The interaction of the Wnt and Notch pathways modulates natural killer versus T cell differentiation

The Wnt and Notch signaling pathways have been independently shown to play a critical role in regulating hematopoietic cell fate decisions. We previously reported that induction of Notch signaling in human CD34(+) CD38(-) cord blood cells by culture with the Notch ligand Delta1 resulted in more cells with T or natural killer ( NK) lymphoid precursor phenotype. Here, we show that addition of Wnt3a to Delta1 further increased the percentage of CD34(-) CD7(+) and CD34(-) CD7(+) cyCD3(+) cells with increased expression of CD3 epsilon and preT alpha. In contrast, culture with Wnt3a alone did not increase generation of CD34(-) CD7(+) precursors or expression of CD3 epsilon or preT alpha gene. Furthermore, Wnt3a increased the amount of activated Notch1, suggesting that Wnt modulates Notch signaling by affecting Notch protein levels. In contrast, addition of a Wnt signaling inhibitor to Delta1 increased the percentage of CD56(+) NK cells. Overall, these results demonstrate that regulation of Notch signaling by the Wnt pathway plays a critical role in differentiation of precursors along the early T or NK differentiation pathways.