The early progenitors of the lymphoid lineages in the mouse are not yet clearly defined. New studies regarding the nature of lymphoid progenitors have suggested that an intermediate progenitor with potential to differentiate only into T and B lineages (common lymphoid progenitor, CLP) can be isolated from adult mouse bone marrow. Other studies have demonstrated progenitors with restricted lympho-myeloid potential in fetal development, but have failed to confirm the existence of CLP. A newly developed selection protocol that completely separates hematopoietic stem cells from early progenitor cells will be utilized to investigate the characteristics of early progenitors for the lymphoid lineages in adult mouse bone marrow.
In Specific Aim 1, the early stages of B cell development will be investigated to determine the identity, growth requirements, developmental potential, and genes expressed by cells defined as B cell progenitors by the new selection protocol.
In Specific Aim 2, an in vivo assay for T cell development will be utilized to isolate and characterize bone marrow progenitors able to localize to and proliferate within the thymus.
In Specific Aim 3, we will test the hypothesis that fate determination of CLP can be regulated by extrinsic cytokine stimulation. We propose that cells normally destined to differentiate as B lymphocytes can be redirected to T cell differentiation in short-term in vitro cultures, and that this redirection of T cell progenitor activity can account for previous discrepancies in defining lymphoid progenitors. The studies outlined in this proposal will define the early stages in the process of lymphoid lineage commitment in mouse hematopoiesis, providing a framework within which future studies aimed at mechanistic analysis of this process can be initiated. In addition, the feasibility of utilizing progenitor populations as a means to replenish the lymphoid lineages through transplantation will be evaluated. Collectively, the proposed experiments will contribute to both basic and clinical research efforts aimed at understanding the nature of early lymphoid lineage commitment in hematopoiesis and the potential of hematopoietic progenitor cells to be utilized in clinical transplant settings.
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