Arnold Rüdiger, Brenner Dirk, Becker Mareike, Frey Christian R, Krammer Peter H
Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany.
Eur J Immunol. 2006 Jul;36(7):1654-8. doi: 10.1002/eji.200636197.
While insufficient cell death of activated T cells can result in autoimmune disorders, elimination of too many T cells can lead to immunodeficiency. Therefore, T lymphocyte fate is highly regulated and requires that cells can switch from an apoptosis-resistant towards an apoptosis-sensitive state. This switch is tightly controlled by various effector molecules. Basically, two separate pathways control the fate of antigen-activated T cells: activation-induced cell death (AICD) and activated T cell autonomous death (ACAD). Autoreactive T lymphocytes are eliminated by restimulation via their T cell receptor (TCR) and undergo AICD involving death receptors (extrinsic pathway). In contrast, ACAD can lead to T cell deletion without TCR restimulation, and is determined by the ratio between anti- and pro-apoptotic Bcl-2 family members at the mitochondria (intrinsic pathway). While the extrinsic and the intrinsic pathway lead to caspase activation, non-caspase proteases (e.g., cathepsins) can be released by the lysosomes and might contribute to AICD as well as to ACAD. Activated T cells poses cell death escape mechanisms which are needed for survival of (memory) T cells, but are deleterious for autoimmune disorders or progression of T cell lymphomas.
虽然活化T细胞的细胞死亡不足会导致自身免疫性疾病，但过多T细胞的清除会导致免疫缺陷。因此，T淋巴细胞的命运受到高度调控，要求细胞能够从抗凋亡状态转变为凋亡敏感状态。这种转变受到各种效应分子的严格控制。基本上，两条独立的途径控制着抗原活化T细胞的命运：活化诱导的细胞死亡（AICD）和活化T细胞自主死亡（ACAD）。自身反应性T淋巴细胞通过其T细胞受体（TCR）的再次刺激而被清除，并经历涉及死亡受体的AICD（外在途径）。相比之下，ACAD可导致T细胞在无TCR再次刺激的情况下发生缺失，并由线粒体处抗凋亡和促凋亡Bcl-2家族成员之间的比例决定（内在途径）。虽然外在途径和内在途径都会导致半胱天冬酶激活，但非半胱天冬酶蛋白酶（如组织蛋白酶）可由溶酶体释放，也可能促成AICD以及ACAD。活化的T细胞具有细胞死亡逃逸机制，这对于（记忆）T细胞的存活是必需的，但对自身免疫性疾病或T细胞淋巴瘤的进展是有害的。
