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.
Bibliographical noteFunding Information:
Research was supported by NIH grants R01AR070760 (R.J.N.), R01CA214062 (R.J.N.), 1R21CA227996-01A1 (C.C.), RR180061 (C.C.), R01 HL56067 (B.R.B.), R01 HL 11879 (B.R.B.), and R37 AI34495 (B.R.B.) and Cancer Prevention and Research institute of Texas grant RR180061 (C.C.).