Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Immunol Rev. 2010 Jul;236:68-82. doi: 10.1111/j.1600-065X.2010.00917.x.
Controlled expansion and contraction of lymphocytes both during and after an adaptive immune response are imperative to sustain a healthy immune system. Both extrinsic and intrinsic pathways of lymphocyte apoptosis are programmed to eliminate cells at the proper time to ensure immune homeostasis. Genetic disorders of apoptosis described in mice and humans have established Fas and Bim as critical pro-apoptotic molecules responsible for T-cell death in response to T-cell receptor restimulation and cytokine withdrawal, respectively. Emerging evidence prompts revision of this classic paradigm, especially for our understanding of restimulation-induced cell death (RICD) and its physiological purpose. Recent work indicates that RICD employs both Fas and Bim for T-cell deletion, dispelling the notion that these molecules are assigned to mutually exclusive apoptotic pathways. Furthermore, new mouse model data combined with our discovery of defective RICD in X-linked lymphoproliferative disease (XLP) patient T cells suggest that RICD is essential for precluding excess T-cell accumulation and associated immunopathology during the course of certain infections. Here, we review how these advances offer a refreshing new perspective on the phenomenon of T-cell apoptosis induced through antigen restimulation, including its relevance to immune homeostasis and potential for therapeutic interventions.
在适应性免疫反应期间和之后，淋巴细胞的受控扩张和收缩对于维持健康的免疫系统至关重要。淋巴细胞凋亡的外在和内在途径都经过编程，以便在适当的时间消除细胞，从而确保免疫稳态。在小鼠和人类中描述的凋亡遗传障碍已经确定 Fas 和 Bim 是负责 T 细胞死亡的关键促凋亡分子，分别负责 T 细胞受体再刺激和细胞因子耗竭时的 T 细胞死亡。新出现的证据促使人们对这一经典范例进行修订，特别是对于我们对再刺激诱导的细胞死亡 (RICD) 及其生理目的的理解。最近的工作表明，RICD 既利用 Fas 也利用 Bim 来进行 T 细胞删除，消除了这些分子被分配到相互排斥的凋亡途径的观念。此外，新的小鼠模型数据结合我们在 X 连锁淋巴组织增生性疾病 (XLP) 患者 T 细胞中发现的 RICD 缺陷表明，RICD 对于防止在某些感染过程中过度 T 细胞积累和相关免疫病理学至关重要。在这里，我们回顾了这些进展如何为通过抗原再刺激诱导的 T 细胞凋亡现象提供了一个全新的视角，包括其与免疫稳态的相关性和潜在的治疗干预措施。
