VISTA is a checkpoint regulator for naïve T cell quiescence and peripheral tolerance

• Published in: Science (American Association for the Advancement of Science) Vol. 367; no. 6475
• Main Authors: ElTanbouly, Mohamed A, Zhao, Yanding, Nowak, Elizabeth, Li, Jiannan, Schaafsma, Evelien, Le Mercier, Isabelle, Ceeraz, Sabrina, Lines, J Louise, Peng, Changwei, Carriere, Catherine, Huang, Xin, Day, Maria, Koehn, Brent, Lee, Sam W, Silva Morales, Milagros, Hogquist, Kristin A, Jameson, Stephen C, Mueller, Daniel, Rothstein, Jay, Blazar, Bruce R, Cheng, Chao, Noelle, Randolph J
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 17.01.2020
• Subjects: Animals; Antibodies; Antibodies, Monoclonal; Antigens; Arthritis; Autoantigens; Autoimmune diseases; B7 Antigens - genetics; B7 Antigens - physiology; CD4 antigen; Cell activation; Cell death; Cell fate; Chronic conditions; Clonal deletion; Clonal selection; Cytokines; Death; Deletion; Domains; Epigenetics; Feedback (Response); Fluorescence; Gene sequencing; Genetics; Graft-versus-host reaction; Heterogeneity; Homeostasis; Immune response; Immune response (cell-mediated); Immune system; Immunoglobulins; Immunological memory; Immunological tolerance; Immunoregulation; In vivo methods and tests; Inflammation; Interferon; Logical Thinking; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Membrane Proteins - genetics; Membrane Proteins - physiology; Memory cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Mortality; Peripheral Tolerance - genetics; Peripheral Tolerance - immunology; Phenotypes; Precipitates; Receptors, Antigen, T-Cell - physiology; Regulators; Rheumatoid arthritis; Ribonucleic acid; RNA; Stimulation; Subpopulations; Systemic lupus erythematosus; T cell receptors; T-Lymphocytes - immunology; Therapeutic targets; Transcription
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aay0524

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 naïve T cells. We report an unexpected heterogeneity within the naïve T cell compartment in mice, where loss of VISTA disrupted the major quiescent naïve 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 naïve T cell homeostasis, the ability of VISTA to restrain naïve T cell responses was lost under inflammatory conditions. VISTA is therefore a distinctive NCR of naïve T cells that is critical for steady-state maintenance of quiescence and peripheral tolerance.