Transforming Growth Factor-β Signaling Curbs Thymic Negative Selection Promoting Regulatory T Cell Development

SummaryThymus-derived naturally occurring regulatory T (nTreg) cells are necessary for immunological self-tolerance. nTreg cell 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 nTreg cells are generated is unclear. Here we showed that transforming growth factor-β (TGF-β) signaling protected nTreg cells and antigen-stimulated conventional T cells from apoptosis. Enhanced apoptosis of TGF-β receptor-deficient nTreg cells was associated with high expression of proapoptotic proteins Bim, Bax, and Bak and low expression of the antiapoptotic protein Bcl-2. Ablation of Bim in mice corrected the Treg cell development and homeostasis defects. Our results suggest that nTreg cell commitment is independent of TGF-β signaling. Instead, TGF-β promotes nTreg cell 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (381 K)Download as PowerPoint slideHighlights► TGF-β suppresses T cell negative selection promoting regulatory T cell survival ► TGF-β signaling protects T cells from mitochondrion-dependent apoptosis ► TGF-β signaling is indispensable for peripheral autoreactive T cell tolerance