Downregulated VISTA enhances Th17 differentiation and aggravates inflammation in patients with acute-on-chronic liver failure

Background and aims Persistent inflammatory response and immune activation are the core mechanisms underlying acute-on-chronic liver failure (ACLF). Previous studies have shown that deficiency of V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA) exacerbates the progression of inflammatory diseases. We aimed to clarify the role of VISTA in the pathogenesis of ACLF. Methods Blood and liver samples were collected from healthy subjects, stable cirrhosis, and ACLF patients to characterize VISTA expression and function. An ACLF mouse model was used to ascertain potential benefits of anti-VISTA monoclonal antibody (mAb) treatment. Results VISTA expression was significantly reduced in the naïve and central memory CD4 + T cells from patients with ACLF. The expression of VISTA on CD4 + T cells was associated with disease severity and prognosis. VISTA downregulation contributed to the activation and proliferation of CD4 + T cells and enhanced the differentiation of T helper 17 cells (Th17) and secretion of inflammatory cytokines through the activated Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway. Moreover, agonistic anti-VISTA mAb treatment inhibited the activation and cytokine production of CD4 + T cells and reduced mortality and liver inflammation of the ACLF mice. Conclusions The decreased expression of VISTA may facilitate development of Th17 cells and promote the progression of inflammation in ACLF patients. These findings are helpful for elucidating the pathogenesis of ACLF and for the identification of new drug targets. Graphical abstract