T lymphocytes must be produced throughout life to maintain immune function. T cells are produced in the thymus, but the thymus contains no self-renewing stem cells or progenitors. Rather, post-natal T cell production depends on the input of progenitor cells that derive from the bone marrow, and home to the thymus via the blood. While marrow progenitors appear to be capable of giving rise to both T and B lineage cells, recent data indicate that intrathymic T cell progenitors do not possess B lineage capacity. This suggests that T cell specification could either take place prior to export from the marrow, or immediately upon entry into the thymus. Understanding where T cell fate is induced, and B potential is lost, is an essential step in understanding what the requirements are for the proximal stages of T cell reconstitution, and thus for preventing or correcting certain T cell immunodeficiencies, including those that accompany the aging process, and even potentially those associated with HIV or other external environmental attacks. In order to address the long-standing paradox of where T lineage divergence occurs, we propose to analyze the lineage potentials of blood populations that possess T lineage capacity. The identity of blood-borne T cell progenitors has also remained mysterious, so the first step will be to identify those populations within the blood that have the capacity to give rise to T lineage cells. This will then be followed by determination of their lineage capacity, both in vitro using conditions designed to reveal various lineage potentials, and then in vivo under normal biological conditions. Together these approaches are expected to reveal the nature of progenitor cells that repopulate the post-natal thymus, as well as providing a basis for further studies on where to look for the signals that specify T lineage commitment and initiate T cell development.
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