ElTanbouly and Zhao et al. studied the role of VISTA – a negative checkpoint regulator expressed constitutively on naïve T-cells – on T cell fate and survival using single cell sequencing and multiple in vivo models. Genetic loss or antibody blockade of VISTA in antigen-specific naïve CD4+ T cells under tolerance-inducing conditions resulted in a loss of quiescent T cells and an increased memory-like activated T cell subset (effects which were lost under inflammatory conditions), while agonistic VISTA mAbs increased T cell tolerance and deletion. These results suggest VISTA maintains quiescence and homeostatic tolerance of self-antigen-specific naïve T cells.
Contributed by Katherine Turner
ABSTRACT: Negative checkpoint regulators (NCRs) temper the T cell immune response to self-antigens and limit the development of autoimmunity. Unlike all other NCRs that are expressed on activated T lymphocytes, V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) is expressed on naive T cells. We report an unexpected heterogeneity within the naive T cell compartment in mice, where loss of VISTA disrupted the major quiescent naive T cell subset and enhanced self-reactivity. Agonistic VISTA engagement increased T cell tolerance by promoting antigen-induced peripheral T cell deletion. Although a critical player in naive T cell homeostasis, the ability of VISTA to restrain naive T cell responses was lost under inflammatory conditions. VISTA is therefore a distinctive NCR of naive T cells that is critical for steady-state maintenance of quiescence and peripheral tolerance.
Author Info: (1) Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. (2) Department of Molecular and Systems Biolog
Author Info: (1) Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. (2) Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. (3) Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. (4) Adimab LLC, Lebanon, NH, USA. (5) Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. (6) KSQ Therapeutics, Cambridge, MA, USA. (7) Immunology Discovery, Janssen Research and Development LLC, Spring House, PA, USA. (8) Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. (9) Division of Rheumatic and Autoimmune Diseases, Center for Immunology, University of Minnesota, Minneapolis, MN, USA. The Center for Immunology, University of Minnesota, Minneapolis, MN, USA. (10) ImmuNext Corporation, Lebanon, NH, USA. (11) ImmuNext Corporation, Lebanon, NH, USA. (12) ImmuNext Corporation, Lebanon, NH, USA. (13) Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA. (14) Yale University School of Medicine, New Haven, CT, USA. (15) Division of Rheumatic and Autoimmune Diseases, Center for Immunology, University of Minnesota, Minneapolis, MN, USA. (16) Division of Rheumatic and Autoimmune Diseases, Center for Immunology, University of Minnesota, Minneapolis, MN, USA. The Center for Immunology, University of Minnesota, Minneapolis, MN, USA. (17) Division of Rheumatic and Autoimmune Diseases, Center for Immunology, University of Minnesota, Minneapolis, MN, USA. The Center for Immunology, University of Minnesota, Minneapolis, MN, USA. (18) Division of Rheumatic and Autoimmune Diseases, Center for Immunology, University of Minnesota, Minneapolis, MN, USA. The Center for Immunology, University of Minnesota, Minneapolis, MN, USA. (19) ImmuNext Corporation, Lebanon, NH, USA. (20) Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA. Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA. (21) Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. rjn@dartmouth.edu chao.cheng@bcm.edu. Department of Medicine, Baylor College of Medicine, Houston, TX, USA. (22) Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. rjn@dartmouth.edu chao.cheng@bcm.edu. ImmuNext Corporation, Lebanon, NH, USA.
