Several lines of evidence suggest that lymphocytes generated during fetal life represent a distinct subpopulation of cells that differ from those produced in the adult. Fetal lymphoid populations seem to develop only during fetal life as adult hematopoietic stem cells have lost the capacity to give rise fetal lymphocytes. The underlying molecular mechanisms involved in the establishment of these fetal lineages are currently not known, but likely reflect differential expression of specific transcription factors. Our current knowledge of the regulation of early lymphocyte-specific gene expression is derived largely from studies on immortalized cell lines that bear little resemblance to normal developing lymphoid cells. Consequently little or nothing is known concerning mechanisms that govern these genes in normal differentiating cells. In addition to the obvious difference in the development stage, fetal lymphocytes show less diversity in their immune receptors than their adult counterparts and exhibit specific behaviors throughout life. These latter differences suggest that fetal lymphoid cells are generated to fulfill a unique function. As defined fetal lymphoid precursors have not been available, the developmental potential of these cells and the function of a fetal immune system generated from them have not been defined. Fetal lymphoid precursors can now been fractionated from mulipotent stem cells. Therefore, it has become possible to work with lymphoid precursors whose analysis will not be obscured by the contribution of differentiating stem cells. The goals of this proposal are to investigate the role of specific transcription factors in the establishment of the fetal lymphoid populations and to define the function of these cells in the animal.
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