A unique intestinal epithelial cell that expresses canonical lymphoid genes

Enterocytes and intestinal secretory cells harbor innate immunity. However, certain transcriptional programs -even beyond rearranged T- and B-cell receptor genes- are considered the exclusive purview of adaptive immune cells, including abundant and diverse intestinal intra-epithelial lymphocytes (IELs). Here, we identify and characterize columnar intestinal secretory cells that co-express classic epithelial and lymphoid genes, including Ptprc, Cd3e, Cd8a, and Gzma/b but not T- or B-cell receptors. These previously unrecognized epithelium-derived lymphoid-like cells (EDLCs) differ from any known resident cell type, including IELs or tuft cells. Rare in healthy mouse and human intestines, their numbers increase upon IL-25 stimulation or IL-10 receptor deficiency in vivo and upon IL-13 stimulation in vitro. EDLC chromatin is uniquely accessible at thousands of cis-elements, including lymphoid and epithelial loci. These findings reveal a transcriptionally and epigenetically distinct intestinal epithelial derivative that expresses prominent lymphoid character.