Cord Blood-Derived T Lymphocytes Differentiation in Human Peripheral and Activation of Wnt Signaling Arrests Effector

The canonical Wnt/b-catenin signaling pathway plays an important role in thymocyte development and T cell migration, but little is known about its role in naive-to-effector differentiation in human peripheral T cells. We show that activation of Wnt/b-catenin signaling arrests human peripheral blood and cord blood T lymphocytes in the naive stage and blocks their transition into functional T effector cells. Wnt signaling was induced in polyclonally activated human T cells by treatment either with the glycogen synthase kinase 3b inhibitor TWS119 or the physiological Wnt agonist Wnt-3a, and these T cells preserved a naive CD45RA + CD62L + phenotype compared with control-activated T cells that progressed to a CD45RO + CD62L 2 effector phenotype, and this occurred in a TWS119 dose-dependent manner. TWS119-induced Wnt signaling reduced T cell expansion, as a result of a block in cell division, and impaired acquisition of T cell effector function, measured by degranulation and IFN-g production in response to T cell activation. The block in T cell division may be attributed to the reduced IL-2Ra expression in TWS119-treated T cells that lowers their capacity to use autocrine IL-2 for expansion. Collectively, our data suggest that Wnt/b-catenin signaling is a negative regulator of naive-to-effector T cell differentiation in human T lymphocytes. The arrest in T cell differentiation induced by Wnt signaling might have relevant clinical applications such as to preserve the naive T cell compartment in Ag-specific T cells generated ex vivo for adoptive T cell immunotherapy. T he canonical Wnt/b-catenin signaling pathway regulates the progression of thymocyte development at different stages (1–3). However, the role of this signaling pathway in postthymic peripheral T lymphocytes is less understood. Resting and effector peripheral T cells express components of the Wnt signaling pathway. Wnt proteins induce T cell production of matrix metalloproteinases, which are required for peripheral T cell transmigration (4). TCR activation also leads to changes in expression patterns of Wnt-targeted transcription factors in peripheral T cells (5). These results indicate that the Wnt signaling pathway is active in peripheral T cells and it may play a role during T cell activation and differentiation. We undertook this study to elucidate the role of the canonical Wnt signaling pathway in naive-to-effector differentiation of human peripheral blood and cord blood T lymphocytes. This question is relevant both to the fundamental understanding of human T cells and our practical ability to expand therapeutic T cells ex vivo for treating …