April 10, 2008

A close relationship between T cells andphagocytes
establishing a new paradigm in hematopoiesis
Scientists in the RIKEN Research Center for Allergy and Immunology have recently
made a discovery that disproves a widely believed model for the process ofhematopoiesis and, instead, proposes a novel model. They have revealed that T cellprogenitors in the adult thymus produce not only T lymphocytes, but also macrophages,
phagocytic cells that belong to myeloid lineage. This work was done by Hiroshi
Kawamoto, a team leader of Laboratory for Lymphocyte Development, together with hiscolleagues including Haruka Wada, a research scientist, and Yoshimoto Katsura, avisiting scientist of the research team. This work will be published in Nature (April, 10).
During hematopoiesis, pluripotent hematopoietic stem cells are sequentially restricted
to give rise to a variety of lineage committed progenitors. The classical model ofhematopoiesis postulates that in the first step of differentiation, the hematopoietic stem
cell generates common myelo-erythroid progenitors and common lymphoid progenitors(CLPs) (Figure 1A). By using a clonal analysis of lympho-hematopoietic cells present in
the fetal liver of mice, however, the research team has previously demonstrated thatmyeloid potential is maintained even as the lineage branches segregate towards T andB cells. The team has therefore proposed the "myeloid-based" model of hematopoiesis,
where the stem cell initially generates common myelo-erythroid progenitors andcommon myelo-lymphoid progenitors (Figure 1B). T and B cell progenitors
subsequently arise from common myelo-lymphoid progenitors through myeloid-T andmyeloid-B stages, respectively. By contrast, I. Weissman's group in Stanford University(USA) previously reported that CLPs are present in a bone marrow subpopulation in theadult mouse. In order to reconcile these disparate findings between fetal liver and adultbone marrow, the concept has emerged that fetal and adult hematopoiesis differ, with
the CLP stage existing only during adult hematopoiesis.
The research team aimed to critically examine whether the CLP stage exists, or not, inthe developmental pathway from the stem cell to T cells during adult hematopoiesis.
Their study provides convincing evidence that the immature cells in the adult thymus

contain progenitors that have lost the potential to generate B cells but still retain
substantial potential to generate macrophages (Figure 2). The study further showed thatsuch T cell progenitors can give rise to macrophages within the thymic environment invivo.
These findings therefore argue against the classical dichotomy model, in which T cells
are derived from CLPs and, instead, support the validity of the myeloid-based model inboth adult and fetal hematopoiesis.

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Figure 1: Models of lineage commitment during hematopoiesis
A. Classic dichotomy model. Hematopoietic stem cells diverge into common
myelo-erythroid progenitors and common lymphoid progenitors. The findings reported
by I. Weissman's group that common lymphoid progenitors are present in adult BM has
provided a support for this model.
B. Myeloid-based model. In this model, the first branch point generates common
myelo-erythroid and common myelo-lymphoid progenitors, and the myeloid potential
persists in the T and B cell branches even after these lineages have diverged. Thismodel postulates that specification towards erythroid, T and B cell lineages proceeds on
the basis of a prototypical myeloid program.

Figure 2.:T cell progenitors retain macrophage potential after shutting off B cell potential