Stepwise specification of lymphocyte developmental lineages

B and T lymphocytes differentiate from multipotent precursors through distinct specification and commitment steps. New findings on the unique role of Pax5 in B-lineage commitment, dichotomous action of Notch signaling in B versus T cell development, and the gene expression changes comprising T-lineage specification and commitment now illuminate this process.     

Entry into the thymic microenvironment triggers Notch activation in the earliest migrant T cell progenitors

Interactions between T cell precursors and thymic stromal cells are essential during thymocyte development. However, the role of the thymus in initial commitment of lymphoid progenitors to the T lineage remains controversial, with data providing evidence for both extra- and intrathymic commitment mechanisms. In this context, it is clear that Notch1 is an important mediator during initiation of T cell development. Here we have analyzed the mechanisms regulating Notch activation in lymphoid precursors at extrathymic sites and in the thymus, including stages representing the first wave of embryonic thymus colonization on embryonic day 12 of gestation. We show that Notch activation in migrant lymphoid precursors requires entry into the thymic microenvironment where they are exposed to Notch ligands expressed by immature thymic epithelial cells. Moreover, continued Notch signaling in such precursors requires sustained interactions with Notch ligands. Collectively, these findings suggest a role for Notch in an intrathymic mechanism of T cell lineage commitment involving sustained interactions with Notch ligand bearing thymic epithelium.