Altered ratio of dendritic cell subsets in skin-draining lymph nodes promotes Th2-driven contact hypersensitivity

Hannah L. Miller, Prabhakar Sairam Andhey, Melissa K. Swiecki, Bruce A. Rosa, Konstantin Zaitsev, Alexandra Chloe Villani, Makedonka Mitreva, Maxim N. Artyomov, Susan Gilfillan, Marina Cella, Marco Colonna

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Plasmacytoid dendritic cells (pDCs) specialize in the production of type I IFN (IFN-I). pDCs can be depleted in vivo by injecting diphtheria toxin (DT) in a mouse in which pDCs express a diphtheria toxin receptor (DTR) transgene driven by the human CLEC4C promoter. This promoter is enriched for binding sites for TCF4, a transcription factor that promotes pDC differentiation and expression of pDC markers, including CLEC4C. Here, we found that injection of DT in CLEC4C-DTR+ mice markedly augmented Th2-dependent skin inflammation in a model of contact hypersensitivity (CHS) induced by the hapten fluorescein isothiocyanate. Unexpectedly, this biased Th2 response was independent of reduced IFN-I accompanying pDC depletion. In fact, DT treatment altered the representation of conventional dendritic cells (cDCs) in the skin-draining lymph nodes during the sensitization phase of CHS; there were fewer Th1-priming CD326+ CD103+ cDC1 and more Th2-priming CD11b+ cDC2. Single-cell RNA-sequencing of CLEC4C-DTR+ cDCs revealed that CD326+ DCs, like pDCs, expressed DTR and were depleted together with pDCs by DT treatment. Since CD326+ DCs did not express Tcf4, DTR expression might be driven by yet-undefined transcription factors activating the CLEC4C promoter. These results demonstrate that altered DC representation in the skin-draining lymph nodes during sensitization to allergens can cause Th2-driven CHS.

Original languageEnglish
Article numbere2021364118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number3
DOIs
StatePublished - Jan 19 2021

Keywords

  • Allergy
  • Contact hypersensitivity
  • Plasmacytoid DC
  • Skin
  • Th2

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