Intestinal plasmacytoid dendritic cells preferentially produce interferon lambda [ATAC-seq]

The healthy intestine mounts immune responses to microbiota to maintain homeostasis, 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). These pDC are recruited to the intestine by bacterial microbiota colonization, and pDC depletion or bone marrow reconstitution with IFN-λ-deficient pDC results in reduced homeostatic ISGs in the intestinal epithelium. Notably, intestinal pDC preferentially produce IFN-λ over Type I IFNs whereas splenic pDC produce more Type I IFNs. Comparison of splenic and intestinal pDC reveal tissue-specific changes in gene expression and genomic accessibility, including evidence of response to transforming growth factor beta (TGF-β) in the intestine. Isolated gut pDC produce more IFN-λ that splenic pDC upon stimulation, and pre-treatment of a human pDC cell line with TGF-β results in enhanced production of IFN-λ upon stimulation. This study implicates pDC as important sources of homeostatic IFN-λ in the intestine and defines the role of 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.