Reduced Chemokine Receptor 9 on Intraepithelial Lymphocytes in Celiac Disease Suggests Persistent Epithelial Activation

Background & Aims: Celiac disease is caused by an inappropriate immune response to dietary gluten, with increased epithelial lymphocyte infiltration in the duodenum/jejunum as a hallmark. The chemokine receptor 9 (CCR9) is a small intestinal homing receptor normally found on most mucosal T cells in this organ. Because CCR9 expression appears to be activation dependent, we examined CCR9 on duodenal T cells from untreated and treated (gluten-free diet) patients with celiac disease and healthy controls. Methods: Duodenal biopsy specimens and blood samples were obtained for histologic analysis and flow-cytometric CCR9 analysis of isolated lymphocytes. CCR9 expression after activation was studied in peripheral blood T cells from healthy volunteers. Results: The median number of CCR9+ cells among CD3+ T cells in epithelium and lamina propria, respectively, was 56% and 48% in controls, 11% and 40% in treated patients, and 1% and 8% in untreated patients. Significant differences occurred between controls and treated or untreated patients in the epithelium but only between controls and untreated patients in the lamina propria (P = .008, all comparisons). No such differences were seen in peripheral blood, but stimulation with phorbol myristate acetate and ionomycin and, to a lesser extent, stimulation via NKG2D reduced the CCR9 expression on blood T cells. Conclusions: CCR9 expression is reduced on epithelial and lamina propria T cells in untreated celiac disease. Down-regulation of CCR9 persists in intraepithelial T cells from well-treated patients. This suggests ongoing immune activation preferentially within the epithelium.