Abstract
Dendritic cell (DC) expression of CD103, the α subunit of αEβ7 integrin, is thought to enable DC interactions with E-cadherin-expressing gastrointestinal epithelia for improved mucosal immunosurveillance. In the stomach, efficient DC surveillance of the epithelial barrier is crucial for the induction of immune responses to H. pylori, the causative agent of peptic ulcers and gastric cancer. However, gastric DCs express only low levels of surface CD103, as we previously showed. We here tested the hypothesis that intracellular pools of CD103 in human gastric DCs can be redistributed to the cell surface for engagement of epithelial cell-expressed E-cadherin to promote DC-epithelial cell adhesion. In support of our hypothesis, immunofluorescence analysis of tissue sections showed that CD103+ gastric DCs were preferentially localized within the gastric epithelial layer. Flow cytometry and imaging cytometry revealed that human gastric DCs expressed intracellular CD103, corroborating our previous findings in monocyte-derived DCs (MoDCs). Using confocal microscopy, we show that CD103 was present in endosomal compartments, where CD103 partially co-localized with clathrin, early endosome antigen-1 and Rab11, suggesting that CD103 undergoes endosomal trafficking similar to β1 integrins. Dynamic expression of CD103 on human MoDCs was confirmed by internalization assay. To analyze whether DC-expressed CD103 promotes adhesion to E-cadherin, we performed adhesion and spreading assays on E-cadherin-coated glass slides. In MoDCs generated in the presence of retinoic acid, which express increased CD103, intracellular CD103 significantly redistributed toward the E-cadherin-coated glass surface. However, DCs spreading and adhesion did not differ between E-cadherin-coated slides and slides coated with serum alone. In adhesion assays using E-cadherin-positive HT-29 cells, DC binding was significantly improved by addition of Mn2+ and decreased in the presence of EGTA, consistent with the dependence of integrin-based interactions on divalent cations. However, retinoic acid failed to increase DC adhesion, and a CD103 neutralizing antibody was unable to inhibit DC binding to the E-cadherin positive cells. In contrast, a blocking antibody to DC-expressed E-cadherin significantly reduced DC binding to the epithelium. Overall, these data indicate that CD103 engages in DC-epithelial cell interactions upon contact with epithelial E-cadherin, but is not a major driver of DC adhesion to gastrointestinal epithelia.
Highlights
Dendritic cells (DCs) frequently interact with the epithelial layer of the gastric mucosa, as shown in previous studies [1,2,3]
These observations suggest that, in spite of an overall low expression of CD103 by human gastric DCs, CD103 might still contribute to DC interactions with the gastric epithelium in those DCs that are integrated into the epithelial cell layer
A number of previous reports had speculated that CD103 might mediate adhesion of gastrointestinal DCs to E-cadherin expressed in the epithelial layer [15,16,17], similar to the mechanism shown for the retention of intraepithelial lymphocytes within the epithelial compartment [22, 50]
Summary
Dendritic cells (DCs) frequently interact with the epithelial layer of the gastric mucosa, as shown in previous studies [1,2,3]. As professional antigen-presenting cells, DCs control the immune response to Helicobacter pylori (H. pylori) [4], a bacterial pathogen that causes chronic gastritis, peptic ulcer disease, and gastric cancer [5,6,7]. The type of T cell response induced by the DCs largely determines whether H. pylori infection causes only mild inflammation or leads to severe inflammatory pathologies including ulcers or cancer [8,9,10]. For those DCs that are located immediately beneath or within the gastric epithelium, their spatial interactions with the epithelial cells have important functional implications for the immune response to H. pylori. In spite of the importance of DC-epithelial interactions for gastrointestinal immune responses, the molecular mechanisms of these interactions are not well-defined
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