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

Intraepithelial lymphocytes expressing the gamma delta T cell receptor (gamma delta IELs) provide immunosurveillance of the intestinal barrier but are reduced in patients with active Crohn's disease (CD). Here, we report an underappreciated role for gamma delta IELs in maintaining immunological tolerance during the onset and progression of CD-like ileitis using TNF Delta ARE/+ mice. We found that TNF-induced down-regulation of epithelial hepatocyte nuclear factor 4-gamma/butyrophilin is followed by a loss of ileal V gamma 7 IELs and impaired barrier surveillance before the histological onset of disease. A reduction of immunoregulatory CD39+ gamma delta IELs coincided with the influx of immature, peripheral CD39neg gamma delta T cells into the epithelium, leading to an expansion of induced IELs, whereas an earlier depletion of gamma delta IELs correlated with accelerated onset of ileal inflammation. Our findings identify multiple layers of gamma delta IEL dysregulation before ileitis development, indicating that the loss of steady-state immunoregulatory gamma delta IELs may contribute to the initiation of ileal CD.