Regulation of DNAM-1 family receptors and their ligands in T lymphocytes and intestinal epithelial cells

Purpose: DNAM-1 family co-receptors are expressed on T lymphocyte subsets and provide activating (DNAM-1) or inhibitory (TIGIT) signals that regulate T cell functions and proliferation. We previously found that the expression pattern of these co-receptors strikingly differs between circulating and mucosal T cell populations. Moreover, perturbed expression of DNAM-1/ligand system distinctly characterizes infiltrate and epithelial counterpart in the inflamed mucosa microenvironment of active Inflammatory Bowel Disease (IBD) pediatric patients. Here we analyzed the capability of polyclonal TCR-dependent stimulation or selected cytokines to modulate the expression of DNAM-1 family co-receptors and shared ligands (PVR and Nectin-2) on peripheral blood (PB) T cell subsets and HT-29 colon carcinoma-derived cell line. Results: IL-2 family cytokines or TCR/CD28 stimulation increases the frequency of TIGIT+ T cells, suggesting that such stimuli may partially explain the higher frequency of TIGIT+ mucosal T cells, as compared to PB counterpart. Differently, DNAM-1 levels are increased by TGF-b, and decreased by IL-17A. The dysregulated abundance of these two cytokines in inflamed mucosa microenvironment could underlie the downregulated DNAM-1 expression on mucosal T cells from active IBD patients. Moreover, Nectin-2 expression on HT-29 cells was decreased by TGF-b and IL-10 anti-inflammatory cytokines, suggesting that the reduced amount of these factors may lead to the increased frequency of Nectin-2+ gut epithelial cells recorded in active IBD lesions. Conclusion: Our data suggest that mucosal microenvironment factors shape the physiological expression pattern of DNAM-1 family co-receptor/ligand system and contribute to its alteration in IBD.