Restriction of innate Tγδ17 cell plasticity by an AP-1 regulatory axis

Abstract

IL-17-producing {gamma}{delta} T (T{gamma}{delta}17) cells are innate-like mediators of intestinal barrier immunity. While Th17 cell and ILC3 plasticity have been extensively studied, the mechanisms governing T{gamma}{delta}17 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 T{gamma}{delta}17 cell plasticity. During homeostasis, T{gamma}{delta}17 cell effector identity was stable across tissues, including for intestinal T-bet+ T{gamma}{delta}17 cells that restrained IFN{gamma} production. However, S. typhimurium infection induced intestinal V{gamma}6+ T{gamma}{delta}17 cell conversion into type 1 effectors, with loss of IL-17A production and partial ROR{gamma}t downregulation. Multiome analysis revealed a trajectory along V{gamma}6+ T{gamma}{delta}17 effector conversion, with TIM-3 marking ex-T{gamma}{delta}17 cells with enhanced type 1 functionality. Lastly, we characterized and validated a critical AP-1 regulatory axis centered around JunB and Fosl2 that controls V{gamma}6+ T{gamma}{delta}17 cell plasticity by stabilizing type 3 identity and restricting type 1 effector conversion.