Analysis of Apoptosis of Memory T Cells and Dendritic Cells during the Early Stages of Viral Infection or Exposure to Toll-Like Receptor Agonists
Analysis of Apoptosis of Memory T Cells and Dendritic Cells during the Early Stages of Viral Infection or Exposure to Toll-Like Receptor Agonists
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DOI：
10.1128/jvi.02571-09
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发表时间：
2010-05-01
影响因子：
5.4
通讯作者：
Welsh, Raymond M.
中科院分区：
文献类型：
--
作者：
Bahl, Kapil;Huebner, Anette;Welsh, Raymond M.
记忆性CD8和CD4 T细胞的深刻的I型干扰素（IFN-I）依赖性损耗在许多感染的早期发生。在小鼠淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染后2至4天是显著的，并且可以由IFN诱导的Toll受体激动剂poly（I：C）引起。我们发现，这种磨损发生在许多器官，表明这是由于T细胞的损失，而不是重新分配。这种损失与活化的半胱天冬酶的离体T细胞的细胞内染色升高相关，但与膜联蛋白V的离体染色仅低水平相关，这可能是由于凋亡细胞在体内的快速清除。相反，随着记忆T细胞群的消失，高频率的膜联蛋白V反应性CD8 α（+）树突状细胞（DC）（已知具有高度吞噬作用）在脾脏中积累。经过短暂的体外孵育，记忆表型T细胞分离LCMV感染的小鼠（第3天）或小鼠与聚（I：C）（12小时）显示大量的DNA片段，通过末端脱氧核苷酸转移酶介导的dUTP-生物素缺口末端标记（TUNEL）检测，与T细胞分离未感染的小鼠相比，表明在记忆T细胞磨损的凋亡的作用。在缺乏促凋亡分子Bim的小鼠中，LCMV感染早期记忆性CD8 T细胞的凋亡减少。有证据表明，高水平的T细胞磨损，如在年轻小鼠中发现的，与交叉反应性记忆细胞的免疫优势降低相关。
Profound type I interferon (IFN-I)-dependent attrition of memory CD8 and CD4 T cells occurs early during many infections. It is dramatic at 2 to 4 days following lymphocytic choriomeningitis virus (LCMV) infection of mice and can be elicited by the IFN-inducing Toll receptor agonist poly(I: C). We show that this attrition occurs in many organs, indicating that it is due to T cell loss rather than redistribution. This loss correlated with elevated intracellular staining of T cells ex vivo for activated caspases but with only low levels of ex vivo staining with annexin V, probably due to the rapid clearance of apoptotic cells in vivo. Instead, a high frequency of annexin V-reactive CD8 alpha(+) dendritic cells (DCs), which are known to be highly phagocytic, accumulated in the spleen as the memory T cell populations disappeared. After short in vitro incubation, memory phenotype T cells isolated from LCMV-infected mice (day 3) or mice treated with poly(I: C) (12 h) displayed substantial DNA fragmentation, as detected by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, compared to T cells isolated from uninfected mice, indicating a role for apoptosis in the memory T cell attrition. This apoptosis of memory CD8 T cells early during LCMV infection was reduced in mice lacking the proapoptotic molecule Bim. Evidence is presented showing that high levels of T cell attrition, as found in young mice, correlate with reduced immunodomination by cross-reactive memory cells.