VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses

Journal of Experimental Medicine - Tập 208 Số 3 - Trang 577-592 - 2011
Li Wang1, Rotem Rubinstein2,3,4, J. Louise Lines1, Anna Wasiuk1, Cory L. Ahonen1, Yanxia Guo1, Li‐Fan Lu1, David Gondek1, Yan Wang1, Roy A. Fava5, András Fiser2,3,4, S.C. Almo2,4, Randolph J. Noelle1,6
1Department of Microbiology and Immunology, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03766 1
2Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461 4 and 5
3Department of Systems and Computational Biology 4 and 5
4Department of Systems and Computational Biology and Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461
5Department of Veterans Affairs Medical Center, White River Junction, VT 05009 3
6Department of Nephrology and Transplantation, Medical Research Council Centre for Transplantation, King’s College London, Guy’s Hospital, London SE1 9RT, England, UK 2

Tóm tắt

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.

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