A Validated Regulatory Network for Th17 Cell Specification

Tags

Top Highlights

• 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