VISTA, a Novel Mouse Ig Superfamily Ligand That Negatively Regulates T Cell Responses

J Exp Med. 2011 Mar 14;208(3):577-92. doi: 10.1084/jem.20100619. Epub 2011 Mar 7.

Abstract

The immunoglobulin (Ig) superfamily consists of many critical immune regulators, including the B7 family ligands and receptors. In this study, we identify a novel and structurally distinct Ig superfamily inhibitory ligand, whose extracellular domain bears homology to the B7 family ligand PD-L1. This molecule is designated V-domain Ig suppressor of T cell activation (VISTA). VISTA is primarily expressed on hematopoietic cells, and VISTA expression is highly regulated on myeloid antigen-presenting cells (APCs) and T cells. A soluble VISTA-Ig fusion protein or VISTA expression on APCs inhibits T cell proliferation and cytokine production in vitro. A VISTA-specific monoclonal antibody interferes with VISTA-induced suppression of T cell responses by VISTA-expressing APCs in vitro. Furthermore, anti-VISTA treatment exacerbates the development of the T cell-mediated autoimmune disease experimental autoimmune encephalomyelitis in mice. Finally, VISTA overexpression on tumor cells interferes with protective antitumor immunity in vivo in mice. These findings show that VISTA, a novel immunoregulatory molecule, has functional activities that are nonredundant with other Ig superfamily members and may play a role in the development of autoimmunity and immune surveillance in cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / physiology
  • B7 Antigens / immunology*
  • B7 Antigens / physiology*
  • B7-1 Antigen / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Flow Cytometry
  • Gene Expression Regulation
  • Immunoglobulins / immunology*
  • Immunoglobulins / physiology
  • Ligands
  • Lymphocyte Activation / immunology
  • Lymphocyte Activation / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes / immunology
  • T-Lymphocytes / physiology*
  • Tumor Cells, Cultured

Substances

  • Antibodies, Monoclonal
  • B7 Antigens
  • B7-1 Antigen
  • Immunoglobulins
  • Ligands
  • VSIR protein, human