title: Evidence for PI-3K-dependent migration of Th17-polarized cells in response to CCR2 and CCR6 agonists.
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 peptide(323-339) 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.
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Webb
authors.forename: Andrew
authors.initials: A
authors.lastname: Johnson
authors.forename: Mara
authors.initials: M
authors.lastname: Fortunato
authors.forename: Adam
authors.initials: A
authors.lastname: Platt
authors.forename: Tom
authors.initials: T
authors.lastname: Crabbe
authors.forename: Mark I
authors.initials: MI
authors.lastname: Christie
authors.forename: Gillian F
authors.initials: GF
authors.lastname: Watt
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Ward
authors.forename: Louise A
authors.initials: LA
authors.lastname: Jopling
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology; D002465:Cell Movement; D002469:Cell Separation; D016207:Cytokines / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D051379:Mice; D008807:Mice, Inbred BALB C; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000819:agonists / Q000502:physiology*; D054399:Receptors, CCR6 / Q000819:agonists / Q000502:physiology*; D019707:Receptors, Chemokine / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000502:physiology*
chemical_list: C498126:CCR6 protein, mouse; C515335:Ccr2 protein, mouse; D016207:Cytokines; D054390:Receptors, CCR2; D054399:Receptors, CCR6; D019707:Receptors, Chemokine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt