Homeostatic IL-13 in healthy skin directs dendritic cell differentiation to promote T H 2 and inhibit T H 17 cell polarization
Johannes U Mayer1,2, Kerry L Hilligan1,3, Jodie S Chandler1, David A Eccles1, Samuel I Old1, Rita G Domingues4, Jianping Yang1, Greta R Webb1, Luis Munoz-Erazo1, Evelyn J Hyde1, Kirsty A Wakelin1, Shiau-Choot Tang1, Sally C Chappell1, Sventja von Daake1, Frank Brombacher5, Charles R Mackay6, Alan Sher3, Roxane Tussiwand7,8, Lisa M Connor1,9, David Gallego-Ortega10,11, Dragana Jankovic12, Graham Le Gros1, Matthew R Hepworth4, Olivier Lamiable1, Franca Ronchese13
- Malaghan Institute of Medical Research, Wellington, New Zealand.
- Department of Dermatology and Allergology, Phillips University Marburg, Marburg, Germany.
- Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
- Lydia Becker Institute of Immunology and Inflammation, Manchester Collaborative Centre for Inflammation Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town component & Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology, Health Science Faculty, University of Cape Town, Cape Town, South Africa.
- Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia.
- Department of Biomedicine, University of Basel, Basel, Switzerland.
- Immune Regulation Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
- School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.
- The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
- Centre for Single-Cell Technology, School of Biomedical Engineering, Faculty of Engineering and IT, University of Technology Sydney, Ultimo, NSW, Australia.
- Immunoparasitology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
- Malaghan Institute of Medical Research, Wellington, New Zealand. fronchese@malaghan.org.nz.
Abstract
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.
Presented By Johannes U Mayer | ORCID iD