Abstract
Abstract CD4+CD8+ double positive (DP) thymocytes are subject to positive and negative selection, and thus the lifespan of DP cells determines T cell repertoire. Previously, we have identified RORγt as a critical player in the regulation of DP thymocyte survival. However, the molecular mechanisms responsible for RORγt-mediated survival remain unknown. Here we demonstrated that β-catenin/TCF acts upstream of RORγt to enhance DP thymocyte survival via up-regulation of anti-apoptotic factor Bcl-xL. Activation of TCF-1 pathway by transgenic expression of a constitutively active β-catenin leads to increase of RORγt level and enhanced DP thymocyte survival via upregulation of Bcl-xL, whereas DP thymocytes from Tcf-1-/- mice undergo accelerated apoptosis and have significantly reduced RORγt and Bcl-xL. More importantly, forced expression of RORγt in Tcf-1-/- thymocytes leads to rescue of massive apoptosis and restoration of Bcl-xL level. We further demonstrated that β-catenin/TCF-1 activates RORγt promoter. Our data thus suggest that β-catenin/TCF-1 acts upstream of RORγt in the regulation of Bcl-xL expression and DP thymocyte survival.
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