Extravasation of pathogenic human type 17 Th cells requires both endothelial cell-bound and non-cell bound chemokines

Abstract Extravasation of pro-inflammatory T cells is critical for their effectiveness in host defense and mediating tissue damage immune-mediated disease. These co-express multiple chemokine receptors understanding the activities individual extravasation essential exploiting system therapeutic benefit – either to block or enhance trafficking these into sites inflammation. CCR6 expressed on all human Th17 cells, we found that +CCR2 +cells are enriched both express a pathogenic signature, including ability produce GM-CSF IFNγ, unusually efficient at transendothelial migration (TEM). Ligands CCR6, CCR5 CXCR3 were secreted by bound endothelial activated with TNFα could mediate firm arrest under flow - but not TEM. TEM required CCR2, whose ligands, CCL2, CCL7 CCL8, failed bind cell surfaces. Chemokines from basal as well apical sides cells. Pre-treating CCL2 transducing surface-bound CCL2-CXCL9 chimera led CCR2-mediated and, importantly, inhibition Taken together, our data suggest while requires chemokine, gradient maintained rapid dilution non-bound luminal flow. Consequently, versus inherent, nonetheless mutually exclusive depend, respectively, binding vs. non-binding chemokines. NIH