316 A unique population of dermal conventional dendritic cells enhances TH2 and inhibits TH17 cell polarization in healthy skin

Abstract

Dendritic cells (DC) play a crucial role in informing the adaptive immune system about infectious, innocuous or self antigens. Two developmentally distinct lineages of conventional DC, termed cDC1 and cDC2, have been described in mice and humans. cDC1 predominantly interact with CD8 T cells, while cDC2 interact with CD4 T cells to promote T helper (Th) and T regulatory cell responses. cDC2 present a high degree of phenotypic and functional heterogeneity in different tissues, suggesting that they adapt to diverse peripheral environments. Using high-dimensional proteomic and transcriptomic single-cell technologies, we could show that cDC2 exhibit unique signatures in different murine tissues at the steady state. Focusing on the developmental requirements of these subsets we could show that CD11blow cDC2, a population uniquely found in skin, required STAT6- and KLF4-dependent IL-13 signaling, while subsets in other tissues were STAT6-independent. IL-13 was not only necessary for the development of CD11blow cDC2, but also sufficient to rescue CD11blow cDC2 development in IL-13 KO mice and to differentiate CD11blow cDC2 in vitro. In naïve murine skin, dermal IL-13 was mostly derived from innate lymphoid cells expressing a resting ICOS+KLRG1-ST2- phenotype. In the absence of IL-13 signaling, dermal cDC2 were stable in number and continued to take up antigen but remained CD11bhi. They furthermore showed defective activation in response to different antigens and a diminished ability to support IL-4+ GATA3+ Th2 cell development, whereas anti-fungal IL-17+ RORyt+ responses were increased. Thus, our work identified that homeostatic IL-13 in healthy skin mediates a DC-driven protective non-inflammatory environment at the steady state, but might also contribute to its pro-allergic conditioning upon dysregulation.