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In mice, HNF4A is indispensable for the maintenance of intestinal homeostasis, yet the underlying mechanisms are poorly characterized. Here, we demonstrate that the expression of HNF4A in intestinal epithelial cells (IECs) is required for the proper development and composition of the intraepithelial lymphocyte (IEL) compartment. HNF4A directly regulates expression of immune signaling molecules including butyrophilin-like (Btnl) 1, Btnl6, H2-T3, and Clec2e that control IEC\u2013IEL crosstalk. HNF4A selectively enhances the expansion of natural IELs that are TCR\u03b3\u03b4+ or TCR\u03b1\u03b2+CD8\u03b1\u03b1+ to shape the composition of IEL compartment. In the small intestine, HNF4A cooperates with its paralog HNF4G, to drive expression of immune signaling molecules. Moreover, the HNF4A\u2013BTNL regulatory axis is conserved in human IECs. Collectively, these findings underscore the importance of HNF4A as a conserved transcription factor controlling IEC\u2013IEL crosstalk and suggest that HNF4A maintains intestinal homeostasis through regulation of the IEL compartment.<\/jats:p>","DOI":"10.1084\/jem.20212563","type":"journal-article","created":{"date-parts":[[2022,7,6]],"date-time":"2022-07-06T13:31:09Z","timestamp":1657114269000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":34,"title":["Epithelial HNF4A shapes the intraepithelial lymphocyte compartment via direct regulation of immune signaling molecules"],"prefix":"10.1084","volume":"219","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3565-6969","authenticated-orcid":true,"given":"Xuqiu","family":"Lei","sequence":"first","affiliation":[{"name":"Program in Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 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