Celiac Disease-Related Inflammation Is Marked By Reduction of NKp44/NKp46-Double Positive Natural Killer Cells

Natural killer(NK)cells are the first line of defense against viruses and down-regulation of NK cell cytotoxic receptors represents one of the strategies by which viruses escape the immune system.NK cells are supposed to contribute to the intestinal epithelial damage in celiac disease(CD),whose onset has been associated with viral infections.However,it remains unclear whether CD-associated inflammation is characterized by abnormal distribution of NK cell receptors recognizing viral-infected cells.Here,we characterized the tissue distribution of NK cells in CD.NK cell markers were analyzed in intraepithelial lymphocytes(IELs)isolated from duodenal biopsies of CD patients(both active and inactive)and healthy controls(HC)and jejunal specimens of patients undergoing gastro-intestinal bypass by flow-cytometry.Cytokines were assessed in cells either freshly isolated or stimulated with IL-15, IL-21 and IFN-α.The percentage of total NK cells and NKT cells did not significantly differ between CD patients and HC and no alteration in the expression of NKG2D, NKG2A and HLA-E was seen in CD.The fractions of NK cells and NKT cells expressingNKp30 were slightly,but not significantly,increased in active CD.Although the percentage of NK cells and NKT cells expressing either NKp44 or NKP46 did not differ between CD and controls,the fraction of NK cells and NKT cells expressing both these cytotoxic receptors was significantly decreased in CD compared to controls.NKp44/NKp46-double positive cells produced granzymeB,but not TNF-α,IL17 or IL-22,and such a production was increased by IL-15,but not IL-21 or IFN-α.Data indicate that NKp44/NKp46 double positive NK cells and NKT cells producing granzymeB, a subset of cells involved in recognition of viral-infected cells, are significantly decreased in active CD.