Résumé
CCR6 is a chemokine receptor that is specifically expressed at the cell surface of Th17 cells, a population of cytokine producing CD4+ T cells with strong inflammatory properties. Ligand-mediated triggering of chemokine receptors is involved in T lymphocyte migration towards and diapedesis into inflamed tissue. Here, we have determined the involvement of CCR6 in this process by analyzing the capacity of CCR6-specific ligands to induce arrest of Th17 lymphocytes onto endothelial cells in vitro under flow conditions. We show that under inflammatory conditions both CCL20 and beta-defensin-2 are capable to induce arrest of tissue-derived Th17, but neither Th1 nor Th2, cells on HUVEC, stimulated with IL-1beta and TNF-alpha 48 h prior to the adhesion assay. Chemokine-induced arrest of Th17 cells was found to be dependent, at least in part, on the expression of CD54. Although specific for Th17 cells, CCR6 expression is not a stable trait, as antigen-specific stimulation resulted in the inhibition of cell surface expression of CCR6 with a complete loss of expression observed after 76h of stimulation. CCR6 expression was restored following subsequent culture in vitro which was intrinsic to Th17 cells and which was independent of the addition of cytokines to the culture medium. As CCL20 is not only secreted by inflamed endothelium, but is also produced rapidly by activated Th17 cells, these results show that CCR6 plays an important role in the migratory capacity of human Th17 cells towards inflamed tissue and, furthermore, that antigen-specific activation induces a transient state of non-responsiveness to CCR6-specific ligands.