1. Evidence for PI-3K-dependent migration of Th17-polarized cells in response to CCR2 and CCR6 agonists
- Author
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Adam Webb, Stephen G. Ward, Louise A. Jopling, Andrew M.F. Johnson, Gillian F. Watt, Adam Samuel Platt, Mark I Christie, Mara Fortunato, and Tom Crabbe
- Subjects
CD4-Positive T-Lymphocytes ,Receptors, CCR6 ,Chemokine ,Receptors, CCR2 ,Receptor expression ,Immunology ,chemical and pharmacologic phenomena ,Cell Separation ,C-C chemokine receptor type 6 ,Biology ,CXCR3 ,Mice ,Phosphatidylinositol 3-Kinases ,Chemokine receptor ,Cell Movement ,Animals ,Immunology and Allergy ,Mice, Inbred BALB C ,Gene Expression Profiling ,hemic and immune systems ,T-Lymphocytes, Helper-Inducer ,Cell Biology ,Acquired immune system ,Cell biology ,CCL20 ,Gene Expression Regulation ,Cancer research ,biology.protein ,Cytokines ,Receptors, Chemokine ,CCL25 ,Proto-Oncogene Proteins c-akt ,Spleen - Abstract
IL-17-producing Th cells (Th17) are a distinct subset of effector cells that bridge the in- nate and adaptive immune system and are impli- cated in autoimmune disease processes. CD4 splenocytes from DO11.10 mice were activated with OVA peptide323-339 and maintained under Th17 polarization conditions, resulting in signifi- cantly higher proportions of IL-17 T cells com- pared with nonpolarized (Th0) cells. Th17-polar- izing conditions significantly increased the propor- tion 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 nonpo- larizing conditions. The respective chemokine ago- nists 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 recep- tors were functionally and biochemically respon- sive. Furthermore, postmigration phenotypic anal- ysis demonstrated that the agonists for CCR2 and CCR6, but not CCR9, stimulated a modest enrich- ment of IL-17 cells compared with the premigra- tion population. Pan-isoform inhibitors of PI-3K/ Akt signaling prevented CCR2- and CCR6-medi- ated, polarized Th17 cell migration in a concentration-dependent manner. The unique che- mokine receptor expression pattern of Th17 cells and their corresponding PI-3K-dependent migra- tory responses are important for understanding the pathogenesis of autoimmune diseases and may pro- vide opportunities for the application of CCR2 and CCR6 antagonists and PI-3K isoform-selective in- hibitors in defined inflammatory settings. J. Leu- koc. Biol. 84: 1202-1212; 2008.
- Published
- 2008