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RORγt is the lineage-specific transcription factor for T helper 17 (Th17) cells whose upregulation in developing Th17 cells is critically regulated by interleukin-6 (IL-6) and TGF-β, the molecular mechanisms of which remain largely unknown. Here we identified conserved non-coding sequences (CNSs) 6 and 9 at the Rorc gene, essential for its expression during Th17 cell differentiation but not required for RORγt expression in innate lymphocytes and γδ T cells. Mechanistically, the IL-6-signal transducer and activator of transcription 3 (STAT3) axis appeared to be largely dependent on CNS9 and only partially on CNS6 in controlling RORγt expression and epigenetic activation of the Rorc locus. TGF-β alone was sufficient to induce RORγt expression in a CNS6- but not CNS9-dependent manner through CNS6 binding by SMAD proteins. Our study reveals an important synergistic mechanism downstream of IL-6 and TGF-β in regulation of RORγt expression and Th17 cell commitment via distinct cis -regulatory elements. • CNS6 and CNS9 are not required for RORγt expression in innate immune cells • Deficiency in CNS6 or CNS9 decreases Th17 cell differentiation and EAE disease • CNS9 and, to a lesser extent, CNS6 are required for IL-6-induced RORγt expression • CNS6, but not CNS9, is indispensable for TGF-β-induced RORγt expression IL-6 and TGF-β induce Th17 cell differentiation. Chang et al. demonstrate that these two cytokines initiate Th17 cell differentiation by inducing de novo Rorc transcription via the distinct conserved non-coding sequences CNS6 and CNS9. [ABSTRACT FROM AUTHOR]

T follicular helper (Tfh) cells provide essential help to B cells in germinal center (GC) reactions. Bcl6 is the obligatory lineage transcription factor in Tfh cells. Here, we examined the molecular pathways that induce Bcl6 gene expression and underscore Bcl6-dependent function during Tfh cell commitment. Integration of genome-wide Bcl6 occupancy in Tfh cells and differential gene expression analyses suggested an important role for the transcription factor Tox2 in Tfh cell differentiation. Ectopic expression of Tox2 was sufficient to drive Bcl6 expression and Tfh development. In genome-wide ChIP-seq analyses, Tox2-bound loci associated with Tfh cell differentiation and function, including Bcl6. Tox2 binding was associated with increased chromatin accessibility at these sites, as measured by ATAC-seq. Tox2 −/− mice exhibited defective Tfh differentiation, and inhibition of both Tox2 and the related transcription factor Tox abolished Tfh differentiation. Thus, a Tox2-Bcl6 axis establishes a transcriptional feed-forward loop that promotes the Tfh program. • Tox2 is highly expressed in Tfh cells and regulated by Bcl6 and STAT3 • Forced expression of Tox2 drives Tfh development • Tox2 directly binds to Tfh-associated genes, promoting chromatin accessibility • Combined deletion of Tox2 and Tox abrogates Tfh development T follicular helper (Tfh) cells provide help to B cells in germinal center reactions and are essential to humoral immunity. Xu et al. define a feed-forward loop mediated by the transcription factors Bcl6 and Tox2 that promotes and establishes the Tfh program. [ABSTRACT FROM AUTHOR]