Recombinant Human VISTA/B7-H5/PD-1H Fc Chimera Protein, CF

VISTA (V-domain immunoglobulin suppressor of T cell activation) is an immune checkpoint receptor expressed primarily on the surface of hematopoietic cells. Specifically, VISTA is expressed on naïve CD4+ T cells and regulatory T cells (1). And it is up regulated in vivo on activated monocytes and dendritic cells (2). VISTA inhibits CD4+ and CD8+ T cell proliferation, and their production of the proinflammatory cytokines IL 2 and IFN gamma (1). VISTA protein is also observed on the surface of cancer cells and attenuates the anti tumor immune response enabling tumor progression (1). In the autoimmune disease model EAE, VISTA limits disease progression by downregulating the overactive immune system (1). VISTA, also known as B7 H5, PD-1H, Platelet receptor Gi24, Dies1, and SISP1, is a 55 65 kDa transmembrane glycoprotein with homology to B7 like immune co stimulatory molecules (3, 4). The mature human VISTA protein contains a 162 amino acid extracellular domain (ECD) with one V type Ig like domain, a 21 aa transmembrane segment, and a 96 aa cytoplasmic domain. Within the ECD, human VISTA shares 70% and 67% amino acid sequence identity with mouse and rat VISTA, respectively (5). The 30 kDa ECD can be shed by MT1 MMP, with a 25 30 kDa fragment remaining in the membrane (5). VISTA promotes both MT1 MMP expression and the MT1 MMP mediated activation of MMP 2 (5). VISTA supports the differentiation of embryonic stem cells (ESC) and enhances BMP 4 induced signaling in ESC but is also down regulated following BMP 4 exposure (2, 6). It binds to BMP 4 directly and also associates with the type I BMP receptor Activin RIB/ALK 4 (2, 6). The identification of a binding partner for VISTA proved elusive for many years until two 2019 publications identified two distinct ligands for VISTA, VSIG-3 and PSGL-1 (7, 8). Both ligands are expressed on T cells and blocking antibodies to VISTA have been shown to reverse immune suppression making VISTA a potential therapeutic target for cancer (7, 8).