Combined PD-1 and IL-10 blockade reinvigorates mucosal CD8T exhaustion and relieves liver damage after intestinal ischemia reperfusion attack.

Currently, impairments in gut mucosal immunity following intestinal ischemia reperfusion (IR) remain unclear. Mucosal CD8T cells are critical for host defense against bacterial translocation from the gut lumen, and exhausted T cells lose robust effector functions. The present study was designed to verify the hypothesis that intestinal IR leads to mucosal CD8T cell exhaustion, and that reinvigoration of exhausted CD8T cell attenuates IR-induced bacterial translocation and liver damage. The intestinal IR model was performed through clamping the superior mesenteric artery in mice. The percent of exhausted CD8T cells and the effector function of CD8T cells were examined to determine the occurrence of intestinal mucosal CD8T cell exhaustion. Subsequently, PD-1 blockade or combined PD-1 and IL-10 blockade was respectively used to reinvigorate exhausted CD8T cells. Serum biomarkers, bacterial RNA and colonies, and inflammatory factors were examined to determine bacterial translocation and liver damage. The results indicated that intestinal IR induced CD8T cell exhaustion in mucosal tissues, as evidenced by increased PD-1 and PD-1LAG-3CD8T cells and decreased IL-2 and TNF-α expression in CD8T cells. Combined PD-1 and IL-10 blockade, but not PD-1 blockade alone, reinvigorated CD8T cell exhaustion, as evidenced by increased generation of exhausted CD8T cells with cytotoxicity and effector function, and elevated production of IFN-γ. Moreover, combined blockade significantly reduced the translocation of gut bacteria and injury to the liver after IR. In conclusion, intestinal IR leads to mucosal CD8T cell exhaustion. Combined PD-1 and IL-10 blockade reinvigorates exhausted CD8T cells, and ameliorates bacterial translocation and liver damage following IR.