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

Abstract

SUMMARY 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 box (HMG) 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.

A Genome-Wide Analysis Identifies a Notch–RBP-Jκ–IL-7Rα Axis That Controls IL-17–Producing γδ T Cell Homeostasis in Mice

“…1B). However, the development of IL-17 + gd T cells increased in TCF1-deficient mice (48), suggesting the different expression mechanisms of IL-7Ra between ILCs and gd T cells.…”

Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis

“…These data suggest that exFoxp3 T H 17 cells are not identical to any known pathogenic T H 17 cell subsets [26][27][28][29] . Notably, we found that exFoxp3 T H 17 cells specifically and highly express the transcription factor Sox4, which positively regulates RORγt (encoded by Rorc) 30 and enhances lymphoid cell survival 31 . The high expression of molecules that are involved in proliferation, such as Pik3r3, and the high frequency of Ki-67 + cells in exFoxp3 T cells (Supplementary Figs.…”

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

“…Both V γ 4 + and V γ 6 + subsets produce IL‐17 after IMQ treatment of the skin 35. Skin inflammation after IMQ treatment is significantly attenuated in Sox4 −/− mice, in which dermal V γ 4 + but not dermal V γ 6 + γδ T cells are greatly reduced 42. Congenic CD45.1 + (B6.SJL) mice with naturally occurring Sox13 mutation, in which dermal V γ 4 + γδ 17 cell development is defective, develop attenuated ear skin inflammation with less acanthosis and fewer epidermal neutrophil pustules upon treatment with IMQ 64.…”

“…On the other hand, V γ 4 + γδ T cells develop in both fetal and adult thymus, have more diverse TCR repertoire and reside in the dermis, lung, liver and secondary lymphoid organs 37, 38. In addition to ROR γ t, transcription factors such as Blk,39 Hes‐1,40 nuclear factor‐ κ B,41 Sox4 and Sox1342 are also important for γδ17 cell development. Transforming growth factor‐ β and IL‐7 are required for γδ 17 thymocyte development and expansion, respectively 43, 44, 45.…”

“…Early T‐cell precursors can produce IL‐17 before TCR recombination50 and Sox4 and Sox13 are expressed before activation with TCR signalling 42. Antigen‐naive γδ T cells in the thymus differentiate into IL‐17 producers, whereas antigen‐experienced cells make IFN‐ γ 28.…”