Roberts Arthur I, Devadas Satish, Zhang Xiaoren, Zhang Liying, Keegan Achsah, Greeneltch Kristy, Solomon Jennifer, Wei Lixin, Das Jyoti, Sun Erwei, Liu Catherine, Yuan Zengrong, Zhou Jian-Nian, Shi Yufang
Department of Molecular Genetics, Microbiology and Immunology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 661 Hoes Lane, Piscataway, New Jersey 08854, USA.
Immunol Res. 2003;28(3):285-93. doi: 10.1385/IR:28:3:285.
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-lpr/lpr) 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.
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的分子机制及其在辅助性T细胞分化中的生理作用仍不明确。最近，我们发现Th1细胞和Th2细胞具有不同的AICD机制。我们的研究结果表明，细胞因子发出的信号启动了分化程序，但死亡效应分子的选择性作用决定了分化中的辅助性T细胞的命运，从而决定了辅助性T细胞亚群之间的最终平衡。在T细胞中，仅在Th2克隆和在Th2条件下分化的原代辅助性T细胞中观察到肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）的活化诱导表达，而CD95L（Fas配体）的表达主要发生在Th1细胞中。此外，Th1细胞比Th2细胞更容易受到TRAIL或CD95L诱导的凋亡影响，放射性标记的Th1细胞可被Th1细胞和Th2细胞通过自相残杀诱导凋亡，而Th2细胞则不受影响。泛半胱天冬酶抑制剂z-VAD可阻止Th1细胞中的AICD，但不能阻止Th2细胞中的AICD，这表明每种辅助性T细胞亚型中的AICD机制不同。对TRAIL和CD95L的抗体阻断在体外显著提高了干扰素-γ（IFN-γ）的产生。此外，具有突变型CD95（MRL/MpJ-lpr/lpr）的幼鼠对卵清蛋白免疫的Th1反应比对照组更强。我们得出结论，由CD95L和TRAIL介导的凋亡对于选择性清除分化中的辅助性T细胞至关重要。
