Targeting of immune, negative checkpoint regulator (NCR) pathways is revolutionizing the treatment of human cancers and has established that these pathways are proven clinical targets in human disease. VISTA (V-region Immunoglobulin-containing Suppressor of T cell Activation), is a recently-identified NCR ligand whose closest phylogenetic relative is PD-L1. VISTA inhibits T cell activation and suppresses immunity. The studies presented investigate the involvement of the VISTA pathway in the development and pathogenesis of SLE, as well as the therapeutic value of targeting the VISTA pathway in the treatment of this disease. The Specific Aims of this proposal are to elucidate the cellular and molecular basis for suppression of murine SLE by VISTA-Ig. Therapy with VISTA-Ig, an agonist that induces immune suppression, in murine SLE has proven strikingly effective in rapidly and profoundly resolving disease. As a monotherapy, it is likely the most effective therapy described to date in resolving late stage SLE. The second specific aim is to define the natural immunoregulatory role of VISTA in regulating tolerance and controlling the development of murine SLE. Together, these complementary specific aims will provide new insights into the immunoregulatory function of VISTA and provide support for developing VISTA-Ig as a new drug to treat lupus.