In mammals, blood cells are constantly produced in the bone marrow through the expansion and differentiation of progenitors that originate from a rare cell type, the hematopoietic stem cell (HSC). The paradigm of multipotent and self-renewable adult stem cells arose from testing the biological activity of HSC, following their prospective isolation and the identification of surface markers they express. The different members of the Unit for Lymphocyte Development study in an integrative manner different aspects of hematopoietic and lymphocyte development.

Hematopoietic Stem Cell generation. HSC are generated in the aorta region, in a short and precise time-window. They colonize the fetal liver where they acquire the property of reconstituting the hematopoietic system of adult individuals, the functional property that characterizes adult stem cells. This property is defined by the up-regulation of MHC class-I and CD45 expressions. It is the unique interaction between the newly generated HSC and the fetal liver environment that determines the expansion of the compartment.

We are presently isolating the different stromal populations in fetal liver to understand the molecular basis of hematopoietic stem cell expansion.

Figure. Newly generated hematopoietic stem cells emerging from the ventral aspect of the aorta.

B-cell development. After migration to the hematopoietic organs, differentiation of hematopoietic stem cells occurs through the contact with the supporting stromal environment. Surface bound signaling molecules and cytokines determine lymphoid and myeloid lineage commitment and differentiation. We have shown that the fetal spleen environment has particular properties preventing hematopoietic stem cell renewal and favoring myeloid versus lymphoid commitment. We have been studying the requirements for B lymphocyte production during fetal and adult life. We showed that differentiating common lymphoid progenitors lose first the capacity to generate T cells giving rise to an intermediate precursor that is restricted to the B and NK pathways of differentiation. This commitment step is regulated by Id proteins through the inhibition of the activity of E2A, a transcription factor essential for lymphocyte development. Developing B cell progenitors, unable to make productive immunoglobulin gene rearrangements undergo apoptosis, in the bone marrow. We have shown that this is partially mediated through the interaction with TLR9 ligands, by an interferon and caspase independent, but cathepsin-B dependent mechanism.

T-cell development. In the thymus hematopoietic progenitors give rise to T lymphocytes. We are currently investigating the rules underlying lineage commitment of γδ versus αβ expressing T cells. Regulatory T cells that are essential for the regulation of T cell homeostasis and autoimmunity are also generated in the thymus. We have shown that in the absence of ets-1, a transcription factor involved in several aspects of lymphocyte development, there is a profound defect in regulatory T cells by a deregulation of Foxp3 expression. We described a new form of autoimmune enteropathy, that is not associated with mutations in the Foxp3 gene but with a milder deficiency of regulatory T cell activity.

Keywords: Hematopoiesis, lymphopoiesis, cytokines, regulatory T cells

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