Abstract Text: Type-III interferons (IFN-λs) are recently described family of IFNs. While sharing many properties with type I IFNs they are particularly important to epithelial and barrier surfaces. The human gene family is composed of four members IFNL1-4 and their unique roles are just starting to be illuminated. In adult tissue, IFN-λ expression is restricted to epithelial cells and participates in anti-viral immunity. However, how IFN-λs contribute to fetal intestinal immunity are largely unknown. We developed an extensive single cell atlas of small intestinal (SI) tissue across the human life span ranging from 8 weeks gestational age to adulthood (350,458 of cells). Surprisingly, there was a strong IFN signature in fetal T cells compared to post-natal SI. Mining the atlas, we determined that in utero IFN production was restricted to memory T cells and included both IFNG and unexpectedly IFNL1. Although IFNγ signature predominated in the SI immune cells, epithelial cells had a stronger IFNγ signature. Differential analysis of IFNLR1+ epithelial cells suggested an enrichment for antigen processing pathways and upregulation of MHCI and II. We next addressed the effects of IFNL1 in fetal SI organoids in vitro. Contrary to previously described effects of IFNL on adult derived organoids, IFNL1 treatment of fetal SI organoids promoted proliferation, reduced apoptosis, and enhanced MHC I expression while still inducing a strong IFNL signature consistent with the scRNAseq data. Taken together, our results suggest a unique function of IFN-λs in fetal intestinal homeostasis and immunity during fetal development.
