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

Mohamed A. ElTanbouly; Yanding Zhao; Elizabeth Nowak; Jiannan Li; Evelien Schaafsma; Isabelle Le Mercier; Sabrina Ceeraz; J. Louise Lines; Changwei Peng; Catherine Carriere; Xin Huang; Maria Day; Brent Koehn; Sam W. Lee; Milagros Silva Morales; Kristin A. Hogquist; Stephen C. Jameson; Daniel Mueller; Jay Rothstein; Bruce R. Blazar; Chao Cheng; Randolph J. Noelle

doi:10.1126/science.aay0524

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

Mohamed A. ElTanbouly, Yanding Zhao, Elizabeth Nowak, Jiannan Li, Evelien Schaafsma, Isabelle Le Mercier, Sabrina Ceeraz, J. Louise Lines, Changwei Peng, Catherine Carriere, Xin Huang, Maria Day, Brent Koehn, Sam W. Lee, Milagros Silva Morales, Kristin A. Hogquist, Stephen C. Jameson, Daniel Mueller, Jay Rothstein, Bruce R. BlazarChao Cheng, Randolph J. Noelle

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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 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.

Original language	English (US)
Article number	eaay0524
Journal	Science
Volume	367
Issue number	6475
DOIs	https://doi.org/10.1126/science.aay0524
State	Published - Jan 17 2020

Bibliographical note

Funding 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.).

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Copyright © 2020 The Authors,

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Research Support, Non-U.S. Gov't

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ElTanbouly, M. A., Zhao, Y., Nowak, E., Li, J., Schaafsma, E., Le Mercier, I., Ceeraz, S., Lines, J. L., Peng, C., Carriere, C., Huang, X., Day, M., Koehn, B., Lee, S. W., Morales, M. S., Hogquist, K. A., Jameson, S. C., Mueller, D., Rothstein, J., ... Noelle, R. J. (2020). VISTA is a checkpoint regulator for naïve T cell quiescence and peripheral tolerance. Science, 367(6475), [eaay0524]. https://doi.org/10.1126/science.aay0524

ElTanbouly, MA, Zhao, Y, Nowak, E, Li, J, Schaafsma, E, Le Mercier, I, Ceeraz, S, Lines, JL, Peng, C, Carriere, C, Huang, X, Day, M, Koehn, B, Lee, SW, Morales, MS, Hogquist, KA , Jameson, SC , Mueller, D, Rothstein, J, Blazar, BR, Cheng, C & Noelle, RJ 2020, 'VISTA is a checkpoint regulator for naïve T cell quiescence and peripheral tolerance', Science, vol. 367, no. 6475, eaay0524. https://doi.org/10.1126/science.aay0524

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title = "VISTA is a checkpoint regulator for na{\"i}ve T cell quiescence and peripheral tolerance",

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

author = "ElTanbouly, {Mohamed A.} and Yanding Zhao and Elizabeth Nowak and Jiannan Li and Evelien Schaafsma and {Le Mercier}, Isabelle and Sabrina Ceeraz and Lines, {J. Louise} and Changwei Peng and Catherine Carriere and Xin Huang and Maria Day and Brent Koehn and Lee, {Sam W.} and Morales, {Milagros Silva} and Hogquist, {Kristin A.} and Jameson, {Stephen C.} and Daniel Mueller and Jay Rothstein and Blazar, {Bruce R.} and Chao Cheng and Noelle, {Randolph J.}",

note = "Funding 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.). Publisher Copyright: Copyright {\textcopyright} 2020 The Authors,",

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language = "English (US)",

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T1 - VISTA is a checkpoint regulator for naïve T cell quiescence and peripheral tolerance

AU - ElTanbouly, Mohamed A.

AU - Zhao, Yanding

AU - Nowak, Elizabeth

AU - Li, Jiannan

AU - Schaafsma, Evelien

AU - Le Mercier, Isabelle

AU - Ceeraz, Sabrina

AU - Lines, J. Louise

AU - Peng, Changwei

AU - Carriere, Catherine

AU - Huang, Xin

AU - Day, Maria

AU - Koehn, Brent

AU - Lee, Sam W.

AU - Morales, Milagros Silva

AU - Hogquist, Kristin A.

AU - Jameson, Stephen C.

AU - Mueller, Daniel

AU - Rothstein, Jay

AU - Blazar, Bruce R.

AU - Cheng, Chao

AU - Noelle, Randolph J.

N1 - Funding 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.). Publisher Copyright: Copyright © 2020 The Authors,

PY - 2020/1/17

Y1 - 2020/1/17

N2 - 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.

AB - 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.

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

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