Department of Immunology, University of Washington, Seattle, WA 98195, USA.
J Immunol. 2011 Jan 15;186(2):799-806. doi: 10.4049/jimmunol.1002933. Epub 2010 Dec 10.
Peripheral CD4(+)Vβ5(+) T cells are tolerized to an endogenous mouse mammary tumor virus superantigen either by deletion or TCR revision. Through TCR revision, RAG reexpression mediates extrathymic TCRβ rearrangement and results in a population of postrevision CD4(+)Vβ5(-) T cells expressing revised TCRβ chains. We have hypothesized that cell death pathways regulate the selection of cells undergoing TCR revision to ensure the safety and utility of the postrevision population. In this study, we investigate the role of Bcl-2-interacting mediator of cell death (Bim)-mediated cell death in autoantigen-driven deletion and TCR revision. Bim deficiency and Bcl-2 overexpression in Vβ5 transgenic (Tg) mice both impair peripheral deletion. Vβ5 Tg Bim-deficient and Bcl-2 Tg mice exhibit an elevated frequency of CD4(+) T cells expressing both the transgene-encoded Vβ5 chain and a revised TCRβ chain. We now show that these dual-TCR-expressing cells are TCR revision intermediates and that the population of RAG-expressing, revising CD4(+) T cells is increased in Bim-deficient Vβ5 Tg mice. These findings support a role for Bim and Bcl-2 in regulating the balance of survival versus apoptosis in peripheral T cells undergoing RAG-dependent TCR rearrangements during TCR revision, thereby ensuring the utility of the postrevision repertoire.
外周血 CD4(+)Vβ5(+)T 细胞通过删除或 TCR 修正而对内源性小鼠乳腺肿瘤病毒超抗原产生耐受性。通过 TCR 修正，RAG 重新表达介导了胸腺外 TCRβ重排，并导致一群修正后的 TCRβ链表达的后修正 CD4(+)Vβ5(-)T 细胞。我们假设细胞死亡途径调节了经历 TCR 修正的细胞的选择，以确保后修正群体的安全性和实用性。在这项研究中，我们研究了 Bcl-2 相互作用的细胞死亡介质（Bim）介导的细胞死亡在自身抗原驱动的删除和 TCR 修正中的作用。Bim 缺陷和 Bcl-2 在 Vβ5 转基因（Tg）小鼠中的过表达都损害了外周血删除。Vβ5TgBim 缺陷和 Bcl-2Tg 小鼠表现出表达转基因编码的 Vβ5 链和修正后的 TCRβ链的 CD4(+)T 细胞的频率升高。我们现在表明，这些双重 TCR 表达的细胞是 TCR 修正中间体，并且在 Bim 缺陷的 Vβ5Tg 小鼠中，表达 RAG 的修正 CD4(+)T 细胞群体增加。这些发现支持了 Bim 和 Bcl-2 在调节外周 T 细胞中 RAG 依赖性 TCR 重排过程中生存与凋亡之间平衡的作用，从而确保了后修正库的实用性。
