Cameron W Paterson, Katherine T Fay, Ching-Wen Chen, Nathan J Klingensmith, Melissa B Gutierrez, Zhe Liang, Craig M Coopersmith, Mandy L Ford
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引用次数: 0
摘要
长期酗酒会增加败血症的发病率和死亡率。慢性酒精中毒和败血症的特点都是免疫失调,包括 T 细胞共抑制分子的过度表达。我们试图利用一种慢性酒精摄入并随后进行盲肠结扎和穿刺的小鼠模型来描述 CTLA-4 在慢性酒精暴露的败血症中的作用。结果表明,与饮酒假对照组或饮水败血症小鼠相比,从饮酒败血症小鼠体内分离出的 CD4+ T 细胞中 CTLA-4 表达增加。此外,检查点抑制 CTLA-4 能提高饮酒败血症小鼠的败血症存活率,但不能提高饮水败血症小鼠的存活率。在药物性 CTLA-4 阻断后,以及在 CD4+ T 细胞中条件性 Ctla4 缺失后,对这些动物体内 T 细胞分区的研究表明,CTLA-4 的缺乏促进了效应调节性 T 细胞的活化和增殖,并促进了常规效应记忆 CD4+ T 细胞的生成。这些数据强调了CTLA-4在慢性酒精暴露情况下介导败血症死亡过程中的重要作用,并可能为未来开发针对这一患者群体的靶向疗法提供参考。
CTLA-4 Checkpoint Inhibition Improves Sepsis Survival in Alcohol-Exposed Mice.
Chronic alcohol use increases morbidity and mortality in the setting of sepsis. Both chronic alcohol use and sepsis are characterized by immune dysregulation, including overexpression of T cell coinhibitory molecules. We sought to characterize the role of CTLA-4 during sepsis in the setting of chronic alcohol exposure using a murine model of chronic alcohol ingestion followed by cecal ligation and puncture. Results indicated that CTLA-4 expression is increased on CD4+ T cells isolated from alcohol-drinking septic mice as compared with either alcohol-drinking sham controls or water-drinking septic mice. Moreover, checkpoint inhibition of CTLA-4 improved sepsis survival in alcohol-drinking septic mice, but not water-drinking septic mice. Interrogation of the T cell compartments in these animals following pharmacologic CTLA-4 blockade, as well as following conditional Ctla4 deletion in CD4+ T cells, revealed that CTLA-4 deficiency promoted the activation and proliferation of effector regulatory T cells and the generation of conventional effector memory CD4+ T cells. These data highlight an important role for CTLA-4 in mediating mortality during sepsis in the setting of chronic alcohol exposure and may inform future approaches to develop targeted therapies for this patient population.