V-domain immunoglobulin suppressor of T-cell activation regulates CD4+ T cell activation and podocyte function through PI3K/AKT signaling pathway.

The activation of V-domain immunoglobulin suppressor of T-cell activation (VISTA) has shown its therapeutic potential in murine lupus-like disease through immunoregulation, particularly suppressing CD4+ T cell activation. Podocytes are critical for preventing proteinuria in lupus nephritis (LN). However, the mechanisms by which VISTA regulate CD4+ T cells and renal podocytes remain unclear. Here, we demonstrated that CD4+ T cells from VISTA knockout mice showed upregulated phosphorylation of PI3K/AKT, increased secretion of IFN-γ, IL-17 and CD40L. Soluble VISTA mitigated inflammation and recovered the expression of structural proteins Podocin through inhibition of PI3K/AKT/mTOR signaling pathway and induction of autophagy. Moreover, previously demonstrated VISTA agonist Baloxavir marboxil decreased renal CD4+ T cells, restored the expression of Nephrin and Podocin, and promoted autophagy. Our study suggests that VISTA plays an important role in the pathogenesis of LN, which offers novel mechanisms and potential target for its application in LN therapy.