Foxp3+ Regulatory T Cells Promote T Helper 17 Cell Development In Vivo through Regulation of Interleukin-2

T helper 17 (Th17) cell development is driven by cytokines including transforming growth factor-β (TGF-β), interleukin-6 (IL-6), IL-1, and IL-23. Regulatory T (Treg) cells can provide the TGF-β in vitro, but their role in vivo remains unclear, particularly because Treg cells inhibit inflammation in many models of Th17 cell-associated autoimmunity. We used mice expressing Diphtheria toxin receptor under control of the Foxp3 promoter to deplete Foxp3+ Treg cells in adult mice during in vivo Th17 cell priming. Treg cell depletion resulted in a reduced frequency of antigen-specific IL-17 producers in draining lymph nodes and blood, correlating with reduced inflammatory skin responses. In contrast, Treg cells did not promote IL-17 secretion after initial activation stages. Treg cell production of TGF-β was not required for Th17 cell promotion, and neither was suppression of Th1 cell-associated cytokines. Rather, regulation of IL-2 availability and resultant signaling through CD25 by Treg cells was found to play an important role. [Display omitted] ► Depletion of Foxp3+ cells at time of immunization impairs Th17 cell development ► Treg cells promote early Th17 cell development but not maintenance of Th17 cells ► Treg cells are not required to produce TGF-β for Th17 cell development ► Treg cells promote Th17 cells through consumption of IL-2, and neutralization of IL-2 restores IL-17