Characterization of thymocyte progenitors in adult bone marrow and effects of cytokines on T cell development

Two basic questions in the T cell development field are how hematopoietic stem cells lose potential for other lineages and commit to the T lineage, and the identity of bona fide T progenitors in the bone marrow that migrate to the thymus and actively give rise to T cells. Thymopoiesis is highly dynamic and regulated by various signaling pathways. This thesis contributes to our understanding of the characteristics of lymphoid progenitors and the balance between different signaling pathways in regulating cell development. My work focused on T cell development in the adult mouse. Lin(neg) Sca-+c-kit'(hi)Thyl.l(neg) cells are multipotent lymphoid progenitors found in mouse bone marrow. To enrich T lymphoid progenitors within this subset, we used the cell surface marker L-selectin to fractionate the population and tested the difference in developmental potential between the L-selectin positive and negative subsets. Our study showed that L-selectin expressing lymphoid progenitors rapidly engraft the thymus after intravenous transplantation. By surface antigen phenotype, this bone marrow-derived population directly connects with early thymic progenitors within the thymus and might be the physiologically relevant bone marrow T lymphoid progenitors. A central question in T cell development is how progenitors become committed to the T lineage. Here, we performed studies to examine the coordination of cytokines with Notch signaling during T cell development. We found that Notch signaling is not sufficient for T cell development through the CD4, CDS double positive stage. Interleukin-7 promotes T cell development from the CD4/CD8 double negative to the concentrations of interleukin-7 promote T lineage commitment and early stages of T cell of interleukin-7. Interleukin-7 and stem cell factor interplay with Notch signaling initiated by Delta-like 1 to promote NK lineage commitment from multipotent lymphoid progenitors. Together, these studies have contributed significantly to our understanding of the regulation of thymopoiesis.