The apoptotic pathway contributing to the deletion of naive CD8 T cells during the induction of peripheral tolerance to a cross-presented self-antigen
The apoptotic pathway contributing to the deletion of naive CD8 T cells during the induction of peripheral tolerance to a cross-presented self-antigen
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DOI：
10.4049/jimmunol.180.8.5275
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发表时间：
2008-04-15
影响因子：
4.4
通讯作者：
Sherman, Linda A.
中科院分区：
文献类型：
--
作者：
Redmond, William L.;Wei, Cheng-Hong;Sherman, Linda A.
外周中T细胞耐受性的维持通过几种机制进行，包括无反应性、免疫调节和经由凋亡的缺失。我们研究了诱导CD 8 T细胞外周耐受胰岛β细胞上表达的自身抗原的机制。过继转移后，Ag特异性克隆4 T细胞经历了与外源性死亡受体（包括Fas、TNFR 1或TNFR 2）无关的缺失。另外的实验表明，诱导克隆4 T细胞凋亡在外周耐受发生通过一个内在的死亡途径，可以抑制Bcl-2的过表达或靶向删除的促凋亡分子，Bim，从而导致激活的克隆4 T细胞的积累。Bcl-2在克隆4 T细胞中的过表达促进了效应功能和胰岛炎的发展，而Bim（-/-）克隆4细胞没有自身攻击性。对克隆4 T细胞凋亡的上游分子机制的研究表明，它以p53，E2 F1和E2 F2独立的方式进行。总之，这些数据表明，在诱导外周耐受交叉呈递的自身Ag的过程中，克隆4 T细胞凋亡的起始通过Bcl-2敏感性和至少部分Bim依赖性机制发生。
The maintenance of T cell tolerance in the periphery proceeds through several mechanisms, including anergy, immuno-regulation, and deletion via apoptosis. We examined the mechanism underlying the induction of CD8 T cell peripheral tolerance to a self-Ag expressed on pancreatic islet beta-cells. Following adoptive transfer, Ag-specific clone 4 T cells underwent deletion independently of extrinsic death receptors, including Fas, TNFR1, or TNFR2. Additional experiments revealed that the induction of clone 4 T cell apoptosis during peripheral tolerance occurred via an intrinsic death pathway that could be inhibited by overexpression of Bcl-2 or targeted deletion of the proapoptotic molecule, Bim, thereby resulting in accumulation of activated clone 4 T cells. Over-expression of Bcl-2 in clone 4 T cells promoted the development of effector function and insulitis whereas Bim(-/-) clone 4 cells were not autoaggressive. Examination of the upstream molecular mechanisms contributing to clone 4 T cell apoptosis revealed that it proceeded in a p53, E2F1, and E2F2-independent manner. Taken together, these data reveal that initiation of clone 4 T cell apoptosis during the induction of peripheral tolerance to a cross-presented self-Ag occurs through a Bcl-2-sensitive and at least partially Bim-dependent mechanism.