Who’s your daddy? This seems like a simple question, but in hematopoiesis the answer may not be so simple. We all know that blood is made up of red cells, white cells, and platelets. They all are derived from a hematopoietic stem cell. The red cells and platelets are derived from a common precursor. White blood cells, on the other hand, come in many different flavors with a very specialized function. They also seem to segregate broadly into differentiated myeloid and lymphoid cells through a series of less well-understood intermediates. The bifurcation or restricted commitment of these two lineages is thought to occur early on in differentiation. The myeloid lineages are derived from a common myeloid progenitor (CMP), and the lymphocytes are derived from a common lymphoid progenitor (CLP). This picture came from the description of the CLP, which was able to give rise to T, B, and NK cells but not to myeloid cells. The cartoon is well entrenched in our thinking of hematopoietic development and in every slide set of hematopoiesis.
But, is it correct? Two recent publications have challenged this dogma and provide definitive data that the picture is not so cut-and-dried. Before delving into the data, a very brief review of thymopoiesis is needed. While all the other blood elements mature in the marrow spaces, T-cell development is thought to proceed from a CLP that migrates from the bone marrow to the thymus where a tightly orchestrated set of events results in the release of a naïve T cell that has been positively selected (to recognize the appropriate MHC molecules) and negatively selected (to remove auto-reactive T cells). The T-cell precursor begins as double-negative (DN) 1 (DN1 [CD44+CD25-CD117+], then DN2 (CD44+CD25+CD117+), and DN3 (CD44-CD25+), CD4/CD8 double-positive, and finally single-positive (CD4 or CD8) naïve T cell. Based on this elegant knowledge of T-cell development, there should not be any question as to whether these T-cell precursors could give rise to myeloid cells.
However, using clonal analysis with single-cell assays, these two group of investigators demonstrated that a substantial number of early T-cell precursors in the thymus at the DN1 and DN2 stage (prior to T-cell receptor rearrangement) have myeloid potential, which is lost at the DN3 stage. These myeloid cells were predominantly macrophages, but granulocytes and dendritic cells were also observed. Transfer of DN1 cells into T-cell-deficient mice demonstrated that up to one-third of the macrophages were derived from the T-cell precursors. Even more surprising was that these myeloid cells demonstrated rearrangement of the T-cell receptor and even expressed RAG recombinase, the enzyme necessary to create T-cell receptor diversity. Taken together, these data demonstrate that the early T-cell precursor is not yet fully committed to becoming only T cells.
In Brief
What are the ramifications? These early T-cell precursors could explain the origin of some leukemias, which are biphenotypic. But more importantly, it is clear that a progenitor’s potential can be different from what actually occurs in vivo. Simple characterization of such precursors may not fully describe their potential. We do not know what the molecular signals are in this case or whether it is similar to the need for PAX5 expression for B-cell lineage commitment, where a single switch may determine the fate of the cell. However, these data go a long way in getting our lineages right.
Competing Interests
Dr. Chao indicated no relevant conflicts of interest.
