A study published in Nature (2010) reveals that Th17 cells, crucial for immunity and autoimmunity, can differentiate in the absence of TGF-β signaling. The research shows that while IL-6 and IL-23 alone are insufficient to generate Th17 cells, their combination with IL-1β effectively induces IL-17 production in naive T cells, independent of TGF-β. Epigenetic modifications of the Il17a/Il17f and Rorc promoters occur without TGF-β, allowing the generation of cells co-expressing Rorγt and T-bet. These T-bet+ Rorγt+ Th17 cells are present in experimental allergic encephalomyelitis (EAE) and are pathogenic when transferred. The findings suggest an alternative mode of Th17 differentiation, emphasizing the role of IL-23 and potentially offering therapeutic implications. The study also demonstrates that TGF-β signaling is not always necessary for Th17 differentiation. IL-6 and IL-1β can induce Il23r mRNA expression without TGF-β, and the combination of IL-6, IL-1β, and IL-23 can induce Il17a transcription and protein expression. Anti-TGF-β antibodies block Th17 differentiation induced by TGF-β/IL-6/IL-1β but not by IL-23/IL-6/IL-1β. These results indicate that Th17 differentiation can occur independently of TGF-β. The study further shows that IL-23/IL-6/IL-1β can induce Th17 differentiation without TGF-β, and that these cells express T-bet and IL-18R1, which are essential for EAE development. Th17 cells generated with IL-23 are more pathogenic than those generated with TGF-β. The findings suggest that Th17 cells may represent heterogeneous populations with distinct trafficking profiles and pathogenic potential. The study also highlights the importance of IL-23R and T-bet in Th17 differentiation and pathogenicity, and suggests that future therapies for autoimmune diseases should consider the phenotypic characteristics of pathogenic Th17 cells generated in the absence of TGF-β.A study published in Nature (2010) reveals that Th17 cells, crucial for immunity and autoimmunity, can differentiate in the absence of TGF-β signaling. The research shows that while IL-6 and IL-23 alone are insufficient to generate Th17 cells, their combination with IL-1β effectively induces IL-17 production in naive T cells, independent of TGF-β. Epigenetic modifications of the Il17a/Il17f and Rorc promoters occur without TGF-β, allowing the generation of cells co-expressing Rorγt and T-bet. These T-bet+ Rorγt+ Th17 cells are present in experimental allergic encephalomyelitis (EAE) and are pathogenic when transferred. The findings suggest an alternative mode of Th17 differentiation, emphasizing the role of IL-23 and potentially offering therapeutic implications. The study also demonstrates that TGF-β signaling is not always necessary for Th17 differentiation. IL-6 and IL-1β can induce Il23r mRNA expression without TGF-β, and the combination of IL-6, IL-1β, and IL-23 can induce Il17a transcription and protein expression. Anti-TGF-β antibodies block Th17 differentiation induced by TGF-β/IL-6/IL-1β but not by IL-23/IL-6/IL-1β. These results indicate that Th17 differentiation can occur independently of TGF-β. The study further shows that IL-23/IL-6/IL-1β can induce Th17 differentiation without TGF-β, and that these cells express T-bet and IL-18R1, which are essential for EAE development. Th17 cells generated with IL-23 are more pathogenic than those generated with TGF-β. The findings suggest that Th17 cells may represent heterogeneous populations with distinct trafficking profiles and pathogenic potential. The study also highlights the importance of IL-23R and T-bet in Th17 differentiation and pathogenicity, and suggests that future therapies for autoimmune diseases should consider the phenotypic characteristics of pathogenic Th17 cells generated in the absence of TGF-β.