POSTNATAL HEMATOGENOUS & INTRATHYMIC T CELL PROGENITORS

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Although the generation of T cells in the fetal thymus and the reestablishment of thymocytopoiesis in the irradiated or grafted thymus is dependent on bone marrow-derived hematogenous immigrants (prothymocytes), the thymus also contains intrinsic T cell progenitors. The relative roles of hematogenous vs. intrinsic progenitors has defied investigation in the steady-state postnatal thymus. Although this question has been of long-standing interest, our preliminary studies have established that congenic parabiotic mice and part body BM chimeras are ideal for exploring this problem: in the steady-state thymus, only 10% of cells are of hematogenous and 90% of intrinsic thymic origin; hematogenous and intrinsic progenitor pools are independent of one another. The proposed studies will characterize the progeny of hematogenous and intrinsic T cell progenitors in the steady-state, post-natal thymus and will provide evidence for the derivation of phenotypically and functionally defined subsets of thymocytes and peripheral T cells from one or the other of the progenitor pools. We will investigate the contribution of these two progenitor pools to the recovery of the thymus following its depletion by hydrocortisone- or tumor- induced atrophy, and by selective irradiation under conditions which do not deplete the animal's own prothymocytes. The in vivo studies will combine multi-parameter flow cytometry and sorting in conjunction with selective lysis of defined T cell populations with their selective labeling for migration studies and with functional assays. The significance of the proposed work is that it will clarify the developmental lineages of T cell subclasses under steady-state conditions and will provide information about the response of different T cell progenitors when T cell production has been compromised by conditions comparable to those that may be clinically encountered in humans.