Restriction of innate Tγδ17 cell plasticity by an AP-1 regulatory axis
Preprint
Abstract
IL-17-producing γδ T (Tγδ17) cells are innate-like mediators of intestinal barrier immunity. While Th17 cell and ILC3 plasticity have been extensively studied, the mechanisms governing Tγδ17 cell effector flexibility remain undefined. Here, we combined type 3 fate-mapping with single cell ATAC/RNA-seq multiome profiling to define the cellular features and regulatory networks underlying Tγδ17 cell plasticity. During homeostasis, Tγδ17 cell effector identity was stable across tissues, including for intestinal T-bet + Tγδ17 cells that restrained IFNγ production. However, S. typhimurium infection induced intestinal Vγ6 + Tγδ17 cell conversion into type 1 effectors, with loss of IL-17A production and partial RORγt downregulation. Multiome analysis revealed a trajectory along Vγ6 + Tγδ17 effector conversion, with TIM-3 marking ex-Tγδ17 cells with enhanced type 1 functionality. Lastly, we characterized and validated a critical AP-1 regulatory axis centered around JunB and Fosl2 that controls Vγ6 + Tγδ17 cell plasticity by stabilizing type 3 identity and restricting type 1 effector conversion.Keywords
All Related Versions
- Published version: Nature Immunology, 26 (8), 1299.
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