Chemokine positioning determines mutually exclusive roles for their receptors in extravasation of pathogenic human T cells

Abstract

Pro-inflammatory T cells co-express multiple chemokine receptors, but the distinct functions of individual receptors on these cells are largely unknown. Human Th17 cells uniformly express the chemokine receptor CCR6, and we discovered that the subgroup of CD4+CCR6+cells that coexpress CCR2 possess a pathogenic Th17 signature, can produce inflammatory cytokines independent of TCR activation, and are unusually efficient at transendothelial migration (TEM). The ligand for CCR6, CCL20, was capable of binding to activated endothelial cells (ECs) and inducing firm arrest of CCR6+CCR2+cells under flow - but CCR6 could not mediate TEM. By contrast, CCL2 and other ligands for CCR2, despite being secreted from both luminal and basal sides of ECs, failed to bind to the EC surfaces - and CCR2 could not mediate arrest. Nonetheless, CCR2 was required for TEM. To understand if CCR2s inability to mediate arrest was due solely to an absence of EC-bound ligands, we generated a CCL2-CXCL9 chimeric chemokine that could bind to the EC surface. Although display of CCL2 on the ECs did indeed lead to CCR2-mediated arrest of CCR6+CCR2+cells, activating CCR2 with surface-bound CCL2 blocked TEM. We conclude that mediating arrest and TEM are mutually exclusive activities of chemokine receptors that depend, respectively, on chemokines that bind to the EC luminal surfaces versus non-binding chemokines that form transendothelial gradients. Our findings provide fundamental insights into mechanisms of leukocyte extravasation and may lead to novel strategies to block or enhance their migration into tissue.

Indole-3-carbinol attenuates lipopolysaccharide-induced acute respiratory distress syndrome through activation of AhR: role of CCR2+ monocyte activation and recruitment in the regulation of CXCR2+ neutrophils in the lungs

“…CD4+CCR6+CCR2+ cells exhibit a pathogenic Th17 signature, produce inflammatory cytokines independent of TCR activation, and efficiently migrate through endothelial cells. While CCR6 mediates firm arrest of cells on endothelial surfaces, CCR2 is essential for transendothelial migration but not for cell arrest, indicating that these activities are mutually exclusive and depend on chemokine binding to different endothelial surfaces or forming transendothelial gradients ( 40 ). On the other hand, neutrophils recruited to the inflamed lungs express CXCR2.…”