Increased Intraepithelial Vα24 Invariant NKT Cells in the Celiac Duodenum

Abstract

Celiac Disease (CD) is an interferon (IFN) -mediated duodenal hypersensitivity to wheat gluten occurring in genetically predisposed individuals. Gluten-free diet (GFD) leads to a complete remission of the disease. V 24-restricted invariant NKT (iNKT) cells are important to maintain immune homeostasis in the gut mucosa because of their unique capacity to rapidly produce large quantities of both T-helper (Th)1 and Th2 cytokines upon stimulation. We studied the presence of these cells in the CD duodenum. Duodenal biopsies were obtained from 45 untreated-CD patients (uCD), 15 Gluten Free Diet-CD patients (GFD-CD), 44 non-inflamed non-CD controls (C-controls) and 15 inflamed non-CD controls (I-controls). Two populations from Spain and Argentina were recruited. Messenger RNA (mRNA) expression of V 24-J 18 (invariant TCR chain of human iNKT cells), IFN and intracellular transcription factor Forkhead Box P3 (Foxp3), and flow cytometry intraepithelial lymphocyte (IEL) profile were determined. Both uCD and GFD-CD patients had higher V 24-J 18 mRNA levels than non-CD controls (I and C-controls). The expression of V 24-J 18 correlated with Marsh score for the severity of mucosal lesion and also with increased mRNA IFN levels. uCD and GFD-CD patients had decreased mRNA expression of FoxP3 but increased expression of V 24-J 18, which revealed a CD-like molecular profile. Increased numbers of iNKT cells were confirmed by flow cytometry within the intraepithelial lymphocyte compartment of uCD and GFD-CD patients and correlated with V 24-J 18 mRNA expression. In conclusion, we have found an increased number of iNKT cells in the duodenum from both uCD and GFD-CD patients, irrespective of the mucosal status. A CD-like molecular profile, defined by an increased mRNA expression of V 24-J 18 together with a decreased expression of FoxP3, may represent a pro-inflammatory signature of the CD duodenum.