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


ABSTRACT: 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.

SUBMITTER: Prodeus A 

PROVIDER: S-EPMC5621893 | biostudies-other | 2017 Sep

REPOSITORIES: biostudies-other

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

Prodeus Aaron A   Abdul-Wahid Aws A   Sparkes Amanda A   Fischer Nicholas W NW   Cydzik Marzena M   Chiang Nicholas N   Alwash Mays M   Ferzoco Alessandra A   Vacaresse Nathalie N   Julius Michael M   Gorczysnki Reginald M RM   Gariépy Jean J  

JCI insight 20170921 18


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 req  ...[more]

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