Differential c-Kit expression identifies two subsets of ILC2s with IL-17 producing capabilities that may contribute to IL-17 mediated pathologies

Group 2 innate lymphoid cells (ILC2s) are linked to type 2 immune diseases but can also molecularly change phenotype and provide type 1 immunity towards pathogens. Here we identify an ILC2 subset which can convert into IL-17 producing NKp44‒ ILC3-like cells. c-Kit and CCR6 define this ILC2 subpopulation which exhibit ILC3 features, including RORγt, which enables the conversion into IL-17 producing cells in response to IL-1β and IL-23. We also report a novel but critical role for TGF-β in promoting the conversion of c-kit‒ ILC2s into RORγt expressing c-Kit+ ILC2s by inducing the upregulation of IL23R, CCR6 and KIT mRNA in these cells. This switch was dependent on RORγt and down-regulation of GATA-3. IL-4 was able to reverse this event supporting a role for this cytokine in maintaining ILC2 identity. Notably, this plasticity has physiological relevance as a subset of RORγt+ ILC2s express the skin homing receptor CCR10 and the frequencies of IL-17‒producing ILC3s are increased at the expense of ILC2s within the lesional skin of psoriatic patients compared to healthy individuals. c-kit‒ and c-Kit+ ILC2 subsets purified from PBMC by flow cytometry were stimulated with different combinations of IL-1β, IL-23 and TGF-β to induce IL-17A production