A Critical Role for the Regulated Wnt–Myc Pathway in Naive T Cell Survival

Wnt signaling is involved in T cell development, activation, and differentiation. However, the role for Wnt signaling in mature naive T cells has not been investigated. In this article, we report that activation of Wnt signaling in T cell lineages by deletion of the Apc (adenomatous polyposis coli) gene causes spontaneous T cell activation and severe T cell lymphopenia. The lymphopenia is the result of rapid apoptosis of newly exported, mature T cells in the periphery and is not due to defects in thymocyte development or emigration. Using chimera mice consisting of both wild-type and Apc-deficient T cells, we found that loss of naive T cells is due to T cell intrinsic dysregulation of Wnt signaling. Because Apc deletion causes overexpression of the Wnt target gene cMyc, we generated mice with combined deletion of the cMyc gene. Because combined deletion of cMyc and Apc attenuated T cell loss, cMyc overexpression is partially responsible for spontaneous T cell apoptosis and lymphopenia. Cumulatively, our data reveal a missing link between Wnt signaling and survival of naive T cells.