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

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-OrtegaDragana Jankovic, Graham Le Gros, Matthew R Hepworth, Olivier Lamiable, Franca Ronchese

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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.

Original languageEnglish
Pages (from-to)1538-1550
Number of pages13
JournalNature Immunology
Volume22
Issue number12
Early online date18 Nov 2021
DOIs
Publication statusPublished - 1 Dec 2021

Keywords

  • Allergens/pharmacology
  • Animals
  • CD11b Antigen/genetics
  • Cell Communication
  • Cell Differentiation
  • Cells, Cultured
  • Databases, Genetic
  • Humans
  • Interleukin-13/genetics
  • Langerhans Cells/drug effects
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • STAT6 Transcription Factor/genetics
  • Signal Transduction
  • Skin/cytology
  • Th17 Cells/drug effects
  • Th2 Cells/drug effects
  • Transcriptome

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