Human VISTA is a 55 to 65kDa type I Ig membrane protein with the extracellular domain homologous to PD-L1. VISTA is mainly expressed on hematopoietic tissues (spleen, thymus and bone marrow) and on myeloid cells with lower expression on CD4+ and CD8+ T cells. VISTA is a new negative checkpoint regulator that potently suppresses T cell activation. Overexpression of VISTA on tumors inhibits the protective anti-tumor immunity and blockade of VISTA enhances antitumor immunity in multiple tumor models. VISTA on APC delivers negative signaling to T cells via a yet-to-identify binding partner on T cells. Recently, it has been reported that the recombinant VISTA protein needs to be multimerized to be active as soluble ligand. The protein VISTA (human):COMP (mouse) (with the extracellular domain of VISTA (human) fused to the pentamerization domain from the cartilage oligomeric matrix protein (COMP)), but not VISTA-Fc, functions as an immunosuppressive agonist in vivo inhibiting the proliferation of CD4+ T cells.