β-catenin inhibits T cell activation by selective interference with LAT-PLC-γ1 phosphorylation. (50.12)

Abstract

Abstract The functional role of β-catenin in post-thymic T cells is poorly understood. We observed that β-catenin protein was constitutively degraded in peripheral T cells. Introduction of a stabilized mutant of β-catenin into primary T cells resulted in reduced proliferation and cytokine secretion following TCR/CD28 stimulation, and interfered with effector cell differentation. The biochemical mechanism of blunted T cell activation was investigated. Stable β-catenin was predominantly localized to the cytosol, and cytokine production was rescued with PMA+Ionomycin, arguing for an inhibitory effect on early TCR signaling. Analysis of specific signaling events revealed a selective inhibition of LAT phosphorylation on tyrosine 136, which was associated with defective PLC-γ1 phosphorylation and calcium signaling but normal ERK activation. Stable β-catenin was detected constitutively in regulatory T cells, and conditional deletion of β-catenin in these cells caused rapid cell death. Contrary to a recent report using GSK-3 inhibitors, we saw no effect on T cell memory differentiation with direct genetic manipulation of β-catenin. Our findings indicate that β-catenin negatively regulates effector T cell activation via a unique biochemical mechanism. Functionally, our observations suggest that conditions under which β-catenin might be inhibited in vivo would potentiate T cell-based immunity at the level of both effector and regulatory T cells.</jats:p