Liu Zi-Meng, Zhang Yi-Nan, Zhang Hu-Fei, Zhang Xu-Yu
Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Biochem Biophys Res Commun. 2025 Jan;742:151137. doi: 10.1016/j.bbrc.2024.151137. Epub 2024 Dec 5.
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.
目前，肠道缺血再灌注（IR）后肠道黏膜免疫损伤仍不清楚。黏膜CD8 T细胞对于宿主抵御细菌从肠腔移位至关重要，而耗竭的T细胞会丧失强大的效应功能。本研究旨在验证以下假设：肠道IR会导致黏膜CD8 T细胞耗竭，而恢复耗竭的CD8 T细胞活力可减轻IR诱导的细菌移位和肝损伤。通过夹闭小鼠肠系膜上动脉建立肠道IR模型。检测耗竭的CD8 T细胞百分比和CD8 T细胞的效应功能，以确定肠道黏膜CD8 T细胞耗竭的发生情况。随后，分别使用PD-1阻断或联合PD-1和IL-10阻断来恢复耗竭的CD8 T细胞活力。检测血清生物标志物、细菌RNA和菌落以及炎性因子，以确定细菌移位和肝损伤情况。结果表明，肠道IR诱导黏膜组织中CD8 T细胞耗竭，表现为PD-1和PD-1LAG-3 CD8 T细胞增加以及CD8 T细胞中IL-2和TNF-α表达降低。联合PD-1和IL-10阻断而非单独的PD-1阻断可恢复CD8 T细胞耗竭，表现为具有细胞毒性和效应功能的耗竭CD8 T细胞生成增加以及IFN-γ产生升高。此外，联合阻断显著减少了IR后肠道细菌的移位和肝脏损伤。总之，肠道IR导致黏膜CD8 T细胞耗竭。联合PD-1和IL-10阻断可恢复耗竭的CD8 T细胞活力，并改善IR后的细菌移位和肝损伤。
