Elevated ascitic interleukin-36 receptor antagonist mediates CD8+T cell exhaustion in vitro in liver cirrhotic patients with spontaneous bacterial peritonitis.

Interleukin-36 (IL-36) signaling pathway plays an important regulatory role in inflammatory and infectious diseases. However, the modulatory function of IL-36 in CD8+T cells that are involved in liver cirrhosis with spontaneous bacterial peritonitis (SBP) has not been understood. Sixty-five liver cirrhotic patients (42 untainted ascites and 23 SBP patients) and 20 controls were included. IL-36 levels were measured by ELISA. CD8+T cells were purified from ascites, and were stimulated with IL-36 receptor antagonist (IL-36RA). CD8+T cells were co-cultured with HepG2 cells in direct contact and indirect contact manners. Target cell death and cytotoxic molecules levels were investigated to assess CD8+T cell cytotoxicity. The immune-checkpoint molecules expressions on CD8+T cells were measured by flow cytometry. There were no significant differences in IL-36alpha, IL-36beta, or IL-36gamma levels between untainted ascites and SBP patients. SBP patients had increased ascitic IL-36RA, which positively correlated with alanine aminotransferase and ascitic neutrophil count. IL-36RA stimulation did not affect CD8+T cell proliferation, but dampened CD8+T cell-induced cell death and proinflammatory cytokine secretions. Perforin and granzyme B productions were down-regulated in direct contact manner. IL-36RA stimulation promoted immune-checkpoint molecules expressions on CD8+T cells. The present findings revealed that elevated ascitic IL-36RA might inhibit ascitic CD8+T cell cytotoxicty in liver cirrhotic patients with SBP.