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• W2562391207 abstract "C187 Wnt proteins are a family of secreted glycoproteins with diverse developmental roles. Wnt signaling has been shown to play a critical role in T cell development. Activation of the Wnt signaling cascade, following the binding of Wnt ligands on Frizzled receptors (Fzd), results in the phosphorylation of the glycogen synthase kinase 3β (GSK3β) and the inhibition of its kinase activity. As a consequence, the β-catenin protein, which is constitutively phosphorylated by GSK3β and subsequently degraded, can accumulate in the cytoplasm and nucleus where it binds TCF family proteins and converts them into transcriptional activators. While this pathway is known to be crucial for proper T cell development, few studies have investigated the role of the Wnt signaling pathway within effector T cells. As a first approach to interrogate the influence of this pathway on effectors T cell function, GSK3β pharmacologic inhibitors (SB216763 and lithium) were utilized. Treatment of effector CD8+ T cells with these drugs resulted in decreased phosphorylation of β-catenin which was accompanied by accumulation of total β-catenin. These effects correlated with inhibition of IFN-γ secretion, while IL-2 secretion was relatively preserved. At the same time, cyclin D2 expression was decreased, as was the proliferation of CD8+ effector T cells. Interestingly, GSK3β inhibition by SB216763 also increased the expression of the CD62L molecule in a dose-dependant fashion, suggesting the reversion of T cells expressing higher β-catenin levels to a less differentiated central memory phenotype. Quantitative RT-PCR confirmed the expression of the Frizzled receptors Fzd5 and LRP6, the receptor and co-receptor of Wnt3A. Experiments exposing CD8+ effector T cells to Wnt3A-conditioned medium have shown significant accumulation of total β-catenin. Our results show that interventions which increase total β-catenin levels inhibit key effector functions by activated CD8+ T cells. As it has been shown that overexpression of Wnt ligands by tumor cells correlates with more aggressive disease, our data generate the hypothesis that activation of the Wnt signaling pathway could represent a novel mechanism for tumors to decrease the effector function of infiltrating CD8+ T cells and thus result in immune escape." @default.
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• W2562391207 date "2007-11-01" @default.
• W2562391207 modified "2023-09-26" @default.
• W2562391207 title "The Wnt/GSK3/β-catenin signaling pathway regulates CD8+ T cell effector functions" @default.
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