TFs binding at key lineage-associated loci (Il17a, Il17f, Il12rb1, Il1r1, Rorc) revealed a high degree of colocalization in Th17 cells (Figures 1A and S1D), indicating that these TFs occupy common cis regulatory regions and highlighting their roles in integrating cytokine and TCR-derived signals.
BATF/IRF4 complexes, transcriptionally induced following TCR signaling, mutually activate the expression of a large set of target genes, together with STAT3
RORγt drives expression of a small subset of key Th17 genes and modulates the expression of genes activated by initiator TFs, BATF/IRF4/STAT3
BATF/IRF4 complexes pioneer the access of other TFs that further specify functional subsets
TGF-β and STAT3-activating signals would recruit STAT3/RORγt to a subset of BATF/IRF4 binding sites
Fosl2 is a negative regulator of IL-17A
requirement for Fosl2 for expression of key loci supporting Th17 cell maintenance
Fosl2 is a highly integrated regulator of T helper cell lineage identity, functioning to limit plasticity of Th17 cells by repressing Th1 and Treg transcriptional programs potentially by balancing the activity of BATF/IRF4 at key loci
RORγt has been described as a “master regulator” for the Th17 program, yet it has a surprisingly small regulatory footprint.
RORγt is not sufficient to specify the full Th17 program, and other TFs, including STAT3, IRF4, BATF, and IκBζ, are required for induction of RORγt and IL-17A in vivo and upon polarization in vitro by IL-6 and TGF-β, with or without IL-1β and IL-23
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