Altered ratio of dendritic cell subsets in skin-draining lymph nodes promotes Th2-driven contact hypersensitivity.
Hannah L MillerPrabhakar Sairam AndheyMelissa K SwieckiBruce A RosaKonstantin ZaitsevAlexandra-Chloé VillaniMakedonka MitrevaMaxim N ArtyomovSusan GilfillanMarina CellaMarco ColonnaPublished in: Proceedings of the National Academy of Sciences of the United States of America (2021)
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.
Keyphrases
- dendritic cells
- transcription factor
- lymph node
- single cell
- immune response
- regulatory t cells
- soft tissue
- dna methylation
- escherichia coli
- poor prognosis
- wound healing
- gene expression
- rna seq
- sentinel lymph node
- dna binding
- oxidative stress
- neoadjuvant chemotherapy
- cell cycle
- type diabetes
- drug induced
- high throughput
- skeletal muscle
- replacement therapy
- genome wide identification