Gfi1 negatively regulates T_h17 differentiation by inhibiting RORγt activity

T_h cells have long been divided into two subsets, T_h1 and T_h2; however, recently, T_h17 and inducible regulatory T (iTreg) cells were identified as new T_hcell subsets. Although T_h1- and T_h 2-polarizing cytokines have been shown to suppress T_h17 and iTreg development, transcriptional regulation of T_h17 and iTreg differentiation by cytokines remains to be clarified. In this study, we found that expression of the growth factor independent 1 (Gfi1) gene, which has been implicated in T_h2 development, was repressed in T_h17 and iTreg cells compared with T_h 1 and T_h2 lineages. Gfi1 expression was enhanced by the IFN-γ/STAT1 and IL-4/STAT6 pathways, whereas it was repressed by the transforming growth factor-β1 stimulation at the promoter level. Over-expression of Gfi1 strongly reduced IL-17A transcription in the EL4 T cell line, as well as in primary T cells. This was due to the blockade of recruitment of retinoid-related orphan receptor γt to the IL-17A promoter. In contrast, IL-17A expression was significantly enhanced in Gfi1-deficient T cells under T_h17-promoting differentiation conditions as compared with wild-type T cells. In contrast, the impacts of Gfi1 in iTregs were not as strong as in T_h17 cells. Taken together, these data strongly suggest that Gfi1 is a negative regulator of T_h17 differentiation, which represents a novel mechanism for the regulation of T_h17 development by cytokines.