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Chemokine positioning determines specialized roles during transdendothelial trafficking of human Th cells with pathogenic features

ABSTRACT: Human Th17/type 17 cells uniformly express the chemokine receptor CCR6. However, the heterogeneity of this cell population and the precise functional role of CCR6 and other chemokine receptors in human Th17 cell extravasation have not been fully delineated. Here we show that CD4+CCR6+ cells co-expressing CCR2 have a pathogenic Th17 signature in the blood, can produce inflammatory cytokines without TCR activation, and show enhanced expression of pathogenicity- and activation-associated genes in the cerebrospinal fluid of patients with multiple sclerosis as compared to control subjects. In flow chambers with activated endothelial cell (EC) monolayers, CD4+CCR6+CCR2+ cells were highly efficient at transendothelial migration (TEM). Ligands for CCR5, CCR6 and CXCR3 localized to EC surfaces and mediated only arrest, whereas CCR2 ligands, although secreted by ECs, failed to bind to ECs and mediated only TEM. Conversely, expressing a chimeric CCR2 ligand engineered to bind glycosaminoglycans on ECs resulted in CCR2-mediated arrest but blocked TEM. Our data suggest T cell arrest requires chemokine bound to EC surfaces, whereas TEM requires a transendothelial chemokine gradient. We show that for human pathogenic-like type 17 T cells, these requirements are met in this system by using separate chemokine/chemokine receptor groups subspecialized to mediate arrest versus TEM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE284426 | GEO | 2024/12/17

REPOSITORIES: GEO

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Chemokine positioning determines specialized roles during transdendothelial trafficking of human Th cells with pathogenic features

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