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

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