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 co-express 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 conditions of 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 and/or their ligands that depend, respectively, on chemokines that bind to the EC luminal surfaces versus non-binding chemokines that form transendothelial gradients under conditions of flow. Our findings provide fundamental insights into mechanisms of lymphocyte extravasation and may lead to novel strategies to block or enhance their migration into tissue.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

* This version of the manuscript has been revised to add some additional data in the result section and some changes in the discussion to reflect those changes.

Details

Title
Chemokine positioning determines mutually exclusive roles for their receptors in extravasation of pathogenic human T cells
Author
Farhat Parween; Singh, Satya P; Zhang, Hongwei H; Kathuria, Nausheen; Otaizo-Carrasquero, Francisco A; Shamsaddini, Amirhossein; Gardina, Paul J; Ganesan, Sundar; Kabat, Juraj; Lorenzi, Hernan A; Myers, Timothy G; Farber, Joshua M
University/institution
Cold Spring Harbor Laboratory Press
Section
New Results
Publication year
2023
Publication date
Feb 13, 2023
Publisher
Cold Spring Harbor Laboratory Press
ISSN
2692-8205
Source type
Working Paper
Language of publication
English
ProQuest document ID
2769438545
Copyright
© 2023. This article is published under https://creativecommons.org/publicdomain/zero/1.0/ (“the License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.