CCR6 is a chemokine receptor that is expressed at the cell surface of Th17 cells, an IL-17- and IL-22-secreting population of CD4(+) T cells with antipathogenic, as well as inflammatory, properties. In the current study, we have determined the involvement of CCR6 in human Th17 lymphocyte migration toward inflamed tissue by analyzing the capacity of its ligands to induce arrest of these cells onto inflamed endothelium in vitro under flow conditions. We show that polarized, in situ-differentiated, skin-derived Th17 clones activated via the TCR-CD3 complex produce CCL20 in addition to IL-17 and IL-22. The latter cytokines induce, in a synergic fashion, the production of human beta-defensin (hBD)-2, but neither hBD-1 nor hBD-3, by epidermal keratinocytes. Both CCL20 and hBD-2 are capable of inducing the arrest of Th17 cells, but not Th1 or Th2 cells, on HUVEC in an CD54-dependent manner that is CCR6 specific and independent from the expression of CXCR4, reported to be an alternative receptor for hBD-2. In addition, Ag-specific activation induces a transient loss of CCR6 expression, both at the transcriptional and protein level, which occurs with slow kinetics and is not due to endogenous CCL20-mediated internalization of CCR6. Together, these results indicate that Ag-specific activation will initially contribute to CCR6-mediated Th17 cell trafficking toward and sequestration in inflamed tissue, but that it eventually results in a transitory state of nonresponsiveness to further stimulation of these cells with CCR6 ligands, thus permitting their subsequent migration out of the inflamed site.
CCL20 and beta-defensin-2 induce arrest of human Th17 cells on inflamed endothelium in vitro under flow conditions
Ghannam, S.; Dejou, C.; Pedretti, N.; Giot, J. P.; Dorgham, K.; Boukhaddaoui, H.; Deleuze, V.; Bernard, F. X.; Jorgensen, C.; Yssel, H.; Pene, J.
2011-02-01 / vol 186 / pages 1411-20
10.4049/jimmunol.1000597 jimmunol.1000597 [pii]
1550-6606 (Electronic) 0022-1767 (Linking)
Humans; Animals; Cells, Cultured; Mice; Ligands; Apoptosis/*immunology; beta-Defensins/*physiology; Blood Flow Velocity/*immunology; Cell Movement/immunology; Chemokine CCL20/*physiology; Endothelium, Vascular/*immunology/metabolism/pathology; Epidermis/cytology/immunology/metabolism; Inflammation Mediators/metabolism/*physiology; Interleukin-17/*biosynthesis; Interleukins/biosynthesis; Keratinocytes/cytology/immunology/metabolism; L Cells (Cell Line); Lymphocyte Activation/immunology; Receptors, CCR6/biosynthesis/genetics/metabolism; T-Lymphocytes, Helper-Inducer/*immunology/metabolism/pathology