A Network of High-Mobility Group Box Transcription Factors Programs Innate Interleukin-17 Production

How innate lymphoid cells (ILCs) in the thymus and gut become specialized effectors is unclear. The prototypic innate-like γδ T cells (Tγδ17) are a major source of interleukin-17 (IL-17). We demonstrate that Tγδ17 cells are programmed by a gene regulatory network consisting of a quartet of high-mobility group (HMG) box transcription factors, SOX4, SOX13, TCF1, and LEF1, and not by conventional TCR signaling. SOX4 and SOX13 directly regulated the two requisite Tγδ17 cell-specific genes, Rorc and Blk, whereas TCF1 and LEF1 countered the SOX proteins and induced genes of alternate effector subsets. The T cell lineage specification factor TCF1 was also indispensable for the generation of IL-22 producing gut NKp46+ ILCs and restrained cytokine production by lymphoid tissue inducer-like effectors. These results indicate that similar gene network architecture programs innate sources of IL-17, independent of anatomical origins. [Display omitted] ► SOX4, SOX13, LEF1, and TCF1 coordinately program innate IL-17 producing γδ T cells ► SOX4 directly regulates RORγt induction ► TCR signaling components of adaptive IL-17+ cells do not drive innate IL-17+ cells ► TCF1 controls the production of innate IL-17 and IL-22 in the gut mucosa