β-catenin, TCF, and ICAT in T cell development, function, and aging

Abstract

Both T cell factor (TCF) and beta-catenin play important roles during different stages of T cell development. Most strikingly, deletion of TCF results in a block early in development, which becomes complete with TCF-LEF double deletion. Similarly, T-cell specific deletion of beta-catenin impairs T cell development at the beta-selection checkpoint. However, in addition to working together to drive expression of beta-catenin-TCF target genes, both TCF and beta-catenin have the potential to work independently of each other. To specifically study the role of beta-catenin-TCF interactions during T cell development, function, and aging, we generated transgenic mice that express ICAT (Inhibitor of beta-Catenin and TCF), a naturally occurring inhibitor of beta-catenin-TCF interactions, in the T cell lineage. We found that disruption of beta-catenin-TCF interactions by ICAT expression impairs survival of thymocytes without significantly affecting their differentiation or proliferation. Interestingly, thymocyte aging shows signs of slowing down in ICAT-Tg mice, implicating beta-catenin-TCF interactions in normal thymic involution. We further show that beta-catenin-TCF interactions provide survival signals to activated T cells and promote differentiation of activated CD4 T cells into the default Th2 lineage. However, TCF represses Th1 differentiation independently of its interaction with beta-catenin. Finally, we show that beta-catenin expression accelerates the onset of aging in mature T cells. Collectively, these findings provide novel insights into the function of TCF and beta-catenin in T cell development, function, and aging.