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Dysregulation of gd intraepithelial lymphocytes precedes Crohn’s disease-like ileitis

Xu, W;Golovchenko, N;Fong, A;Achi, S;Bucar, E;Vidmar, K;Zhang, L;Frey, M;Prinz, I;Pizarro, T;Kollias, G;Edelblum, K;

Intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IELs) provide immunosurveillance of the intestinal barrier. Interestingly, γδ IEL number is reduced in patients with active Crohn’s disease (CD). Here, we report an underappreciated role for γδ IELs in maintaining mucosal tolerance during the onset and progression of CD-like ileitis using the TNFΔARE/+ mouse model. Decreased epithelial HNF4G/BTNL expression is followed by a loss of ileal γδ IELs and impaired barrier surveillance prior to the histological onset of disease. A reduction of immunoregulatory CD39+ γδ IELs coincides with the influx of immature, peripheral CD39- γδ T cells into the epithelium leading to an expansion of induced IELs, while an earlier depletion of γδ IELs correlates with accelerated onset of ileal inflammation. Our findings identify multiple layers of γδ IEL dysregulation prior to ileitis development indicating that the loss of tissue-resident immunoregulatory γδ IELs may contribute to the initiation of ileal CD.