Attrition of memory CD8 T cells during sepsis requires LFA-1
Attrition of memory CD8 T cells during sepsis requires LFA-1
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DOI：
10.1189/jlb.4a1215-563rr
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发表时间：
2016-11-01
影响因子：
5.5
通讯作者：
McConnell, Kevin W.
中科院分区：
文献类型：
--
作者：
Serbanescu, Mara A.;Ramonell, Kimberly M.;McConnell, Kevin W.
CD8 T 细胞丢失和功能障碍与脓毒症后期免疫抑制阶段机会性感染的易感性增加有关，但脓毒症早期 CD8 T 细胞的激活和损耗仍不完全清楚。通过使用 CLP 模型，我们评估了 5 个连续时间点的 CD8 T 细胞活化，发现脓毒症后的活化导致独特的表型 (CD69(+)CD25(int)CD62L(HI))，独立于同源抗原识别和 TCR 参与，并且可能通过旁观者介导的细胞因子效应。此外，我们观察到脓毒症同时导致记忆表型 CD8 T 细胞子集的优先耗尽，这些细胞通过细胞凋亡而保持“未激活”（即无法上调激活标记）。 CLP后1小时，未激活的CD44(HI) OT-I细胞免受脓毒症引起的损耗，用抗LFA-1 mAb处理的小鼠的记忆表型CD8 T细胞也是如此。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IL-6水平升高与脓毒症小鼠中记忆表型CD8 T细胞数量减少有关，并且在施用抗LFA-1 mAb后保留该子集可提高7天的存活率。总而言之，这些数据确定了早期脓毒症中记忆表型 CD8 T 细胞的潜在可改变反应，并且对于脓毒症免疫调节疗法的应用可能特别重要。
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 (CD69(+)CD25(int)CD62L(HI)) 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(HI) 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.