Di Somma M M, Somma F, Gilardini Montani M S, Mangiacasale R, Cundari E, Piccolella E
Department of Cellular and Developmental Biology, "La Sapienza" University, Rome, Italy.
J Immunol. 1999 Apr 1;162(7):3851-8.
In this work, we have tried to establish whether human memory T cells may be protected from Fas (CD95)-induced apoptosis when correctly activated by Ag, and not protected when nonspecifically or incorrectly activated. In particular, we wanted to investigate the molecular mechanisms that regulate the fate of memory T cells following an antigenic challenge. To address this issue, we chose an experimental system that closely mimics physiological T cell activation such as human T cell lines and clones specific for viral peptides or alloantigens. We demonstrate that memory T cells acquire an activation-induced cell death (AICD)-resistant phenotype when TCRs are properly engaged by specific Ag bound to MHC molecules. Ag concentration and costimulation are critical parameters in regulating the protective effect. The analysis of the mechanisms involved in the block of CD95 signal transduction pathways revealed that the crucial events are the inhibition of CD95-associated IL-1beta-converting enzyme (ICE)-like protease (FLICE) activation and poly(ADP)-ribose polymerase cleavage, and the mRNA expression of FLICE-like inhibitory protein. Furthermore, we have observed that TCR-mediated neosynthesis of FLICE-like inhibitory protein mRNA is suppressed either by protein tyrosine kinase inhibitors or cyclosporin A. In conclusion, the present analysis of the effects of TCR triggering on the regulation of AICD suggests that AICD could be inhibited in human memory T cells activated in vivo by a foreign Ag, but may become operative when the Ag has been cleared.
在本研究中，我们试图确定人类记忆性T细胞在被抗原正确激活时是否能免受Fas（CD95）诱导的凋亡，而在非特异性或错误激活时是否不能受到保护。特别是，我们想研究抗原刺激后调节记忆性T细胞命运的分子机制。为了解决这个问题，我们选择了一个紧密模拟生理性T细胞激活的实验系统，如针对病毒肽或同种异体抗原的人类T细胞系和克隆。我们证明，当TCRs被与MHC分子结合的特异性抗原正确结合时，记忆性T细胞获得抗激活诱导细胞死亡（AICD）的表型。抗原浓度和共刺激是调节保护作用的关键参数。对CD95信号转导途径阻断所涉及机制的分析表明，关键事件是抑制与CD95相关的白介素-1β转换酶（ICE）样蛋白酶（FLICE）的激活和聚（ADP）-核糖聚合酶的裂解，以及FLICE样抑制蛋白的mRNA表达。此外，我们观察到，蛋白酪氨酸激酶抑制剂或环孢素A均可抑制TCR介导的FLICE样抑制蛋白mRNA的新生合成。总之，目前对TCR触发对AICD调节作用的分析表明，在体内被外来抗原激活的人类记忆性T细胞中，AICD可能被抑制，但当抗原被清除后，AICD可能会起作用。
