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

• Published in: Nature immunology Vol. 22; no. 12; pp. 1538 - 1550
• Main Authors: Mayer, Johannes U., Hilligan, Kerry L., Chandler, Jodie S., Eccles, David A., Old, Samuel I., Domingues, Rita G., Yang, Jianping, Webb, Greta R., Munoz-Erazo, Luis, Hyde, Evelyn J., Wakelin, Kirsty A., Tang, Shiau-Choot, Chappell, Sally C., von Daake, Sventja, Brombacher, Frank, Mackay, Charles R., Sher, Alan, Tussiwand, Roxane, Connor, Lisa M., Gallego-Ortega, David, Jankovic, Dragana, Le Gros, Graham, Hepworth, Matthew R., Lamiable, Olivier, Ronchese, Franca
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2021; Nature Publishing Group
• Subjects: 631/250/2152/1566; 631/250/2504/133/2505; 631/250/2504/2506; Allergens; Biomedical and Life Sciences; Biomedicine; CD11b antigen; Cell differentiation; Dendritic cells; Dermis; GATA-3 protein; Helper cells; Immunology; Infectious Diseases; Interleukin 13; Interleukin 17; Interleukin 4; KLF4 protein; Lungs; Lymphocytes T; Lymphoid cells; Microbiota; Skin; Small intestine; Spleen; Stat6 protein; Thymic stromal lymphopoietin; Transcription factors
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/s41590-021-01067-0

The signals driving the adaptation of type 2 dendritic cells (DC2s) to diverse peripheral environments remain mostly undefined. We show that differentiation of CD11b lo 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 CD11b hi and showed defective activation in response to allergens, with diminished ability to support the development of IL-4 + GATA3 + helper T cells (T H ), whereas antifungal IL-17 + RORγt + T H cells were increased. Therefore, homeostatic IL-13 fosters a noninflammatory skin environment that supports allergic sensitization. Ronchese and colleagues show that IL-13 secreted homeostatically by dermal ILCs contributes to the differentiation of a CD11b lo type 2 dendritic cell subset, which supports the development of T H 2 cells and curtails the development of T H 17 cells in the skin of mice and humans.