Combined PD-1 and IL-10 blockade reinvigorates mucosal CD8⁺T exhaustion and relieves liver damage after intestinal...

Currently, impairments in gut mucosal immunity following intestinal ischemia reperfusion (IR) remain unclear. Mucosal CD8⁺T 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 CD8⁺T cell exhaustion, and that reinvigoration of exhausted CD8⁺T 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 CD8⁺T cells and the effector function of CD8⁺T cells were examined to determine the occurrence of intestinal mucosal CD8⁺T cell exhaustion. Subsequently, PD-1 blockade or combined PD-1 and IL-10 blockade was respectively used to reinvigorate exhausted CD8⁺T 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 CD8⁺T cell exhaustion in mucosal tissues, as evidenced by increased PD-1⁺ and PD-1⁺LAG-3⁺CD8⁺T cells and decreased IL-2 and TNF-α expression in CD8⁺T cells. Combined PD-1 and IL-10 blockade, but not PD-1 blockade alone, reinvigorated CD8⁺T cell exhaustion, as evidenced by increased generation of exhausted CD8⁺T 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 CD8⁺T cell exhaustion. Combined PD-1 and IL-10 blockade reinvigorates exhausted CD8⁺T cells, and ameliorates bacterial translocation and liver damage following IR.