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The developmental pathways of regulatory T cells (T(reg)) generation in the thymus are not fully understood. In this study, we reconstituted thymic development of Zap70-deficient thymocytes with a tetracycline-inducible Zap70 transgene to allow temporal dissection of T(reg) development. We find that T(reg) develop with distinctive kinetics, first appearing by day 4 among CD4 single-positive (SP) thymocytes. Accepted models of CD25(+)Foxp3(+) T(reg) selection suggest development via CD25(+)Foxp3(-) CD4 SP precursors. In contrast, our kinetic analysis revealed the presence of abundant CD25(-)Foxp3(+) cells that are highly efficient at maturing to CD25(+)Foxp3(+) cells in response to IL-2. CD25(-)Foxp3(+) cells more closely resembled mature T(reg) both with respect to kinetics of development and avidity for self-peptide MHC. These population also exhibited distinct requirements for cytokines during their development. CD25(-)Foxp3(+) cells were IL-15 dependent, whereas generation of CD25(+)Foxp3(+) specifically required IL-2. Finally, we found that IL-2 and IL-15 arose from distinct sources in vivo. IL-15 was of stromal origin, whereas IL-2 was of exclusively from hemopoetic cells that depended on intact CD4 lineage development but not either Ag-experienced or NKT cells.

Differential Requirement for IL-2 and IL-15 during Bifurcated Development of Thymic Regulatory T Cells