- Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
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34
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Osum KC, Jenkins MK. Toward a general model of CD4 + T cell subset specification and memory cell formation. Immunity 2023; 56:475-484. [PMID: 36921574 PMCID: PMC10084496 DOI: 10.1016/j.immuni.2023.02.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 02/16/2023] [Indexed: 03/17/2023]
Abstract
In the past few decades, a number of transformative discoveries have been made regarding memory CD8+ T cell biology; meanwhile, the CD4+ T cell field has lagged behind this progress. This perspective focuses on CD4+ helper T (Th) cell subset specification and memory cell formation. Here, we argue that the sheer number of Th effector and memory cell subsets and a focus on their differences have been a barrier to a general model of CD4+ memory T cell formation that applies to all immune responses. We highlight a bifurcation model that relies on an IL-2 signal-dependent switch as an explanation for the balanced production of diverse Th memory cells that participate in cell-mediated or humoral immunity in most contexts.
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Affiliation(s)
- Kevin C Osum
- Department of Microbiology and Immunology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Marc K Jenkins
- Department of Microbiology and Immunology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
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35
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Shanmuganad S, Ferguson A, Paranjpe A, Cianciolo EE, Katz JD, Herold MJ, Hildeman DA. Subset-specific and temporal control of effector and memory CD4+ T cell survival. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.01.530323. [PMID: 36909576 PMCID: PMC10002744 DOI: 10.1101/2023.03.01.530323] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/07/2023]
Abstract
Following their proliferative expansion and differentiation into effector cells like Th1, Tfh, and T central memory precursors (Tcmp), most effector CD4+ T cells die, while some survive and become memory cells. Here, we explored how Bcl-2 family members controlled the survival of CD4+ T cells during distinct phases of mouse acute LCMV infection. During expansion, we found that Th1 cells dominated the response, downregulated expression of Bcl-2, and did not require Bcl-2 for survival. Instead, they relied on the anti-apoptotic protein, A1 for survival. Similarly, Th17 cells in an EAE model also depended on A1 for survival. However, after the peak of the response, CD4+ effector T cells required Bcl-2 to counteract Bim to aid their transition into memory. This Bcl-2 dependence persisted in established memory CD4+ T cells. Combined, these data show a temporal switch in Bcl-2 family-mediated survival of CD4+ T cells over the course of an immune response. This knowledge can help improve T cell survival to boost immunity and conversely, target pathogenic T cells.
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36
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Thelen B, Schipperges V, Knörlein P, Hummel JF, Arnold F, Kupferschmid L, Klose CSN, Arnold SJ, Boerries M, Tanriver Y. Eomes is sufficient to regulate IL-10 expression and cytotoxic effector molecules in murine CD4 + T cells. Front Immunol 2023; 14:1058267. [PMID: 36756120 PMCID: PMC9901365 DOI: 10.3389/fimmu.2023.1058267] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 01/02/2023] [Indexed: 01/20/2023] Open
Abstract
The T-box transcription factors T-bet and Eomesodermin regulate type 1 immune responses in innate and adaptive lymphocytes. T-bet is widely expressed in the immune system but was initially identified as the lineage-specifying transcription factor of Th1 CD4+ T cells, where it governs expression of the signature cytokine IFN- γ and represses alternative cell fates like Th2 and Th17. T-bet's paralog Eomes is less abundantly expressed and Eomes+ CD4+ T cells are mostly found in the context of persistent antigen exposure, like bone marrow transplantation, chronic infection or inflammation as well as malignant disorders. However, it has remained unresolved whether Eomes executes similar transcriptional activities as T-bet in CD4+ T cells. Here we use a novel genetic approach to show that Eomes expression in CD4+ T cells drives a distinct transcriptional program that shows only partial overlap with T-bet. We found that Eomes is sufficient to induce the expression of the immunoregulatory cytokine IL-10 and, together with T-bet, promotes a cytotoxic effector profile, including Prf1, Gzmb, Gzmk, Nkg7 and Ccl5, while repressing alternative cell fates. Our results demonstrate that Eomes+ CD4+ T cells, which are often found in the context of chronic antigen stimulation, are likely to be a unique CD4+ T cell subset that limits inflammation and immunopathology as well as eliminates antigen-presenting and malignant cells.
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Affiliation(s)
- Benedikt Thelen
- Institute of Medical Microbiology and Hygiene, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Vincent Schipperges
- Institute of Medical Bioinformatics and Systems Medicine, Faculty of Medicine, Medical Center - University of Freiburg, University of Freiburg, Freiburg, Germany
| | - Paulina Knörlein
- Institute of Medical Microbiology and Hygiene, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Jonas F. Hummel
- Institute of Medical Microbiology and Hygiene, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Frederic Arnold
- Institute of Medical Microbiology and Hygiene, Faculty of Medicine, University of Freiburg, Freiburg, Germany,Department of Internal Medicine IV, Faculty of Medicine, Medical Center - University of Freiburg, University of Freiburg, Freiburg, Germany,Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Laurence Kupferschmid
- Institute of Medical Microbiology and Hygiene, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Christoph S. N. Klose
- Department of Microbiology, Infectious Diseases and Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Sebastian J. Arnold
- Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany,CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
| | - Melanie Boerries
- Institute of Medical Bioinformatics and Systems Medicine, Faculty of Medicine, Medical Center - University of Freiburg, University of Freiburg, Freiburg, Germany,German Cancer Consortium (Deutsches Konsortium für Translationale Krebsforschung, DKTK), Partner Site Freiburg, and German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), Heidelberg, Germany
| | - Yakup Tanriver
- Institute of Medical Microbiology and Hygiene, Faculty of Medicine, University of Freiburg, Freiburg, Germany,Department of Internal Medicine IV, Faculty of Medicine, Medical Center - University of Freiburg, University of Freiburg, Freiburg, Germany,*Correspondence: Yakup Tanriver,
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Künzli M, O’Flanagan SD, LaRue M, Talukder P, Dileepan T, Stolley JM, Soerens AG, Quarnstrom CF, Wijeyesinghe S, Ye Y, McPartlan JS, Mitchell JS, Mandl CW, Vile R, Jenkins MK, Ahmed R, Vezys V, Chahal JS, Masopust D. Route of self-amplifying mRNA vaccination modulates the establishment of pulmonary resident memory CD8 and CD4 T cells. Sci Immunol 2022; 7:eadd3075. [PMID: 36459542 PMCID: PMC9832918 DOI: 10.1126/sciimmunol.add3075] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
Respiratory tract resident memory T cells (TRM), typically generated by local vaccination or infection, can accelerate control of pulmonary infections that evade neutralizing antibody. It is unknown whether mRNA vaccination establishes respiratory TRM. We generated a self-amplifying mRNA vaccine encoding the influenza A virus nucleoprotein that is encapsulated in modified dendron-based nanoparticles. Here, we report how routes of immunization in mice, including contralateral versus ipsilateral intramuscular boosts, or intravenous and intranasal routes, influenced influenza-specific cell-mediated and humoral immunity. Parabiotic surgeries revealed that intramuscular immunization was sufficient to establish CD8 TRM in the lung and draining lymph nodes. Contralateral, compared with ipsilateral, intramuscular boosting broadened the distribution of lymph node TRM and T follicular helper cells but slightly diminished resulting levels of serum antibody. Intranasal mRNA delivery established modest circulating CD8 and CD4 T cell memory but augmented distribution to the respiratory mucosa. Combining intramuscular immunizations with an intranasal mRNA boost achieved high levels of both circulating T cell memory and lung TRM. Thus, routes of mRNA vaccination influence humoral and cell-mediated immunity, and intramuscular prime-boosting establishes lung TRM that can be further expanded by an additional intranasal immunization.
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Affiliation(s)
- Marco Künzli
- Center for Immunology, Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Stephen D. O’Flanagan
- Center for Immunology, Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Madeleine LaRue
- Center for Immunology, Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USA
| | | | - Thamotharampillai Dileepan
- Center for Immunology, Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USA
| | - J. Michael Stolley
- Center for Immunology, Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Andrew G. Soerens
- Center for Immunology, Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Clare F. Quarnstrom
- Center for Immunology, Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Sathi Wijeyesinghe
- Center for Immunology, Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Yanqi Ye
- Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA
| | | | - Jason S. Mitchell
- Center for Immunology, Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USA
| | | | - Richard Vile
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Marc K. Jenkins
- Center for Immunology, Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Rafi Ahmed
- Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Vaiva Vezys
- Center for Immunology, Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USA
| | | | - David Masopust
- Center for Immunology, Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USA
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38
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Svensson-Arvelund J, Cuadrado-Castano S, Pantsulaia G, Kim K, Aleynick M, Hammerich L, Upadhyay R, Yellin M, Marsh H, Oreper D, Jhunjhunwala S, Moussion C, Merad M, Brown BD, García-Sastre A, Brody JD. Expanding cross-presenting dendritic cells enhances oncolytic virotherapy and is critical for long-term anti-tumor immunity. Nat Commun 2022; 13:7149. [PMID: 36418317 PMCID: PMC9684150 DOI: 10.1038/s41467-022-34791-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 11/08/2022] [Indexed: 11/25/2022] Open
Abstract
Immunotherapies directly enhancing anti-tumor CD8+ T cell responses have yielded measurable but limited success, highlighting the need for alternatives. Anti-tumor T cell responses critically depend on antigen presenting dendritic cells (DC), and enhancing mobilization, antigen loading and activation of these cells represent an attractive possibility to potentiate T cell based therapies. Here we show that expansion of DCs by Flt3L administration impacts in situ vaccination with oncolytic Newcastle Disease Virus (NDV). Mechanistically, NDV activates DCs and sensitizes them to dying tumor cells through upregulation of dead-cell receptors and synergizes with Flt3L to promote anti-tumor CD8+ T cell cross-priming. In vivo, Flt3L-NDV in situ vaccination induces parallel amplification of virus- and tumor-specific T cells, including CD8+ T cells reactive to newly-described neoepitopes, promoting long-term tumor control. Cross-presenting conventional Type 1 DCs are indispensable for the anti-tumor, but not anti-viral, T cell response, and type I IFN-dependent CD4+ Th1 effector cells contribute to optimal anti-tumor immunity. These data demonstrate that mobilizing DCs to increase tumor antigen cross-presentation improves oncolytic virotherapy and that neoepitope-specific T cells can be induced without individualized, ex vivo manufactured vaccines.
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Affiliation(s)
- Judit Svensson-Arvelund
- Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Division of Molecular Medicine and Virology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, 582 25, Sweden.
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
| | - Sara Cuadrado-Castano
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Gvantsa Pantsulaia
- Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Kristy Kim
- Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Mark Aleynick
- Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Linda Hammerich
- Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Hepatology and Gastroenterology, Campus Virchow- Klinikum, Charité Universitätsmedizin Berlin, Berlin, 13353, Germany
| | - Ranjan Upadhyay
- Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | | | - Henry Marsh
- Celldex Therapeutics, Inc, Needham, MA, 02494, USA
| | | | | | | | - Miriam Merad
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Brian D Brown
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Adolfo García-Sastre
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Joshua D Brody
- Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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39
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Liu J, Du L, Yi S, Li L, Lin Y, Bi Y, Zhu G, Jing X, Song W, Tang H. Murine lung cDC1s inhibit memory Th2 cell generation by reducing CD62L + memory precursors via IL-12. Allergy 2022; 77:3467-3470. [PMID: 35933716 DOI: 10.1111/all.15470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 07/08/2022] [Accepted: 08/04/2022] [Indexed: 01/28/2023]
Affiliation(s)
- Jianguo Liu
- Department of Rheumatology and Autoimmunology, Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China.,School of Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Linqing Du
- School of Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Shuying Yi
- School of Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Lina Li
- School of Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Yan Lin
- School of Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Yanan Bi
- School of Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Guangming Zhu
- School of Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Xiuli Jing
- School of Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Wengang Song
- Department of Rheumatology and Autoimmunology, Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China.,School of Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Hua Tang
- Department of Rheumatology and Autoimmunology, Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China.,Institute of Infection and Immunity, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
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40
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Regulation of CD4 T Cell Responses by the Transcription Factor Eomesodermin. Biomolecules 2022; 12:biom12111549. [PMID: 36358898 PMCID: PMC9687629 DOI: 10.3390/biom12111549] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/20/2022] [Accepted: 10/21/2022] [Indexed: 11/16/2022] Open
Abstract
Central to the impacts of CD4 T cells, both positive in settings of infectious disease and cancer and negative in the settings of autoimmunity and allergy, is their ability to differentiate into distinct effector subsets with specialized functions. The programming required to support such responses is largely dictated by lineage-specifying transcription factors, often called ‘master regulators’. However, it is increasingly clear that many aspects of CD4 T cell immunobiology that can determine the outcomes of disease states involve a broader transcriptional network. Eomesodermin (Eomes) is emerging as an important member of this class of transcription factors. While best studied in CD8 T cells and NK cells, an increasing body of work has focused on impacts of Eomes expression in CD4 T cell responses in an array of different settings. Here, we focus on the varied impacts reported in these studies that, together, indicate the potential of targeting Eomes expression in CD4 T cells as a strategy to improve a variety of clinical outcomes.
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41
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Zander R, Khatun A, Kasmani MY, Chen Y, Cui W. Delineating the transcriptional landscape and clonal diversity of virus-specific CD4 + T cells during chronic viral infection. eLife 2022; 11:e80079. [PMID: 36255051 PMCID: PMC9629829 DOI: 10.7554/elife.80079] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 10/17/2022] [Indexed: 11/24/2022] Open
Abstract
Although recent evidence indicates that CD4+ T cells responding to chronic viral infection are functionally heterogenous, our understanding of the developmental relationships between these subsets, and a determination of how their transcriptional landscape compares to their acute infection counterparts remains unclear. Additionally, whether cell-intrinsic factors such as TCR usage influence CD4+ T cell fate commitment during persistent infection has not previously been studied. Herein, we perform single-cell RNA sequencing (scRNA-seq) combined with single-cell T cell receptor sequencing (scTCR-seq) on virus-specific CD4+ T cells isolated from mice infected with chronic lymphocytic choriomeningitis virus (LCMV) infection. We identify several transcriptionally distinct states among the Th1, Tfh, and memory-like T cell subsets that form at the peak of infection, including the presence of a previously unrecognized Slamf7+ subset with cytolytic features. We further show that the relative distribution of these populations differs substantially between acute and persistent LCMV infection. Moreover, while the progeny of most T cell clones displays membership within each of these transcriptionally unique populations, overall supporting a one cell-multiple fate model, a small fraction of clones display a biased cell fate decision, suggesting that TCR usage may impact CD4+ T cell development during chronic infection. Importantly, comparative analyses further reveal both subset-specific and core gene expression programs that are differentially regulated between CD4+ T cells responding to acute and chronic LCMV infection. Together, these data may serve as a useful framework and allow for a detailed interrogation into the clonal distribution and transcriptional circuits underlying CD4+ T cell differentiation during chronic viral infection.
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Affiliation(s)
- Ryan Zander
- Blood Research Institute, Versiti WisconsinMilwaukeeUnited States
| | - Achia Khatun
- Blood Research Institute, Versiti WisconsinMilwaukeeUnited States
- Department of Microbiology and Immunology, Medical College of WisconsinMilwaukeeUnited States
| | - Moujtaba Y Kasmani
- Blood Research Institute, Versiti WisconsinMilwaukeeUnited States
- Department of Microbiology and Immunology, Medical College of WisconsinMilwaukeeUnited States
| | - Yao Chen
- Blood Research Institute, Versiti WisconsinMilwaukeeUnited States
- Department of Microbiology and Immunology, Medical College of WisconsinMilwaukeeUnited States
| | - Weiguo Cui
- Blood Research Institute, Versiti WisconsinMilwaukeeUnited States
- Department of Microbiology and Immunology, Medical College of WisconsinMilwaukeeUnited States
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42
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Endo Y, Kanno T, Nakajima T. Fatty acid metabolism in T-cell function and differentiation. Int Immunol 2022; 34:579-587. [PMID: 35700102 DOI: 10.1093/intimm/dxac025] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 06/12/2022] [Indexed: 01/07/2023] Open
Abstract
Immunometabolism has recently emerged as a field of study examining the intersection between immunology and metabolism. Studies in this area have yielded new findings on the roles of a diverse range of metabolic pathways and metabolites, which have been found to control many aspects of T-cell biology, including cell differentiation, function and fate. A particularly important finding has been the discovery that to meet the energy requirements associated with their proliferation, activation and specific functions, T cells switch their metabolic signatures during differentiation. For example, whereas the induction of de novo fatty acid biosynthesis and fatty acid uptake programs are required for antigen-stimulation-induced proliferation and differentiation of effector T cells, fatty acid catabolism via β-oxidation is essential for the generation of memory T cells and the differentiation of regulatory T cells. In this review, we discuss recent advances in our understanding of the metabolism in different stages of T cells and how fatty acid metabolism in these cells controls their specific functions.
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Affiliation(s)
- Yusuke Endo
- Department of Frontier Research and Development, Laboratory of Medical Omics Research, Kazusa DNA Research Institute, 2-6-7 Kazusa Kamatari, Kisarazu, Chiba 292-0818, Japan.,Department of Omics Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Toshio Kanno
- Department of Frontier Research and Development, Laboratory of Medical Omics Research, Kazusa DNA Research Institute, 2-6-7 Kazusa Kamatari, Kisarazu, Chiba 292-0818, Japan
| | - Takahiro Nakajima
- Department of Frontier Research and Development, Laboratory of Medical Omics Research, Kazusa DNA Research Institute, 2-6-7 Kazusa Kamatari, Kisarazu, Chiba 292-0818, Japan
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Rana M, Setia M, Suvas PK, Chakraborty A, Suvas S. Diphenyleneiodonium Treatment Inhibits the Development of Severe Herpes Stromal Keratitis Lesions. J Virol 2022; 96:e0101422. [PMID: 35946937 PMCID: PMC9472634 DOI: 10.1128/jvi.01014-22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 07/21/2022] [Indexed: 11/20/2022] Open
Abstract
Reactive oxygen species (ROS) play an important role in tissue inflammation. In this study, we measured the intracellular level of ROS in herpes stromal keratitis (HSK) corneas and determined the outcome of manipulating ROS level on HSK severity. Our results showed the predominance of ROS generation in neutrophils but not CD4 T cells in HSK corneas. NADPH oxidase 2 (NOX2) enzyme is known to generate ROS in myeloid cells. Our results showed baseline expression of different NOX2 subunits in uninfected corneas. After corneal herpes simplex virus-1 (HSV-1) infection, an enhanced expression of NOX2 subunits was detected in infected corneas. Furthermore, flow cytometry results showed a higher level of gp91 (Nox2 subunit) protein in neutrophils from HSK corneas, suggesting the involvement of NOX2 in generating ROS. However, no significant decrease in ROS level was noticed in neutrophils from HSV-1-infected gp91-/- mice than in C57BL/6J (B6) mice, suggesting NOX2 is not the major contributor in generating ROS in neutrophils. Next, we used diphenyleneiodonium (DPI), a flavoenzyme inhibitor, to pharmacologically manipulate the ROS levels in HSV-1-infected mice. Surprisingly, the neutrophils from peripheral blood and corneas of the DPI-treated group exhibited an increased level of ROS than the vehicle-treated group of infected B6 mice. Excessive ROS is known to cause cell death. Accordingly, DPI treatment resulted in a significant decrease in neutrophil frequency in peripheral blood and corneas of infected mice and was associated with reduced corneal pathology. Together, our results suggest that regulating ROS levels in neutrophils can ameliorate HSK severity. IMPORTANCE Neutrophils are one of the primary immune cell types involved in causing tissue damage after corneal HSV-1 infection. This study demonstrates that intracellular ROS production in the neutrophils in HSK lesions is not NOX2 dependent. Furthermore, manipulating ROS levels in neutrophils ameliorates the severity of HSK lesions. Our findings suggest that excessive intracellular ROS in neutrophils disrupt redox homeostasis and affect their survival, resulting in a decrease in HSK lesion severity.
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Affiliation(s)
- Mashidur Rana
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Mizumi Setia
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Pratima K. Suvas
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Anish Chakraborty
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Susmit Suvas
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, USA
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Myeloperoxidase as a Marker to Differentiate Mouse Monocyte/Macrophage Subsets. Int J Mol Sci 2022; 23:ijms23158246. [PMID: 35897821 PMCID: PMC9330004 DOI: 10.3390/ijms23158246] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/21/2022] [Accepted: 07/23/2022] [Indexed: 02/01/2023] Open
Abstract
Macrophages are present in every tissue in the body and play essential roles in homeostasis and host defense against microorganisms. Some tissue macrophages derive from the yolk sac/fetal liver that populate tissues for life. Other tissue macrophages derive from monocytes that differentiate in the bone marrow and circulate through tissues via the blood and lymphatics. Circulating monocytes are very plastic and differentiate into macrophages with specialized functions upon entering tissues. Specialized monocyte/macrophage subsets have been difficult to differentiate based on cell surface markers. Here, using a combination of "pan" monocyte/macrophage markers and flow cytometry, we asked whether myeloperoxidase (MPO) could be used as a marker of pro-inflammatory monocyte/macrophage subsets. MPO is of interest because of its potent microbicidal activity. In wild-type SPF housed mice, we found that MPO+ monocytes/macrophages were present in peripheral blood, spleen, small and large intestines, and mesenteric lymph nodes, but not the central nervous system. Only monocytes/macrophages that expressed cell surface F4/80 and/or Ly6C co-expressed MPO with the highest expression in F4/80HiLy6CHi subsets regardless of tissue. These cumulative data indicate that MPO expression can be used as an additional marker to differentiate between monocyte/macrophage subsets with pro-inflammatory and microbicidal activity in a variety of tissues.
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45
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Shaw LA, Deng TZ, Omilusik KD, Takehara KK, Nguyen QP, Goldrath AW. Id3 expression identifies CD4 + memory Th1 cells. Proc Natl Acad Sci U S A 2022; 119:e2204254119. [PMID: 35858332 PMCID: PMC9303986 DOI: 10.1073/pnas.2204254119] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 05/05/2022] [Indexed: 01/30/2023] Open
Abstract
Memory CD4+ T cells play a pivotal role in mediating long-term protective immunity, positioning them as an important target in vaccine development. However, multiple functionally distinct helper CD4+ T-cell subsets can arise in response to a single invading pathogen, complicating the identification of rare populations of memory precursor cells during the effector phase of infection and memory CD4+ T cells following pathogen clearance and the contraction phase of infection. Furthermore, current literature remains unclear regarding whether a single CD4+ memory T-cell lineage gives rise to secondary CD4+ T helper subsets or if there are unique memory precursor cells within each helper lineage. A majority of T follicular helper (Tfh) cells, which have established memory potential, express Id3, an inhibitor of E protein transcription factors, following acute viral infection. We show that expression of Id3 definitively identified a subset of cells within both the CD4+ Tfh and T helper 1 (Th1) lineages at memory time points that exhibited memory potential, with the capacity for significant re-expansion in response to secondary infection. Notably, we demonstrate that a subset of Th1 cells that survive into the memory phase were marked by Id3 expression and possessed the potential for enhanced expansion and generation of both Th1 and Tfh secondary effector cell populations in a secondary response to pathogen. Additionally, these cells exhibited enrichment of key molecules associated with memory potential when compared with Id3lo Th1 cells. Therefore, we propose that Id3 expression serves as an important marker to indicate multipotent potential in memory CD4+ T cells.
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Affiliation(s)
- Laura A. Shaw
- Department of Biological Sciences, University of California, La Jolla, CA 92093
| | - Tianda Z. Deng
- Department of Biological Sciences, University of California, La Jolla, CA 92093
| | - Kyla D. Omilusik
- Department of Biological Sciences, University of California, La Jolla, CA 92093
| | - Kennidy K. Takehara
- Department of Biological Sciences, University of California, La Jolla, CA 92093
| | - Quynh P. Nguyen
- Department of Biological Sciences, University of California, La Jolla, CA 92093
| | - Ananda W. Goldrath
- Department of Biological Sciences, University of California, La Jolla, CA 92093
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46
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Andreatta M, Tjitropranoto A, Sherman Z, Kelly MC, Ciucci T, Carmona SJ. A CD4 + T cell reference map delineates subtype-specific adaptation during acute and chronic viral infections. eLife 2022; 11:e76339. [PMID: 35829695 PMCID: PMC9323004 DOI: 10.7554/elife.76339] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 07/12/2022] [Indexed: 11/13/2022] Open
Abstract
CD4+ T cells are critical orchestrators of immune responses against a large variety of pathogens, including viruses. While multiple CD4+ T cell subtypes and their key transcriptional regulators have been identified, there is a lack of consistent definition for CD4+ T cell transcriptional states. In addition, the progressive changes affecting CD4+ T cell subtypes during and after immune responses remain poorly defined. Using single-cell transcriptomics, we characterized the diversity of CD4+ T cells responding to self-resolving and chronic viral infections in mice. We built a comprehensive map of virus-specific CD4+ T cells and their evolution over time, and identified six major cell states consistently observed in acute and chronic infections. During the course of acute infections, T cell composition progressively changed from effector to memory states, with subtype-specific gene modules and kinetics. Conversely, in persistent infections T cells acquired distinct, chronicity-associated programs. By single-cell T cell receptor (TCR) analysis, we characterized the clonal structure of virus-specific CD4+ T cells across individuals. Virus-specific CD4+ T cell responses were essentially private across individuals and most T cells differentiated into both Tfh and Th1 subtypes irrespective of their TCR. Finally, we showed that our CD4+ T cell map can be used as a reference to accurately interpret cell states in external single-cell datasets across tissues and disease models. Overall, this study describes a previously unappreciated level of adaptation of the transcriptional states of CD4+ T cells responding to viruses and provides a new computational resource for CD4+ T cell analysis.
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Affiliation(s)
- Massimo Andreatta
- Department of Oncology, UNIL CHUV and Ludwig Institute for Cancer Research Lausanne, University of LausanneLausanneSwitzerland
- Agora Cancer Research CenterLausanneSwitzerland
- Swiss Institute of BioinformaticsLausanneSwitzerland
| | - Ariel Tjitropranoto
- David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of RochesterRochesterUnited States
| | - Zachary Sherman
- David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of RochesterRochesterUnited States
| | - Michael C Kelly
- Single Cell Analysis Facility, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research IncFrederickUnited States
| | - Thomas Ciucci
- David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of RochesterRochesterUnited States
- Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthBethesdaUnited States
| | - Santiago J Carmona
- Department of Oncology, UNIL CHUV and Ludwig Institute for Cancer Research Lausanne, University of LausanneLausanneSwitzerland
- Agora Cancer Research CenterLausanneSwitzerland
- Swiss Institute of BioinformaticsLausanneSwitzerland
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47
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Xia Y, Sandor K, Pai JA, Daniel B, Raju S, Wu R, Hsiung S, Qi Y, Yangdon T, Okamoto M, Chou C, Hiam-Galvez KJ, Schreiber RD, Murphy KM, Satpathy AT, Egawa T. BCL6-dependent TCF-1 + progenitor cells maintain effector and helper CD4 + T cell responses to persistent antigen. Immunity 2022; 55:1200-1215.e6. [PMID: 35637103 PMCID: PMC10034764 DOI: 10.1016/j.immuni.2022.05.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 03/04/2022] [Accepted: 05/04/2022] [Indexed: 12/12/2022]
Abstract
Soon after activation, CD4+ T cells are segregated into BCL6+ follicular helper (Tfh) and BCL6- effector (Teff) T cells. Here, we explored how these subsets are maintained during chronic antigen stimulation using the mouse chronic LCMV infection model. Using single cell-transcriptomic and epigenomic analyses, we identified a population of PD-1+ TCF-1+ CD4+ T cells with memory-like features. TCR clonal tracing and adoptive transfer experiments demonstrated that these cells have self-renewal capacity and continue to give rise to both Teff and Tfh cells, thus functioning as progenitor cells. Conditional deletion experiments showed Bcl6-dependent development of these progenitors, which were essential for sustaining antigen-specific CD4+ T cell responses to chronic infection. An analogous CD4+ T cell population developed in draining lymph nodes in response to tumors. Our study reveals the heterogeneity and plasticity of CD4+ T cells during persistent antigen exposure and highlights their population dynamics through a stable, bipotent intermediate state.
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Affiliation(s)
- Yu Xia
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Katalin Sandor
- Department of Pathology, Stanford University, Stanford, CA 94305, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA
| | - Joy A Pai
- Department of Pathology, Stanford University, Stanford, CA 94305, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA
| | - Bence Daniel
- Department of Pathology, Stanford University, Stanford, CA 94305, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA
| | - Saravanan Raju
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Renee Wu
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Sunnie Hsiung
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Yanyan Qi
- Department of Pathology, Stanford University, Stanford, CA 94305, USA
| | - Tenzin Yangdon
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Mariko Okamoto
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Chun Chou
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | | | - Robert D Schreiber
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Kenneth M Murphy
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Ansuman T Satpathy
- Department of Pathology, Stanford University, Stanford, CA 94305, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA.
| | - Takeshi Egawa
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
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48
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Hong SW, Krueger PD, Osum KC, Dileepan T, Herman A, Mueller DL, Jenkins MK. Immune tolerance of food is mediated by layers of CD4 + T cell dysfunction. Nature 2022; 607:762-768. [PMID: 35794484 PMCID: PMC10336534 DOI: 10.1038/s41586-022-04916-6] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 05/27/2022] [Indexed: 11/08/2022]
Abstract
Gastrointestinal health depends on the adaptive immune system tolerating the foreign proteins in food1,2. This tolerance is paradoxical because the immune system normally attacks foreign substances by generating inflammation. Here we addressed this conundrum by using a sensitive cell enrichment method to show that polyclonal CD4+ T cells responded to food peptides, including a natural one from gliadin, by proliferating weakly in secondary lymphoid organs of the gut-liver axis owing to the action of regulatory T cells. A few food-specific T cells then differentiated into T follicular helper cells that promoted a weak antibody response. Most cells in the expanded population, however, lacked canonical T helper lineage markers and fell into five subsets dominated by naive-like or T follicular helper-like anergic cells with limited capacity to form inflammatory T helper 1 cells. Eventually, many of the T helper lineage-negative cells became regulatory T cells themselves through an interleukin-2-dependent mechanism. Our results indicate that exposure to food antigens causes cognate CD4+ naive T cells to form a complex set of noncanonical hyporesponsive T helper cell subsets that lack the inflammatory functions needed to cause gut pathology and yet have the potential to produce regulatory T cells that may suppress it.
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Affiliation(s)
- Sung-Wook Hong
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA
- Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Peter D Krueger
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA
- Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Kevin C Osum
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA
- Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Thamotharampillai Dileepan
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA
- Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Adam Herman
- Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, USA
| | - Daniel L Mueller
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA
- Division of Rheumatic and Autoimmune Diseases, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Marc K Jenkins
- Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA.
- Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA.
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49
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Yang J, Zhang Q, Wang J, Lou Y, Hong Z, Wei S, Sun K, Wang J, Chen Y, Sheng J, Su W, Bai X, Liang T. Dynamic profiling of immune microenvironment during pancreatic cancer development suggests early intervention and combination strategy of immunotherapy. EBioMedicine 2022; 78:103958. [PMID: 35316682 PMCID: PMC8943259 DOI: 10.1016/j.ebiom.2022.103958] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 03/05/2022] [Accepted: 03/07/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) has little response to immune checkpoint inhibitors. An in-depth understanding of the immune microenvironment from a comprehensive and dynamic perspective is critical to generate effective therapeutic strategies for PDAC. METHODS Using mass cytometry and immunohistochemistry, we explored the dynamic changes of tumor-infiltrating immune cells during the development of PDAC in a genetically engineered mouse model (KrasG12D/+; Trp53R172H/+; Pdx1-cre) and human specimens. PD-L1-/- mice were crossed with KrasG12D/+; TgfβR2flox/flox; Ptf1a-cre mice to achieve early depletion of PD-L1 in pancreatic cancer. Combination therapy of Arginase-1 (Arg-1) inhibitor and anti-PD-1 mAb was validated in syngeneic mouse models. FINDINGS Two different stages of immunosuppression with unique features were observed in both mouse model and human specimens. Early stage of immunosuppression featured highly abundant Tregs during acinar-to-ductal metaplasia, despite of a prominent and continuous presence of effector lymphocytes. The differentiation/activation branch of Ly-6C+ monocytes changed from a BST2+/MHC-II+ phenotype to an Arg-1+ phenotype over time during PDAC development. The late stage of immunosuppression thus featured the presence of a large number of myeloid suppressive cells together with a significant reduction of effector lymphocytes. Removal of PD-L1 from the beginning efficiently triggered anti-tumor immunity and significantly prolonged survival in PDAC-developing mice. Targeting Arg1+ macrophages with an Arg-1 inhibitor synergized with anti-PD-1 immunotherapy and led to PDAC-specific immune memory. INTERPRETATION By demonstrating the coevolution of histopathology and immunology in PDAC, this study highlights the necessity and value of early intervention and combinational approach in leveraging immunotherapy to treat pancreatic cancer. FUNDING A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
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Affiliation(s)
- Jiaqi Yang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China; Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Qi Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China; Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China
| | - Junli Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China; Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Yu Lou
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China; Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Zhengtao Hong
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China; Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Shumei Wei
- Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ke Sun
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058 China; Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianing Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China; Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China
| | - Yiwen Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China; Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China
| | - Jianpeng Sheng
- Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China
| | - Wei Su
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China; Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China; Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058 China.
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, China; Key Laboratory of Pancreatic Disease of Zhejiang Province, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058 China.
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50
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Zander R, Kasmani MY, Chen Y, Topchyan P, Shen J, Zheng S, Burns R, Ingram J, Cui C, Joshi N, Craft J, Zajac A, Cui W. Tfh-cell-derived interleukin 21 sustains effector CD8 + T cell responses during chronic viral infection. Immunity 2022; 55:475-493.e5. [PMID: 35216666 PMCID: PMC8916994 DOI: 10.1016/j.immuni.2022.01.018] [Citation(s) in RCA: 75] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 10/14/2021] [Accepted: 01/27/2022] [Indexed: 02/03/2023]
Abstract
CD4+ T cell-derived interleukin 21 (IL-21) sustains CD8+ T cell responses during chronic viral infection, but the helper subset that confers this protection remains unclear. Here, we applied scRNA and ATAC-seq approaches to determine the heterogeneity of IL-21+CD4+ T cells during LCMV clone 13 infection. CD4+ T cells were comprised of three transcriptionally and epigenetically distinct populations: Cxcr6+ Th1 cells, Cxcr5+ Tfh cells, and a previously unrecognized Slamf6+ memory-like (Tml) subset. T cell differentiation was specifically redirected toward the Tml subset during chronic, but not acute, LCMV infection. Although this subset displayed an enhanced capacity to accumulate and some developmental plasticity, it remained largely quiescent, which may hinder its helper potential. Conversely, mixed bone marrow chimera experiments revealed that Tfh cell-derived IL-21 was critical to sustain CD8+ T cell responses and viral control. Thus, strategies that bolster IL-21+Tfh cell responses may prove effective in enhancing CD8+ T cell-mediated immunity.
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Affiliation(s)
- Ryan Zander
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI 53226, USA
| | - Moujtaba Y Kasmani
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI 53226, USA; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Yao Chen
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI 53226, USA; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Paytsar Topchyan
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI 53226, USA; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Jian Shen
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI 53226, USA; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Shikan Zheng
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI 53226, USA
| | - Robert Burns
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI 53226, USA
| | - Jennifer Ingram
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Can Cui
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA
| | - Nikhil Joshi
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA
| | - Joseph Craft
- Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA
| | - Allan Zajac
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | - Weiguo Cui
- Blood Research Institute, Versiti Wisconsin, Milwaukee, WI 53226, USA; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
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