VISTA.COMP - an engineered checkpoint receptor agonist that potently suppresses T cell-mediated immune responses

V-domain immunoglobulin suppressor of T cell activation (VISTA) is a recently discovered immune checkpoint ligand that functions to suppress T cell activity. The therapeutic potential of activating this immune checkpoint pathway to reduce inflammatory responses remains untapped, largely due to the i...

Full description

Saved in:

Bibliographic Details
Published in:	JCI insight Vol. 2; no. 18
Main Authors:	Prodeus, Aaron, Abdul-Wahid, Aws, Sparkes, Amanda, Fischer, Nicholas W, Cydzik, Marzena, Chiang, Nicholas, Alwash, Mays, Ferzoco, Alessandra, Vacaresse, Nathalie, Julius, Michael, Gorczysnki, Reginald M, Gariépy, Jean
Format:	Journal Article
Language:	English
Published:	United States American Society for Clinical Investigation 21-09-2017
Subjects:	Animals CD4-Positive T-Lymphocytes - immunology Cells, Cultured Ligands Lymphocyte Activation Membrane Proteins - immunology Mice Mice, Inbred C57BL Protein Engineering Receptors, Cell Surface - agonists Recombinant Proteins - genetics Recombinant Proteins - immunology Recombinant Proteins - pharmacology Immunotherapy Immunology Therapeutics
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	V-domain immunoglobulin suppressor of T cell activation (VISTA) is a recently discovered immune checkpoint ligand that functions to suppress T cell activity. The therapeutic potential of activating this immune checkpoint pathway to reduce inflammatory responses remains untapped, largely due to the inability to derive agonists targeting its unknown receptor. A dimeric construct of the IgV domain of VISTA (VISTA-Fc) was shown to suppress the activation of T cells in vitro. However, this effect required its immobilization on a solid surface, suggesting that VISTA-Fc may display limited efficacy as a VISTA-receptor agonist in vivo. Herein, we have designed a stable pentameric VISTA construct (VISTA.COMP) by genetically fusing its IgV domain to the pentamerization domain from the cartilage oligomeric matrix protein (COMP). In contrast to VISTA-Fc, VISTA.COMP does not require immobilization to inhibit the proliferation of CD4+ T cells undergoing polyclonal activation. Furthermore, we show that VISTA.COMP, but not VISTA-Fc, functions as an immunosuppressive agonist in vivo capable of prolonging the survival of skin allografts in a mouse transplant model as well as rescuing mice from acute concanavalin-A-induced hepatitis. Collectively, we believe our data demonstrate that VISTA.COMP is a checkpoint receptor agonist and the first agent to our knowledge targeting the putative VISTA-receptor to suppress T cell-mediated immune responses.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2379-3708 2379-3708
DOI:	10.1172/jci.insight.94308