TGF-β Cytokine Signaling Promotes CD8+ T Cell Development and Low-Affinity CD4+ T Cell Homeostasis by Regulation of Interleukin-7 Receptor α Expression

• TGF-β controls IL-7Rα expression promoting CD8+ T cell lineage commitment
• TGF-β controls IL-7Rα expression promoting CD4+ T cell homeostasis
• TGF-β regulation of IL-7Rα expression is modulated by TCR affinity in CD4+ T cells
• TGF-β regulates IL-7Rα expression via the inhibition of Gfi-1 expression

SummaryInterleukin-7 receptor α chain (IL-7Rα) is induced upon T cell positive selection and controls thymic CD8-lineage specification and peripheral naive T cell homeostasis. How IL-7Rα expression is regulated in developing thymocytes is unclear. Here, we show that transforming growth factor β (TGF-β) signaling promoted IL-7Rα expression and CD8+ T cell differentiation. In addition, TGF-β signaling was required for high IL-7Rα expression in CD4+ T cells bearing low-affinity T cell receptors, and the abrogation of TGF-β receptor expression led to failed maintenance of peripheral CD4+ T cells. Compromised IL-7Rα expression in TGF-β-receptor-deficient T cells was associated with increased expression of the Il7ra transcriptional repressor, Gfi-1. IL-7Rα transgenesis or T-cell-specific ablation of Gfi-1 restored IL-7Rα expression and largely ameliorated the development and homeostasis defects of TGF-β-receptor-deficient T cells. These findings reveal functions for TGF-β signaling in controlling IL-7Rα expression and in promoting T cell repertoire diversification.

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