IFN-induced attrition of CD8 T cells in the presence or absence of cognate antigen during the early stages of viral infections
IFN-induced attrition of CD8 T cells in the presence or absence of cognate antigen during the early stages of viral infections
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DOI：
10.4049/jimmunol.176.7.4284
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发表时间：
2006-04-01
影响因子：
4.4
通讯作者：
Welsh, Raymond M.
中科院分区：
文献类型：
--
作者：
Bahl, Kapil;Kim, Sung-Kwon;Welsh, Raymond M.
在许多急性病毒感染期间已经观察到严重的淋巴细胞减少症，并且我们的实验室先前已经记录了在抗病毒T细胞应答的发展之前立即发生的CD 8 T细胞的I型IFN依赖性损失。大多数记忆（CD 44（高））和一些幼稚（CD 44（低））CD 8 T细胞对IFN诱导的损耗敏感，并且我们在这项研究中表明，IFN诱导的CD 8（+）CD 44（高）T细胞的损耗与caspase-3和caspase-8的活化升高相关。我们质疑TCR与Ag的结合是否会使CD 8 T细胞抵抗磨损。我们测试了高浓度的Ag（GP 33肽）是否会保护淋巴细胞性脉络丛脑膜炎（LCMV）特异性初始CD 8 T细胞（对LCMV的GP 33表位特异性的TCR转基因P14细胞）和记忆CD 8 T细胞（GP 33特异性LCMV免疫细胞）免于耗竭。无论是否预先给予宿主小鼠高浓度的GP 33肽，在接种Toll受体激动剂和IFN诱导剂poly（I：C）后16 h，幼稚P14和记忆GP 33特异性供体CD 8 T细胞均显著减少。此外，供体幼稚P14和LCMV特异性记忆细胞从第2天LCMV感染的宿主中耗尽，转移后16小时。这些结果表明，Ag接合不能保护CD 8 T细胞免受与病毒感染相关的IFN诱导的T细胞磨损。此外，计算机模型表明，记忆T细胞的早期耗竭可能通过减少由交叉反应性T细胞引起的免疫优势而允许产生对感染的更多样化的T细胞应答。
Profound lymphopenia has been observed during many acute viral infections, and our laboratory has previously documented a type I IFN-dependent loss of CD8 T cells immediately preceding the development of the antiviral T cell response. Most memory (CD44(high)) and some naive (CD44(low)) CD8 T cells are susceptible' to IFN-induced attrition, and we show in this study that the IFN-induced attrition of CD8(+)CD44(high) T cells is associated with elevated activation of caspase-3 and caspase-8. We questioned whether TCR engagement by Ag would render CD8 T cells resistant to attrition. We tested whether a high concentration of Ag (GP33 peptide) would protect lymphocytic choriomeningitis (LCMV)-specific naive CD8 T cells (TCR transgenic P14 cells specific for the GP33 epitope of LCMV) and memory CD8 T cells (GP33-specific LCMV-immune cells) from depletion. Both naive P14 and memory GP33-specific donor CD8 T cells decreased substantially 16 h after inoculation with the Toll receptor agonist and IFN inducer, poly(I:C), regardless of whether a high concentration of GP33 peptide was administered to host mice beforehand. Moreover, donor naive P14 and LCMV-specific memory cells were depleted from day 2 LCMV-infected hosts by 16 h posttransfer. These results indicate that Ag engagement does not protect CD8 T cells from the IFN-induced T cell attrition associated with viral infections. In addition, computer models indicated that early depletion of memory T cells may allow for the generation for a more diverse T cell response to infection by reducing the immunodomination caused by cross-reactive T cells.