Commensal-myeloid crosstalk in neonatal skin regulates interleukin-1 signaling and cutaneous type 17 inflammation.

Early-life microbe-immune interactions at barrier surfaces have lasting impacts on the trajectory toward health versus disease. Monocytes, macrophages, and dendritic cells are primary sentinels in barrier tissues, yet the salient contributions of commensal-myeloid crosstalk during tissue development remain poorly understood. Here, we identify that commensal microbes facilitate accumulation of a population of monocytes in neonatal skin. Transient post-natal depletion of these monocytes resulted in heightened interleukin (IL)-17A production by skin T cells, which was particularly sustained among CD4(+) T cells and was sufficient to exacerbate inflammatory skin pathologies. Neonatal skin monocytes were enriched in expression of negative regulators of the IL-1 pathway. Functional in vivo experiments confirmed a key role of excessive IL-1R1 signaling in T cells as contributing to the dysregulated type 17 response in neonatal monocyte-depleted mice. Thus, a commensal-driven wave of monocytes into neonatal skin critically facilitates immune homeostasis in this prominent barrier tissue.