Intestinal plasmacytoid dendritic cells preferentially produce interferon lambda [scRNA-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-?) 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-? 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-?-deficient pDC results in reduced homeostatic ISGs in the intestinal epithelium. Notably, intestinal pDC preferentially produce IFN-? 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-ß) in the intestine. Isolated gut pDC produce more IFN-? that splenic pDC upon stimulation, and pre-treatment of a human pDC cell line with TGF-ß results in enhanced production of IFN-? upon stimulation. This study implicates pDC as important sources of homeostatic IFN-? in the intestine and defines the role of barrier cytokine TGF-ß 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. Overall design: Pooled myeloid cells from small intestinla epithelial fractions of wildtype mice were analylzed by single-cell RNA sequencing to identify cellular sources of interferon lambda gene produciton at homeostasis.