Homeostatic IL-13 in healthy skin directs dendritic cell differentiation to promote TH2 and inhibit TH17 cell polarization

• DOI: 10.1038/s41590-021-01067-0
• Publication Date: 2021-11-18T17:03:28Z
• Authors: Johannes U. Mayer; Kerry L. Hilligan; Jodie S. Chandler; David A. Eccles; Samuel I. Old; Rita G. Domingues; Jianping Yang; Greta R. Webb; Luis Munoz-Erazo; Evelyn J. Hyde; Kirsty A. Wakelin; Shiau-Choot Tang; Sally C. Chappell; Sventja von Daake; Frank Brombacher; Charles R. Mackay; Alan Sher; Roxane Tussiwand; Lisa M. Connor; David Gallego-Ortega; Dragana Jankovic; Graham Le Gros; Matthew R. Hepworth; Olivier Lamiable; Franca Ronchese
• Keywords: GATA3; Innate lymphoid cell; STAT6; KLF4; T helper cell

The signals driving the adaptation of type 2 dendritic cells (DC2s) to diverse peripheral environments remain mostly undefined. We show that differentiation of CD11blo migratory DC2s-a DC2 population unique to the dermis-required IL-13 signaling dependent on the transcription factors STAT6 and KLF4, whereas DC2s in lung and small intestine were STAT6-independent. Similarly, human DC2s in skin expressed an IL-4 and IL-13 gene signature that was not found in blood, spleen and lung DCs. In mice, IL-13 was secreted homeostatically by dermal innate lymphoid cells and was independent of microbiota, TSLP or IL-33. In the absence of IL-13 signaling, dermal DC2s were stable in number but remained CD11bhi and showed defective activation in response to allergens, with diminished ability to support the development of IL-4+GATA3+ helper T cells (TH), whereas antifungal IL-17+RORγt+ TH cells were increased. Therefore, homeostatic IL-13 fosters a noninflammatory skin environment that supports allergic sensitization.