Intestinal plasmacytoid dendritic cells preferentially produce interferon lambda, contributing to localized innate immune responses

The healthy intestine maintains homeostasis in part via immune responses to microbiota, which includes basal production of interferon cytokines. Previous work showed that Type III Interferon (IFN-λ) stimulates localized pockets of interferon-stimulated genes (ISGs) in the adult mouse intestinal epithelium at homeostasis that provide preemptive protection from viral pathogens. Here, we demonstrate that a major source of homeostatic IFN-λ production in the intestine is a population of epithelium-associated plasmacytoid dendritic cells (pDC). Expansion of the pDC population increases epithelial ISG expression at homeostasis, suggesting the abundance of these cells is a limiting factor in IFN-λ responses. On the other hand, depletion of pDC or bone marrow reconstitution with IFN-λ-deficient pDC results in reduced expression of homeostatic ISGs in the intestinal epithelium. Notably, intestinal pDC preferentially produce homeostatic IFN-λ, whereas splenic pDC produce Type I IFNs. Comparison of intestinal and splenic pDC reveal tissue-specific changes in gene expression and genomic accessibility, including evidence of responses to transforming growth factor beta (TGF-β) in the intestine. Isolated gut pDC produce more IFN-λ than splenic pDC upon stimulation, and pretreatment of a human pDC cell line with TGF-β results in enhanced transcription of IFN-λ upon stimulation. This study demonstrates that pDC are a substantial source of homeostatic IFN-λ in the intestine and implicates the barrier cytokine TGF-β in regulating IFN types produced by pDC upon stimulation. Reprogramming of recruited pDC by tissue cytokines may have important implications for balancing effective antimicrobial responses with damaging inflammation at barrier tissues.