VISTA (V-region Immunoglobulin-containing Suppressor of T cell Activation) is a member of the B7 negative checkpoint regulator (NCR) family that controls normal immunity and prevents autoimmunity. Unlike other NCRs (PD-1, BTLA, etc.), many of the unique immunologic activities of VISTA would predict an important role in preventing SLE. VISTA has bi-directional functionality, acting as both a ligand and a receptor. As a ligand expressed on myeloid cells, we have shown that it suppresses the earliest events in T cell activation through a putative VISTA counter-receptor, V-set and immunoglobulin domain containing 8 (VSIG8). VISTA can also act as a receptor on T cells and myeloid cells that regulates their biology. In addition, VISTA mediates the uptake of apoptotic cells, a central mechanism in the pathogenesis of SLE. All of these functions bear heavily on the central role of the VISTA-VSIG8 pathway in the development of SLE. In this application, we now provide genetic proof that the VISTA pathway does indeed protect susceptible hosts from the development of fatal lupus. Furthermore, we present evidence that VISTA may prevent end organ damage in SLE by regulating the critical myeloid cell effector phase. Our identification of VSIG8 as the VISTA counter-receptor will allow us to elucidate in full detail how this pathway controls the development of SLE. Furthermore, strategic approaches to target this pathway for therapeutic gain will be tested. The unique engineered tools and genetic models we have created in our lab will allow us to define the critical mechanisms by which the VISTA-VSIG8 pathway impacts on SLE. Finally, these studies will facilitate the design of therapeutic strategies to intervene in human SLE, a disease with a large unmet therapeutic need. Specific Aim 1. Identify the cellular and molecular mechanisms responsible for the development of fatal SLE when the VISTA-VSIG8 pathway is disrupted. With the lineage-restricted deficiency of VISTA in the T, myeloid and/or dendritic cell compartments, we will evaluate how this loss results in the emergence of specific SLE pathologies and how VISTA deficiency on the sle1,3 background impacts on leukocyte immune function. Mice in which VSIG8 is conditionally-deleted will be used in parallel to address the impact of VSIG8-deficiency in the development of SLE. Specific Aim 2. Define the immune functions of VSIG8 as the VISTA counter-receptor. Studies show VSIG8 binds specifically to VISTA and is involved with VISTA-mediated suppression. As little is known about the function of VSIG8 in the immune system, a comprehensive, systematic approach is presented to demonstrate that VSIG8 is the receptor for VISTA that mediates defined VISTA-specific functions in vitro and in vivo. Specific Aim 3. Targeting the VISTA-VSIG8 pathway in SLE for therapeutic gain. Multiple strategies to target the VISTA-VSIG8 pathway to achieve therapeutic success are presented. First is the use of VISTA-Ig that has demonstrated impressive therapeutic activity. Secondly, the use of ?VISTA antibodies that profoundly suppress T cell immunity in vivo. Finally, the identity of the VISTA receptor, VSIG8, provides a novel target for intervening in this pathway in SLE.