Journal of Leukocyte Biology BioLegend: Treg, Th17, Stem Cell
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A more recent version of this article appeared on October 1, 2008

Published online before print June 27, 2008
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0408234

Received for publication April 9, 2008.
Revised May 14, 2008.
Accepted for publication May 30, 2008.

Article

Evidence for PI-3K-dependent migration of Th17-polarized cells in response to CCR2 and CCR6 agonists

Adam Webb *, Andrew Johnson {dagger}, Mara Fortunato {dagger}, Adam Platt {dagger}, Tom Crabbe {ddagger}, Mark I. Christie {dagger}, Gillian F. Watt {dagger}, Stephen G. Ward *@, and Louise A. Jopling {dagger}

*Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom; {dagger}UCB, Granta Park, Great Abington, Cambridge, United Kingdom; and {ddagger}UCB, Slough, United Kingdom

@ To whom correspondence should be addressed. E-mail: S.G.Ward{at}bath.ac.uk.


  Abstract

IL-17-producing Th cells (Th17) are a distinct subset of effector cells that bridge the innate and adaptive immune system and are implicated in autoimmune disease processes. CD4+ splenocytes from DO11.10 mice were activated with OVA peptide323–339 and maintained under Th17 polarization conditions, resulting in significantly higher proportions of IL-17+ T cells compared with nonpolarized (Th0) cells. Th17-polarizing conditions significantly increased the proportion of cells expressing the chemokine receptors CCR2, CCR6, and CCR9 when compared with Th0 cells. In contrast, there was a significant decrease in the proportion of cells expressing CXCR3 under Th17-polarizing conditions compared with nonpolarizing conditions. The respective chemokine agonists for CCR2 (CCL2 and CCL12), CCR6 (CCL20), and CCR9 (CCL25) elicited migration and PI-3K-dependent signaling events in Th17-polarized cells, thus indicating that all three receptors were functionally and biochemically responsive. Furthermore, postmigration phenotypic analysis demonstrated that the agonists for CCR2 and CCR6, but not CCR9, stimulated a modest enrichment of IL-17+ cells compared with the premigration population. Pan-isoform inhibitors of PI-3K/Akt signaling prevented CCR2- and CCR6-mediated, polarized Th17 cell migration in a concentration-dependent manner. The unique chemokine receptor expression pattern of Th17 cells and their corresponding PI-3K-dependent migratory responses are important for understanding the pathogenesis of autoimmune diseases and may provide opportunities for the application of CCR2 and CCR6 antagonists and PI-3K isoform-selective inhibitors in defined inflammatory settings.

Key Words: T cells • chemokines • cell trafficking • inflammation • signal transduction






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