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


Dr M. H. Kaplan, Departments of Pediatrics, and Microbiology and Immunology, Wells Center for Pediatric Research, Indiana University School of Medicine, 702 Barnhill Dr RI 2600, Indianapolis, IN 46202, USA. Email:
Senior author: Mark H. Kaplan


Summary T-cell responses to a cytokine milieu instruct the development of multiple effector phenotypes. While transforming growth factor-β1 (TGF-β1) 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-β1-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.