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

  • Science. 2020 Jan 17;367(6475):eaay0524. doi: 10.1126/science.aay0524.
Mohamed A ElTanbouly  #  1 ,  Yanding Zhao  #  2  3 ,  Elizabeth Nowak  1 ,  Jiannan Li  4 ,  Evelien Schaafsma  2  3 ,  Isabelle Le Mercier  5 ,  Sabrina Ceeraz  6 ,  J Louise Lines  1 ,  Changwei Peng  7  8 ,  Catherine Carriere  9 ,  Xin Huang  9 ,  Maria Day  9 ,  Brent Koehn  10 ,  Sam W Lee  11 ,  Milagros Silva Morales  7 ,  Kristin A Hogquist  7  8 ,  Stephen C Jameson  7  8 ,  Daniel Mueller  7  8 ,  Jay Rothstein  9 ,  Bruce R Blazar  10  12 ,  Chao Cheng  13  14 ,  Randolph J Noelle  15  9
Affiliations
  • 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.
  • 3. Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
  • 4. Adimab LLC, Lebanon, NH, USA.
  • 5. KSQ Therapeutics, Cambridge, MA, USA.
  • 6. Immunology Discovery, Janssen Research and Development LLC, Spring House, PA, USA.
  • 7. Division of Rheumatic and Autoimmune Diseases, Center for Immunology, University of Minnesota, Minneapolis, MN, USA.
  • 8. The Center for Immunology, University of Minnesota, Minneapolis, MN, USA.
  • 9. ImmuNext Corporation, Lebanon, NH, USA.
  • 10. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
  • 11. Yale University School of Medicine, New Haven, CT, USA.
  • 12. Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
  • 13. Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH, USA. [email protected] [email protected].
  • 14. Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
  • 15. Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. [email protected] [email protected].
  • # Contributed equally.
PMID: 31949051 DOI: 10.1126/science.aay0524
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.

Products