VISTA is an activating receptor that binds the proteoglycan Syndecan-2 on monocytes.

As indicated by its name, V-domain Ig suppressor of T cell activation (VISTA) is thought to primarily serve as an inhibitory protein that limits immune responses. VISTA-antibodies can dampen the effects of several concomitantly elicited activation signals including T cell receptor (TCR) and Toll-like receptor (TLR) activation, but it is currently unclear if VISTA agonism could singly affect immune cell biology. In this study, we discovered two novel agonistic VISTA antibodies and characterized their effects on human peripheral blood mononuclear cells (PBMC) by scRNA/CITE-seq. Both antibodies agonize VISTA in an Fc-functional manner to elicit transcriptional and functional changes in monocytes consistent with activation. We also used pentameric VISTA to identify Syndecan-2 (Sdc2) and several heparan sulfate proteoglycan (HSPG) synthesis genes as novel regulators of VISTA binding to monocytic cells adding further evidence of bidirectional signaling. Together, our study highlights several novel aspects of VISTA biology that have yet to be uncovered in myeloid cells and serves as a foundation for future research. Examination of immune response to anti-VISTA treatment. There are four treatments included in the study: two anti-VISTA treatments (1B1-G1 and 5B1-G3) and two control (095 and msl109).