Intestinal epithelial ERBB3 maintains intraepithelial lymphocyte populations by modulating immune signaling pathways 2697

Abstract Description Intraepithelial lymphocytes (IELs) of gut mucosa maintain intestinal immunity. Imbalanced IEL subsets can compromise epithelial integrity and promote inflammation. IELs are known to crosstalk with intestinal epithelial cells (IECs), but the mechanistic details and the role of IECs in survival and proliferation of IELs are not clearly understood. The neuregulin receptor ERBB3 mediates anti-inflammatory signals in IECs, and mice with IEC-specific ERBB3 deletion (Erbb3f/f;Villin-Cre, hereafter Erbb3ΔIE) are more susceptible to experimental colitis than Cre-negative (WT) littermates. Moreover, human inflammatory bowel disease patients have low ERBB3 in IECs compared to healthy controls. We hypothesize that epithelial ERBB3 is required for homeostatic epithelial-IEL interactions. Using flow cytometric analysis of IELs from WT and Erbb3ΔIE ileums, we found reduced natural IELs (TCRγδ+ and TCRβ+CD8αα+cells) with ERBB3 deletion; in contrast, we saw increased induced IELs (TCRβ+CD8αβ+). Single cell and bulk RNA sequencing of WT and Erbb3ΔIE ileums showed changes in immune pathways—compared to WT, Erbb3ΔIE ileal IECs had decreased ICOS-L and IL-18 production as well as increased non-classical MHC-Ib molecules H2-Q6 and H2-Q7. Cytotoxic factors such as Granzyme A, Granzyme B, and IDO1 were also elevated with ERBB3 loss. These results suggest that epithelial ERBB3 is indispensable for maintenance of natural IELs and regulation of induced IELs, and thus for controlling gut immunity. Funding Sources California Institute of Regenerative Medicine Topic Categories Mucosal and Regional Immunology (MUC)