Selective expansion of intraepithelial lymphocytes expressing the HLA-E-specific natural killer receptor CD94 in celiac disease

Background & Aims: Celiac disease is a gluten-induced enteropathy character ized by the presence of gliadin-specific CD4(+) T cells in the lamina propr ia and by a prominent intraepithelial T-cell infiltration of unknown mechan ism. The aim of this study was to characterize the subset(s) of intraepithe lial lymphocytes (IELs) expanding during active celiac disease to provide i nsights into the mechanisms involved in their expansion. Methods: Flow-cyto metric analysis of isolated IELs and/or immunohistochemical staining of fro zen sections were performed in 51 celiac patients and 50 controls with a pa nel of monoclonal antibodies against T-cell and natural killer (NK) recepto rs, In addition, in vitro studies were performed to identify candidate stim uli for NK receptor expression. Results: In normal intestine, different pro portions of IELs, which were mainly T cells, expressed the NK receptors CD9 4/ NKG2, NKR-P1A, KIR2D/3D, NKp46, Pen5, or CD56. During the active phase o f celiac disease, the frequency of CD94(+) IELs, which were mostly alpha be ta T cells, was conspicuously increased over controls. In contrast, the exp ression of other NK markers was not modified. Furthermore, expression of CD 94 could be selectively induced in vitro by T-cell receptor activation and/ or interleukin 15, a cytokine produced by intestinal epithelial cells. Conc lusions: The gut epithelium favors the development of T cells that express NK receptors. In active celiac disease, there is a specific and selective i ncrease of IELs expressing CD94, the HLA-E-specific NK receptor that may be related to T-cell receptor activation and/or interleukin 15 secretion.