Developmental Stage-Related Changes in Lymphopoiesis

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DESCRIPTION (provided by applicant): The immune system is initially formed and replenished by differentiation of hematopoietic stem cells into various types of lymphocytes. Recently developed knock-in mice now make it possible to study early specification of stem cells into lymphoid fates, correlating changes in gene expression, function and surface markers with activation of the RAG-1 locus. As information accumulates about the sequence of events in adult bone marrow, it has become increasingly clear that it differs substantially from the fetal/neonatal process. Stem cells emerge in at least two sites in embryonic life, but developmental relationships between those populations and their counterparts in adult marrow remain poorly understood. Unique features and limitations to the newborn immune system could result from differentiation mechanisms that are only used for fetal lymphocyte production. We will chart emergence of the earliest lymphoid progenitors in murine embryos, comparing and contrasting their characteristics with ones in adults. Transplantation and culture experiments may attribute many differences to residence in fetal versus adult environments, exposure to unique differentiation cues and/or the recent proliferation of stem cells. Other properties of lymphoid progenitors in embryos may be intrinsic and related to their origin from fetal, rather than adult, stem cells. We will use new transgenic animal models to test the hypothesis that early emerging hematopoietic stem cells are replaced by ones that arise later. The resulting information may suggest new ways to augment neonatal immunity, treat immunodeficiency and restore lymphocytes following transplantation. It will also be useful within a broader context of developmental changes in stem cells, highlighting limitations and opportunities in regenerative medicine. For example, desirable properties of fetal stem cells may be used to advantage or artificially conferred on their adult counterparts. Furthermore, basic investigation of this type could provide explanations for the sensitivity of neonates to lymphocytic leukemia.