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Lymphocyte Development

Process of lineage commitment in hematopoiesis

The classic dichotomy model of hematopoiesis postulates that the first step of differentiation from HSC generates common myelo-erythroid and common lymphoid progenitors (CLP). Our previous studies in fetal mice, however, indicated that the first step of lineage restriction in HSC is the generation of myelo-lymphoid lineage progenitors and myelo-erythroid lineage progenitors. Most importantly, the myeloid potential is retained even after the segregation of myelo-lymphoid progenitor towards T and B cell lineages. Thus, each process of specification towards T, B and erythroid lineages appears to proceed accompanying the prototypical myeloid program. Recently, we call this model the “myeloid-based model” (Kawamoto H, Trends Immunol, in press). The CLP have, however, persisted in models of adult hematopoiesis, as several groups have provided experimental results supporting the presence of CLP in bone marrow. We are now studying whether the myeloid-based model is also applicable to adult hematopoiesis.

Prethymic stages of T cell development

We have previously reported that T cell lineage restricted progenitors are present in prethymic organs such as the AGM region, fetal liver, and fetal blood. However, it remains controversial whether the thymus-colonizing progenitors are committed to the T cell lineage. One problem is that the earliest intrathymic progenitors do not necessarily represent genuine thymic immigrants because their developmental potential should have been influenced by contact with the thymic microenvironment. We then examined the developmental potential of the ontogenically earliest thymic progenitors of day 11 murine fetus, which reside in the surrounding mesenchymal region and have not encountered thymic epithelial components. We examined the developmental potential of these cells, and the results provided direct evidence that the progenitors restricted to the T/NK/DC lineage selectively immigrate into the thymus. Very recently, we have found that the prethymic T cell progenitors express PIR (paired-immunoglobulin-like receptors) on their surface. This finding not only provides a tool for the isolation of prethymic T cell progenitors but also substantiates that the prethymic stage of T cell development is distinct from intrathymic stages. The isolated T cell progenitors will be a useful tool for gene therapy and regenerative medicine. (EMBO J. 24, 4052-4060, 2005)

Besides the above two projects, we are interested in whether environmental factors instructively induce lineage commitment or selectively support autonomously committed progenitors in lymphopoiesis. To this end, it is important to establish an experimental system by which lineage commitment of progenitors can be monitored with real-time imaging. We have previously shown that the earliest T cell progenitors in the thymus retain the potential to generate NK cells and dendritic cells, and that the discontinuation of this tri-potentiality and clear T cell lineage committment happens before the initiation of TCRβ chain gene rearrangement. To establish an experimental system to directly visualize this differentiation step, we are using GFP transgenic mice in which the expression of GFP is controlled by the proximal promoter of T cell specific tyrosine kinase lck.
Research activities include the study of human lympho-hematopoiesis. Cord blood cells are used as the progenitor source, and the basic culture system is a modification of co-culture with murine stromal cells.
We are also interested in the development of thymic epithelial cells. Thymic epithelial cells support thymocyte development, while it is known that thymocytes in turn support the development of thymic epithelial cells. This mutual interaction is called thymic crosstalk. In collaboration with Professor van Ewijk, we are studying the molecular mechanisms of the regulation of thymic epithelial cell development by thymocytes, using the organ culture system. This project also includes studies on the progenitors of thymic epithelial cells.
The information and technology that will be acquired through these studies can be applied directly to regeneration therapy and gene therapy. We are trying to induce mature T cells from progenitors on monolayered stromal cells, which can be a source for immune cell therapy in the future.