Dysregulation of γδ intraepithelial lymphocytes precedes Crohn's disease-like ileitis

Abstract

Intraepithelial lymphocytes expressing the {gamma}{delta} T cell receptor ({gamma}{delta} IELs) provide immunosurveillance of the intestinal barrier. Interestingly, {gamma}{delta} IEL number is reduced in patients with active Crohns disease (CD). Here, we report an underappreciated role for {gamma}{delta} IELs in maintaining mucosal tolerance during the onset and progression of CD-like ileitis using the TNF{Delta}ARE/+ mouse model. Decreased epithelial HNF4G/BTNL expression is followed by a loss of ileal {gamma}{delta} IELs and impaired barrier surveillance prior to the histological onset of disease. A reduction of immunoregulatory CD39+ {gamma}{delta} IELs coincides with the influx of immature, peripheral CD39- {gamma}{delta} T cells into the epithelium leading to an expansion of induced IELs, while an earlier depletion of {gamma}{delta} IELs correlates with accelerated onset of ileal inflammation. Our findings identify multiple layers of {gamma}{delta} IEL dysregulation prior to ileitis development indicating that the loss of tissue-resident immunoregulatory {gamma}{delta} IELs may contribute to the initiation of ileal CD.