The IL-23/IL-17A axis is critical in the defense against extracellular pathogens as well as the development of several autoimmune diseases including psoriasis. Here we focused on the capability of human innate lymphoid cell (ILC) subsets to produce IL-17A. Initial experiments revealed unexpectedly that purified dermis-derived group 2 ILCs (ILC2s), but not ILC3s, were induced to produce this cytokine after co-culture with Candida albicans-exposed undivided dermal cells. The CRTH2+ ILC2s transdifferentiated towards IL-17A‒producing NKp44‒ ILC3-like cells. This feature was also found in ILC2s derived from peripheral blood or cord blood and appeared to be driven by IL-1β, IL-23 and TGF-β and coincided with up-regulation of RORγt and reciprocal down-regulation of GATA3. Flow cytometry, RNA expression microarray, and unbiased single-cell RNA analyses disclosed a c-Kit (CD117)+ CCR6+ ILC2 subpopulation having some features in common with ILC3s, including expression of RORγt which accommodates IL-17A production in response to IL-1β and IL-23. This ILC2 subset also expressed the skin homing receptor CCR10. The c-Kit‒ ILC2s were also able to produce IL-17A but required during stimulation with IL-1β and IL-23 the additional presence of TGF-β, which promoted the upregulation of IL23R, CCR6 and c-Kit in these cells. The switch into IL-17A‒producing ILC3-like cells could be reversed by IL-4. The plasticity process we describe here has clinical relevance as we show that the proportion of IL-17A‒producing ILC3s is increased at the expense of ILC2s within the lesional skin of psoriatic patients as compared to healthy control skin. We identify ILC2s as a novel cellular source of IL-17A, providing a novel therapeutic target to ameliorate IL-17A pathogenicity.

Human group 2 innate lymphoid cells differentiate into interleukin-17A producing cells in psoriasis