Conditional depletion uncovers redundant and non-redundant functions of tissue-resident IL-17-producing ?d T cells

?d T cells are highly conserved in all vertebrates, suggesting an important benefit. However, ?d T cell-deficient Tcrd–/– mice display a surprisingly mild phenotype. To investigate the function of IL-17 producing ?d T cells (?dT17 cells) in experimental models for psoriasis and chronic fungal infection, we established and applied diphtheria toxin-mediated conditional ?d T cell-depletion. IFN-? producing ?d T cell subsets reappeared quickly after depletion, while ?dT17 cells recovered inefficiently and their empty homeostatic niches were filled by expanding ILC3s. Direct visualization, parabiosis, and complementary genetic labeling further revealed that ?dT17 cells are motile but partially tissue-resident, long-lived and self-renewing lymphocytes. Together, this clarifies that ?dT17 cells act as innate local and systemic regulators of IL-17-driven inflammation.