Signal transducer and activator of transcription 4 limits the development of adaptive regulatory T cells.

T-cell responses to a cytokine milieu instruct the development of multiple effector phenotypes. While transforming growth factor-beta(1) (TGF-beta(1)) inhibits the development of T helper type 1 (Th1) and Th2 cells, we demonstrate that like interleukin-6 (IL-6) and IL-4, IL-12 can inhibit the development of TGF-beta(1)-induced Foxp3-expressing adaptive T regulatory (aTreg) cells. Signal transducer and activator of transcription 4 (STAT4) is critical for the response to IL-12, although there is a parallel pathway involving T box expressed in T cells (T-bet), and cells from mice double-deficient in STAT4 and T-bet are refractory to the inhibition of aTreg-cell development by IL-12. While the ability of these cytokines to promote Th differentiation may contribute to this effect, we observe that culture with IL-12, or other instructive cytokines, results in an increase in repressive chromatin modifications at the Foxp3 locus that limit STAT5 binding to Foxp3, without observed effects on IL-2 signalling pathways. In a model of allergic lung inflammation there are increased percentages of Treg cells in the lungs of Stat4(-/-) mice, compared with wild-type mice, and increases in Treg cells correlate with decreased allergic inflammation. Overall, these results suggest an important role for STAT4 in regulating Treg-cell development.