Jinghua Wang, Guoping Wu, Brian Manick, Vida Hernandez, Mark Renelt, Ming Bi, Jun Li, and Vassilios Kalabokis
B7 family members and their receptors play a central role in the regulation of T cell responses through T cell co-stimulatory and co-inhibitory pathways that constitute very attractive targets for the development of immunotherapeutic drugs. In this study, we report that VSIG-3/IGSF11 is a ligand of the B7 family member VISTA/PD-1H that inhibits human T cell functions through a novel VSIG-3/VISTA pathway. An extensive functional ELISA binding screening assay reveals that VSIG-3 binds the new B7 family member VISTA, but does not interact with other known members of the B7 family. Furthermore, VSIG-3 inhibits human T cell proliferation in the presence of T cell receptor signaling. In addition, VSIG-3 significantly reduces cytokine and chemokine production by human T cells including IFN-g, IL-2, IL-17, CCL5/RANTES, CCL3/MIP-1a, and CXCL11/I-TAC. Anti-VISTA neutralization antibodies attenuate the binding of VSIG-3 to VISTA, as well as VSIG-3-induced T cell inhibition. Thus, we have identified a novel B7 pathway that is able to inhibit human T cell proliferation and cytokine production. This unique VSIG-3/VISTA co-inhibitory pathway may provide new strategies for the treatment of human cancers, autoimmune disorders, infection, and transplant rejection, and may help to design better vaccines.