Caspase-3 is transiently activated without cell death during early antigen driven expansion of CD8(+) T cells in vivo.
Caspase-3 is transiently activated without cell death during early antigen driven expansion of CD8(+) T cells in vivo.
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DOI：
10.1371/journal.pone.0015328
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发表时间：
2010-12-22
期刊：
影响因子：
3.7
通讯作者：
Sad S
中科院分区：
文献类型：
--
作者：
McComb S;Mulligan R;Sad S
CD8+ T细胞反应在感染期间迅速发展，在收缩期间迅速减少，其中约90%的启动CD8+ T细胞被消除。凋亡机制在控制CD8+ T细胞快速增殖和收缩中的作用尚不清楚。令人惊讶的是，有证据表明caspase-3的非凋亡激活发生在体外T细胞增殖过程中，但这些机制与体内CD8+ T细胞反应的相关性尚未得到检验。我们已经评估了caspase-3的活性，caspase-3是凋亡的关键下游诱导剂，贯穿于CD8+ T细胞应答的整个过程。我们使用了两种感染模型，它们在抗原呈递和炎症的强度、发作和持续时间上有所不同。cleaved caspase-3在抗原特异性CD8+ T细胞中的表达与淋巴器官中抗原呈递的时间和强度有关。我们还观察到其他典型凋亡标志物的协调激活，包括磷脂酰丝氨酸暴露。限制性稀释分析直接显示，在IL7存在的情况下，caspase-3hi和caspase-3low CD8+ T细胞都很少发生细胞死亡。活性caspase-3的表达在效应表型（cd62low） CD8+ T细胞出现之前达到峰值，在效应表型细胞中检测不到。此外，ova特异性CD8+细胞在整个收缩期保持caspase- 30低活性。我们的结果特别暗示抗原而不是炎症在驱动凋亡机制的激活而不导致增殖的CD8+ T细胞死亡。此外，CD8+ T细胞扩增后反应的收缩可能不是由关键的下游凋亡诱导剂caspase-3介导的。
CD8+ T cell responses develop rapidly during infection and are swiftly reduced during contraction, wherein >90% of primed CD8+ T cells are eliminated. The role of apoptotic mechanisms in controlling this rapid proliferation and contraction of CD8+ T cells remains unclear. Surprisingly, evidence has shown non-apoptotic activation of caspase-3 to occur during in vitro T-cell proliferation, but the relevance of these mechanisms to in vivo CD8+ T cell responses has yet to be examined. We have evaluated the activity of caspase-3, a key downstream inducer of apoptosis, throughout the entirety of a CD8+ T cell response. We utilized two infection models that differ in the intensity, onset and duration of antigen-presentation and inflammation. Expression of cleaved caspase-3 in antigen specific CD8+ T cells was coupled to the timing and strength of antigen presentation in lymphoid organs. We also observed coordinated activation of additional canonical apoptotic markers, including phosphatidylserine exposure. Limiting dilution analysis directly showed that in the presence of IL7, very little cell death occurred in both caspase-3hi and caspase-3low CD8+ T cells. The expression of active caspase-3 peaked before effector phenotype (CD62Llow) CD8+ T cells emerged, and was undetectable in effector-phenotype cells. In addition, OVA-specific CD8+ cells remained active caspase-3low throughout the contraction phase. Our results specifically implicate antigen and not inflammation in driving activation of apoptotic mechanisms without cell death in proliferating CD8+ T cells. Furthermore, the contraction of CD8+ T cell response following expansion is likely not mediated by the key downstream apoptosis inducer, caspase-3.
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