Serbanescu Mara A, Ramonell Kimberly M, Hadley Annette, Margoles Lindsay M, Mittal Rohit, Lyons John D, Liang Zhe, Coopersmith Craig M, Ford Mandy L, McConnell Kevin W
Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, Georgia, USA.
Department of Infectious Diseases and Emory Critical Care Center, Emory University School of Medicine, Atlanta, Georgia, USA; and.
J Leukoc Biol. 2016 Nov;100(5):1167-1180. doi: 10.1189/jlb.4A1215-563RR. Epub 2016 Jun 10.
CD8 T cell loss and dysfunction have been implicated in the increased susceptibility to opportunistic infections during the later immunosuppressive phase of sepsis, but CD8 T cell activation and attrition in early sepsis remain incompletely understood. With the use of a CLP model, we assessed CD8 T cell activation at 5 consecutive time points and found that activation after sepsis results in a distinct phenotype (CD69CD25CD62L) independent of cognate antigen recognition and TCR engagement and likely through bystander-mediated cytokine effects. Additionally, we observed that sepsis concurrently results in the preferential depletion of a subset of memory-phenotype CD8 T cells that remain "unactivated" (i.e., fail to up-regulate activation markers) by apoptosis. Unactivated CD44 OT-I cells were spared from sepsis-induced attrition, as were memory-phenotype CD8 T cells of mice treated with anti-LFA-1 mAb, 1 h after CLP. Perhaps most importantly, we demonstrate that attrition of memory phenotype cells may have a pathologic significance, as elevated IL-6 levels were associated with decreased numbers of memory-phenotype CD8 T cells in septic mice, and preservation of this subset after administration of anti-LFA-1 mAb conferred improved survival at 7 d. Taken together, these data identify potentially modifiable responses of memory-phenotype CD8 T cells in early sepsis and may be particularly important in the application of immunomodulatory therapies in sepsis.
CD8 T细胞的丧失和功能障碍与脓毒症后期免疫抑制阶段对机会性感染易感性增加有关，但脓毒症早期CD8 T细胞的激活和损耗仍未完全明确。利用盲肠结扎穿孔（CLP）模型，我们在5个连续时间点评估了CD8 T细胞的激活情况，发现脓毒症后的激活导致一种独特的表型（CD69⁺CD25⁺CD62L⁻），该表型独立于同源抗原识别和TCR参与，可能是通过旁观者介导的细胞因子效应产生的。此外，我们观察到脓毒症同时导致一部分记忆表型CD8 T细胞通过凋亡被优先消耗，这些细胞保持“未激活”状态（即未能上调激活标志物）。未激活的CD44⁺ OT-I细胞以及CLP术后1小时用抗LFA-1单克隆抗体处理的小鼠的记忆表型CD8 T细胞未受到脓毒症诱导的损耗。也许最重要的是，我们证明记忆表型细胞的损耗可能具有病理意义，因为脓毒症小鼠中IL-6水平升高与记忆表型CD8 T细胞数量减少有关，而给予抗LFA-1单克隆抗体后该亚群的保留使7天时的生存率提高。综上所述，这些数据确定了脓毒症早期记忆表型CD8 T细胞潜在的可调节反应，这在脓毒症免疫调节治疗的应用中可能尤为重要。
