Chemokines Induce Wnt-Frizzled Gene Expression in Human T Cells

National Institute On Aging

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Abstract

Chemokines have been shown to induce and direct adhesion, chemotaxis, activation, and degranulation of human and rodent leukocytes both in vitro and in vivo. CXCL12 and CCL19 are two important chemokines that regulate T cell motility and activation under normal and inflammatory conditions. Despite numerous reports examining the function of chemokines, little is known about the transcriptional events involved therein. We have recently performed microarray analysis on CXCL12- and CCL19-treated T-cells, and found that the Wnt family of proteins was significantly upregulated during CXCL12 treatment. In the CXCL12 studies, we found that the expression of Wnt5A and other members of the non-canonical Wnt pathway were specifically upregulated during ligand stimulation of T cells, while beta-catenin and canonical Wnt family members were selectively downregulated. Wnt5A was found to augment signaling through the CXCL12-CXCR4 axis via the activation of protein kinase C (PKC). Moreover, our data has revealed that Wnt5A expression is required to mediate directional T-cell migration in response to CXCL12, and that the treatment of human T-cells with recombinant Wnt5A sensitized T-cells to CXCL12-induced migration. Furthermore,Wnt5A expression was also required for the sustained expression of CXCR4, both transcriptionally and translationally. Interestingly, in CCL19-treated T cells, we found that Wnt10A, not Wnt5A plays a role in CCL19-mediated chemotaxis and in the maintenance of CCR7 expression on T cells. This work has recently been completed and a manuscript on these data has been completed. These findings may reveal a novel cooperative signaling network between various chemokine and Wnt receptors and ligands that may control cell polarization and directional migration. Also, the functional role of the endogenous Wnt pathway regulator, Klotho, is also currently being examined. Moreover, under these studies, we have also been verifying and characterizing several additional gene families that are highly expressed in T cells after migration in response to or simply stimulation with CXCL12, CCL19, gp120 and HIV-1 virus. Moreover, the role of lipid rafts in chemokine biology and HIV infectivity are also under examination using microarray analysis. A greater understanding of the transcriptional signals differentially induced by the ligation of various chemokine receptors may provide a means to dissect the pathways by which these chemoattractants induce cell migration and activation as well as any host transcriptional signals important in HIV entry and replication.