Notch signaling induces and supports T cell lineage differentiation in the intrathymic microenvironment. Although the antigen-independent specification of the B cell lineage is known to occur in the bone marrow, it is not clear whether engagement of Notch1 receptors on hematopoietic progenitors is required to initiate T cell lineage development.

In this issue, Yu et al. assessed the influence of bone marrow stromal cells on the generation of thymic-seeding progenitors (TSPs). The authors took advantage of several in vivo mouse models to tackle this question and showed that osteoblasts appear to influence the generation of TSPs through expression of DLL4, thus providing an initial Notch signal within the bone marrow and initiating T cell lineage specification. When osteoblasts were destroyed, or their ability to express DLL4 was compromised, lower numbers of putative TSPs (defined as LineageSca+cKit+IL7R+Thy1.2Ly6D cells) were detected in the bone marrow. This also led to a reduced number of early thymocyte progenitors (ETPs, typically defined as CD4CD8CD44+CD117+(ckit+)CD24CD25 cells) and other subsets of developing thymocytes, including reduced numbers of mature CD4+ and CD8+ T cells.

These results strongly point to a prethymic defect in the generation of several lymphocyte progenitor subsets. However it is curious, and somewhat unexpected, to note a decreased number of intrathymic precursor cells, such as later CD4 CD8 subsets; due to their strong proliferative capacity, these cells typically compensate for defects associated with decreased progenitor cell numbers. A cursory analysis of genes expressed by immature thymic epithelial cells (TECs), or subsets of TECs, points to the possibility that the osteocalcin gene promoter (used to drive the loss of osteoblasts or loss of DLL4 expression) may also be expressed by these cells. Additionally, it is well established that reduced Notch signaling during T cell development can lead to severe blocks in differentiation and cell survival of early thymocyte subsets. So, although the authors conclude that the “data demonstrate the role of Notch ligands expressed by osteocalcin-positive cells as the basis for the decrease in T lymphopoiesis,” this may not entirely reside with the bone marrow and could potentially be due to osteocalcin-positive stromal cells within the thymus.

Nevertheless, it is clear that Notch signaling is important for T-lineage specification prior to thymic entry, and that this is mediated by bone marrow stromal cells. This knowledge will likely influence how we view the branching points of B and T lymphopoiesis, as well as the development of therapies to alleviate deficiencies in immune cell reconstitution.

, et al
J. Exp. Med.