Chemokines Induce Wnt-Frizzled Gene Expression in Human T Cells

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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. We have recently found that T cells express the Klotho protein and the expression of Klotho in immune cells declines with age. We have found that over-expression of T cell Klotho levels diminishes T-cell Wnt expression and also diminishes chemokine receptor expression. In contrast, knockdown of T cell Klotho expression in T cells resulted in increases in Wnt5a and Wnt10A levels and chemokine receptor expression. This work has recently been completed and several manuscripts on these data are being written up for possible publication. 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. 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. This is relevant as modulation of Wnt expression in T cells modulates the HIV-1 infectivity of a cell through the regulation of relevant chemokine co-receptor expression. Klotho gene expression was examined in murine and human CD4+T cells as a function of age. In both systems basal expression of Klotho gene decreased with age.