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Homeostatic IL-13 in healthy skin directs dendritic cell differentiation to promote T H 2 and inhibit T H 17 cell polarization

Nicholas Liao

Nat Immunol. 2021 Dec;22(12):1538-1550. doi: 10.1038/s41590-021-01067-0. | PubMed

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

  1. Malaghan Institute of Medical Research, Wellington, New Zealand.
  2. Department of Dermatology and Allergology, Phillips University Marburg, Marburg, Germany.
  3. Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  4. 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.
  5. 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.
  6. Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia.
  7. Department of Biomedicine, University of Basel, Basel, Switzerland.
  8. Immune Regulation Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
  9. School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.
  10. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
  11. Centre for Single-Cell Technology, School of Biomedical Engineering, Faculty of Engineering and IT, University of Technology Sydney, Ultimo, NSW, Australia.
  12. Immunoparasitology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  13. 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+RORĪ³t+ TH cells were increased. Therefore, homeostatic IL-13 fosters a noninflammatory skin environment that supports allergic sensitization.

Presented By Johannes U Mayer | ORCID iD