BioProject

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. More...

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 Th17 cell differentiation in vitro and in vivo. Mechanistically, extracellular-signal-regulated kinase (ERK) phosphorylation, which was essential for pathogenic Th17 cell differentiation, was suppressed by TGF-β1-ALK5 but not Activin-A-ALK4 signaling. Thus, Activin-A drives pathogenic Th17 cell differentiation, implicating the Activin-A-ALK4-ERK axis as a therapeutic target for Th17 cell-related diseases. Overall design: A: mRNA profiles of CA-ALK4 and CA-ALK5 transduced Th17 cells in the presence of IL-6 were generated by deep sequencing, in triplicate, using BGI’s unique DNBseq™. B: mRNA profiles of Th17 cells differentiated by IL-1b+IL-6+IL-23, TGFb1+IL-6 and Activin A+IL-6 were generated by deep sequencing, in triplicate, using BGI’s unique DNBseq™. C: mRNA profiles of Th17 cells differentiated by IL-1b+IL-6+IL-23, IL-1b+IL-6+IL-23+anti-Activin-A were generated by deep sequencing, in triplicate, using BGI?s unique DNBseq. D: mRNA profiles of T cells differentiated by IL-6, IL-6+ Activin-A were generated by deep sequencing, in triplicate, using BGI?s unique DNBseq. Less...