The skin environment controls local dendritic cell differentiation and function through innate IL-13

Abstract

The signals driving the adaptation of type-2 dendritic cells (DC2s) to diverse peripheral environments are not well understood. We show that the development of CD11blow migratory DC2s, a DC2 population unique to the dermis, requires STAT6- and KLF4-dependent IL-13 signaling, whereas DC2s in lung and small intestine are STAT6-independent. Dermal IL-13 is mostly derived from innate lymphoid cells expressing a resting ICOS+ KLRG1-ST2-phenotype. Analysis of public datasets indicates that human skin DC2s also express an IL-4/IL-13 gene signature compared to blood or spleen, suggesting a similar developmental pathway in mice and humans. In the absence of IL-13 signaling, dermal DC2s are stable in number but remain CD11bhi and show defective activation in response to allergen with diminished ability to support IL-4+ GATA3+ Th development, whereas anti-fungal IL-17+ RORγt+ responses are increased. Thus, steady-state IL-13 fosters a non-inflammatory and pro-allergic environment in healthy skin via conditioning of local DC2s.

Innate type 2 immunity controls hair follicle commensalism by Demodex mites

“…To investigate mechanisms by which IL-13 from ILC2s confers protection of HF after mite colonization, we used well-characterized reporter mice for the type 2 cytokines IL-5 and IL-13 (Liang et al, 2011;Nussbaum et al, 2013) to assess the location and activation of ILC2s in resting skin. ILC2s were the most prevalent cells expressing these cytokines under basal conditions, corroborating prior findings (Mayer et al, 2021;Ricardo-Gonzalez et al, 2018;Schneider et al, 2019), and localized predominantly within the epithelial layer in close association with HF (Figures 7A and 7B). We observed cyclic IL-13 expression in skin ILC2s, with high expression in the early postnatal period as previously observed (Schneider et al, 2019), and then oscillating expression with phases of the hair cycle, which remains synchronous in the first months of life, with low IL-13 during telogen (rest) and high IL-13 during anagen (growth) (Figure 7C).…”