The role of activation-induced cell death in the differentiation of T-helper-cell subsets
The role of activation-induced cell death in the differentiation of T-helper-cell subsets
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DOI：
10.1385/ir:28:3:285
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发表时间：
2003-01-01
影响因子：
4.4
通讯作者：
Shi, YF
中科院分区：
文献类型：
--
作者：
Roberts, AI;Devadas, S;Shi, YF
活化诱导的细胞死亡（AICD）已在T细胞杂交瘤、未成熟胸腺细胞和活化的成熟T细胞中得到证实。然而，AICD的分子机制及其在T辅助细胞分化中的生理作用仍不清楚。最近，我们发现Th 1和Th 2细胞具有不同的AICD机制。我们的研究结果表明，从细胞因子的信号启动分化程序，但死亡效应的选择性行动决定分化的T辅助细胞的命运，因此，T辅助细胞亚群之间的最终平衡。在T细胞中，活化诱导的肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）表达仅在Th 2克隆和Th 2条件下分化的原代辅助性T细胞中观察到，而CD 95 L（Fas配体）的表达主要发生在Th 1细胞中。此外，Th 1细胞比Th 2细胞更容易受到通过TRAIL或CD 95 L诱导的凋亡的影响，并且放射性标记的Th 1细胞可以通过Th 1和Th 2细胞的自相残杀而被诱导凋亡，而Th 2细胞则不受影响。泛半胱天冬酶抑制剂，z-VAD，防止AICD在Th 1细胞，但不是Th 2细胞，表明不同的机制AICD在每个辅助性T细胞亚型。TRAIL和CD 95 L的抗体阻断显著增强干扰素-γ（IFN-γ）的体外产生。此外，年轻的小鼠与突变的CD 95（MRL/MpJ-1 pr/1 pr）有一个更强的Th 1卵清蛋白免疫的反应比对照组。我们的结论是CD 95 L和TRAIL介导的细胞凋亡是关键的选择性去除分化的T辅助细胞。
Activation-induced cell death (AICD) has been demonstrated in T-cell hybridomas, immature thymocytes, and activated mature T cells. However, the molecular mechanisms of AICD and its physiological role in T-helper-cell differentiation remain uncertain. Recently, we have shown that Th1 and Th2 cells have distinct mechanisms of AICD. Our findings suggest that signaling from cytokines initiates the differentiation program, but that the selective action of death effectors determines the fate of differentiating T-helper cells, and thus, the ultimate balance between T-helper subpopulations. Among T cells, activation-induced expression of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is observed exclusively in Th2 clones and primary T-helper cells differentiated under Th2 conditions, while the expression of CD95L (Fas ligand) occurs mainly in Th1 cells. Furthermore, Th1 cells are more susceptible than Th2 cells to apoptosis induced through either TRAIL or CD95L, and radiolabeled Th1 cells can be induced into apoptosis via fratricide by both Th1 and Th2 cells, while Th2 cells are spared. The pan-caspase inhibitor, z-VAD, prevents AICD in Th1 cells, but not Th2 cells, indicating different mechanisms of AICD in each T-helper subtype. Antibody blockade of TRAIL and CD95L significantly boosts interferon-gamma (IFN-gamma) production in vitro. Also, young mice with mutant CD95 (MRL/MpJ-1pr/1pr) have a stronger Th1 response to ovalbumin immunization than do controls. We conclude that apoptosis mediated by CD95L and TRAIL is critical in the selective removal of differentiating T helper cells.