A critical function for TGF-β signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells

The molecular mechanisms directing the development of 'natural' CD4+CD25+Foxp3+ regulatory T cells (Treg cells) in the thymus are not thoroughly understood. We show here that conditional deletion of transforming growth factor-β receptor I (TβRI) in T cells blocked the appearance of CD4+CD25+Foxp3+ thymocytes at postnatal days 3–5. Paradoxically, however, beginning 1 week after birth, the same TβRI-mutant mice showed accelerated expansion of thymic CD4+CD25+Foxp3+ populations. This rapid recovery of Foxp3+ thymocytes was attributable mainly to overproduction of and heightened responsiveness to interleukin 2, as genetic ablation of interleukin 2 in TβRI-mutant mice resulted in a complete absence of CD4+CD25+Foxp3+ cells from the thymus and periphery. Thus, transforming growth factor-β signaling is critical to the thymic development of natural CD4+CD25+Foxp3+ Treg cells.