{"title":"Combined PD-1 and IL-10 blockade reinvigorates mucosal CD8<sup>+</sup>T exhaustion and relieves liver damage after intestinal ischemia reperfusion attack.","authors":"Zi-Meng Liu, Yi-Nan Zhang, Hu-Fei Zhang, Xu-Yu Zhang","doi":"10.1016/j.bbrc.2024.151137","DOIUrl":null,"url":null,"abstract":"<p><p>Currently, impairments in gut mucosal immunity following intestinal ischemia reperfusion (IR) remain unclear. Mucosal CD8<sup>+</sup>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<sup>+</sup>T cell exhaustion, and that reinvigoration of exhausted CD8<sup>+</sup>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<sup>+</sup>T cells and the effector function of CD8<sup>+</sup>T cells were examined to determine the occurrence of intestinal mucosal CD8<sup>+</sup>T cell exhaustion. Subsequently, PD-1 blockade or combined PD-1 and IL-10 blockade was respectively used to reinvigorate exhausted CD8<sup>+</sup>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<sup>+</sup>T cell exhaustion in mucosal tissues, as evidenced by increased PD-1<sup>+</sup> and PD-1<sup>+</sup>LAG-3<sup>+</sup>CD8<sup>+</sup>T cells and decreased IL-2 and TNF-α expression in CD8<sup>+</sup>T cells. Combined PD-1 and IL-10 blockade, but not PD-1 blockade alone, reinvigorated CD8<sup>+</sup>T cell exhaustion, as evidenced by increased generation of exhausted CD8<sup>+</sup>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<sup>+</sup>T cell exhaustion. Combined PD-1 and IL-10 blockade reinvigorates exhausted CD8<sup>+</sup>T cells, and ameliorates bacterial translocation and liver damage following IR.</p>","PeriodicalId":8779,"journal":{"name":"Biochemical and biophysical research communications","volume":"742 ","pages":"151137"},"PeriodicalIF":2.5000,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochemical and biophysical research communications","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.bbrc.2024.151137","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/12/5 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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.
期刊介绍:
Biochemical and Biophysical Research Communications is the premier international journal devoted to the very rapid dissemination of timely and significant experimental results in diverse fields of biological research. The development of the "Breakthroughs and Views" section brings the minireview format to the journal, and issues often contain collections of special interest manuscripts. BBRC is published weekly (52 issues/year).Research Areas now include: Biochemistry; biophysics; cell biology; developmental biology; immunology
; molecular biology; neurobiology; plant biology and proteomics