biostudies-literatureWu BNational Institute of Environmental Health SciencesNational Institute of Allergy and Infectious DiseasesNational Multiple Sclerosis SocietyNIAID NIH HHS308-323.e6https://www.ebi.ac.uk/biostudies/studies/S-EPMC7878438biostudies-literatureUnknown54(2)Th17 cells are known to exert pathogenic and non-pathogenic functions. Although the cytokine transforming growth factor β1 (TGF-β1) is instrumental for Th17 cell differentiation, it is dispensable for generation of pathogenic Th17 cells. Here, we examined the T cell-intrinsic role of Activin-A, a TGF-β superfamily member closely related to TGF-β1, in pathogenic Th17 cell differentiation. Activin-A expression was increased in individuals with relapsing-remitting multiple sclerosis and in mice with experimental autoimmune encephalomyelitis. Stimulation with interleukin-6 and Activin-A induced a molecular program that mirrored that of pathogenic Th17 cells and was inhibited by blocking Activin-A signaling. Genetic disruption of Activin-A and its receptor ALK4 in T cells impaired pathogenic ThImmunityThe TGF-β superfamily cytokine Activin-A is induced during autoimmune neuroinflammation and drives pathogenic Th17 cell differentiation.PMC7878438R01 AI123193R01 AI131238R01 AI160774Zhou MWan YYGuo ZMarkovic-Plese SWu BLi PLi JLZhang SXu XSeyedsadr MBi YfalseThe TGF-β superfamily cytokine Activin-A is induced during autoimmune neuroinflammation and drives pathogenic Th17 cell differentiation.Th17 cells are known to exert pathogenic and non-pathogenic functions. Although the cytokine transforming growth factor β1 (TGF-β1) is instrumental for Th17 cell differentiation, it is dispensable for generation of pathogenic Th17 cells. Here, we examined the T cell-intrinsic role of Activin-A, a TGF-β superfamily member closely related to TGF-β1, in pathogenic Th17 cell differentiation. Activin-A expression was increased in individuals with relapsing-remitting multiple sclerosis and in mice with experimental autoimmune encephalomyelitis. Stimulation with interleukin-6 and Activin-A induced a molecular program that mirrored that of pathogenic Th17 cells and was inhibited by blocking Activin-A signaling. Genetic disruption of Activin-A and its receptor ALK4 in T cells impaired pathogenic Th2021-01-01T00:00:00Z2021 Feb2026-04-14T19:12:28.451Z2025-04-06T14:57:10.551ZS-EPMC78784383342136210.1016/j.immuni.2020.12.010