Gliadin Regulates the NK-Dendritic Cell Cross-Talk by HLA-E Surface Stabilization

Abstract

We analyzed the autologous NK cell interaction with gliadin-presenting dendritic cells. Gliadin is the known Ag priming the celiac disease (CD) pathogenesis. We demonstrate that gliadin prevents immature dendritic cells (iDCs) elimination by NK cells. Furthermore, cooperation between human NK cells-iDCs and T cells increases IFN-γ production of anti-gliadin immune response. Gliadin fractions were analyzed for their capability to stabilize HLA-E molecules. The α and ω fractions conferred the protection from NK cell lysis to iDCs and increased their HLA-E expression. Gliadin pancreatic enzyme digest and a peptide derived from gliadin α increased HLA-E levels on murine RMA-S/HLA-E-transfected cells. Analysis of HLA-E expression in the small intestinal mucosa of gluten-containing diet celiac patients and organ culture experiments confirmed the in vitro data.

Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion

“…This may result in direct stimulation of NK cells present in the lamina propia by gliadin or APCs [38,39]. It has also been suggested that gluten peptides might be presented by DCs sampling the intestinal lumen [40], which may increase the crosstalking with NK cells [14], thus making it possible for gliadin to activate NK cells even in the absence of a leaky gut epithelium.…”

“…Gliadin fragments have also been shown to stimulate TLR4 and activate innate cells such as monocytes, macrophages, and DCs [13], and to regulate the NK-cell DC crosstalk by stabilizing HLA-E on the cell surface [14]. The exact role of dietary gluten and gliadin fragments in NK-cell activity and T1D has not yet been elucidated.…”

“…2014. 44: 3056-3067 Innate immunity 3057 stabilizing HLA-E on the cell surface [14]. The exact role of dietary gluten and gliadin fragments in NK-cell activity and T1D has not yet been elucidated.…”

“…This may result in direct stimulation of NK cells present in the lamina propia by gliadin or APCs [38,39]. It has also been suggested that gluten peptides might be presented by DCs sampling the intestinal lumen [40], which may increase the crosstalking with NK cells [14], thus making it possible for gliadin to activate NK cells even in the absence of a leaky gut epithelium.It is well known that priming of lymphocytes in gut-associated lymphoid tissue is important in T1D [41], and a similar mechanism may be important for gut-homing NK cells. Furthermore, increased islet endothelial permeability has been observed in prediabetic mice [42], and gliadin fragments have been detected in breast milk from healthy women [43].…”

Dendritic cells in intestinal homeostasis and disease

“…Interestingly, gliadin enhanced the maturation of blood-derived immature DCs in all subjects irrespective of their genotype or of the presence of celiac disease, although gliadin-stimulated DCs from untreated celiac patients showed increased stimulation of autologous T cells compared with the other groups (110). Furthermore, gliadin plays a detrimental role in the regulation of NK cell-DC interactions, as it may switch the NK cell-DC cross-talk from a tolerogenic pathway (based on immature DC elimination) to a pathogenic one in which gliadin inhibits NK cell cytotoxicity against immature DCs via the CD94/ NKG2A pathway (111).…”