Transforming growth factor-beta signaling curbs thymic negative selection promoting regulatory T cell development.

Thymus-derived naturally occurring regulatory T cells (nTregs) are necessary for immunological self-tolerance. nTreg development is instructed by the T cell receptor, and can be induced by agonist antigens that trigger T cell negative selection. How T cell deletion is regulated so that nTregs are generated is unclear. Here we showed that transforming growth factor-β (TGF-β) signaling protected nTregs and antigen-stimulated conventional T cells from apoptosis. Enhanced apoptosis of TGF-β receptor-deficient nTregs was associated with high expression of pro-apoptotic proteins Bim, Bax, and Bak, and low expression of the anti-apoptotic protein Bcl-2. Ablation of Bim in mice corrected the Treg development and homeostasis defects. Our results suggest that nTreg commitment is independent of TGF-β signaling. Instead, TGF-β promotes nTreg survival by antagonizing T cell negative selection. These findings reveal a critical function for TGF-β in control of autoreactive T cell fates with important implications for understanding T cell self-tolerance mechanisms.

胸腺来源的天然调节性T细胞（nTregs）对免疫自身耐受是必需的。nTreg的发育受T细胞受体的调控，并且可由触发T细胞阴性选择的激动剂抗原诱导。T细胞的缺失是如何被调控从而产生nTregs的尚不清楚。在此我们发现，转化生长因子 -β（TGF -β）信号传导保护nTregs以及抗原刺激的常规T细胞免于凋亡。TGF -β受体缺陷型nTregs凋亡增强与促凋亡蛋白Bim、Bax和Bak的高表达以及抗凋亡蛋白Bcl - 2的低表达相关。在小鼠中敲除Bim可纠正Treg发育和内稳态缺陷。我们的研究结果表明，nTreg的定型不依赖于TGF -β信号传导。相反，TGF -β通过拮抗T细胞阴性选择来促进nTreg的存活。这些发现揭示了TGF -β在控制自身反应性T细胞命运方面的关键作用，对理解T细胞自身耐受机制具有重要意义。