While most blood lineages develop in the bone marrow (BM), T cells uniquely complete the majority of their development in a specialized organ, the thymus. The thymus does not contain self-renewing stem cells, and thus must continuously import hematopoietic progenitors from the blood throughout adult life. The molecular mechanisms by which progenitors settle the thymus remain unclear. Our work intends to further characterize the signals and cells involved in this process. Better understanding in this area could lead to new efforts to increase T cell production in the elderly and in people undergoing BM transplantation. The process of thymic settling by BM-derived progenitors is selective, mediated at least in part by the chemokine receptor CCR9. We have preliminary evidence that the chemokine receptor CCR7 additionally supports thymic settling. In the proposed work, we will first determine whether these two receptors are necessary and sufficient for thymic settling. We will analyze mice that are deficient for both CCR7 and CCR9 to identify whether these mice have defects in early T lineage development. We will also investigate whether the dual absence of these receptors affects thymic settling by using adoptive transfer studies and mixed BM chimeras. Experiments will explore whether the enforced expression of these molecules can enhance thymopoiesis, a finding which would have significant clinical implications. Our work will also analyze rare BM progenitors that co-express CCR7 and CCR9 through in vivo adoptive transfer assays to identify whether these cells are the physiologically relevant thymic settling progenitors. These studies will provide new insights into the prethymic steps that allow rare progenitors to settle the thymus and generate downstream T cells. The identification of the signals and cells that underlie normal T cell development would lead to a greater understanding of the pathogenesis of T cell cancers and the age- associated loss in T cells. Additionally, the proposed work would provide a conceptual stepping-stone towards the development of therapeutic interventions for these and other pathologic conditions. Public Health Relevance: The blood contains many cell types that help to fight off infections, including a cell type called T cells. We are studying how T cells develop to better understand how we might enhance the body's immune system, especially in people that have received bone marrow transplants.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1-F07-K (20))
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Mitchell, Phyllis
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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De Obaldia, Maria Elena; Bell, J Jeremiah; Wang, Xinxin et al. (2013) T cell development requires constraint of the myeloid regulator C/EBP-? by the Notch target and transcriptional repressor Hes1. Nat Immunol 14:1277-84
Zlotoff, Daniel A; Zhang, Shirley L; De Obaldia, Maria Elena et al. (2011) Delivery of progenitors to the thymus limits T-lineage reconstitution after bone marrow transplantation. Blood 118:1962-70
Zlotoff, Daniel A; Bhandoola, Avinash (2011) Hematopoietic progenitor migration to the adult thymus. Ann N Y Acad Sci 1217:122-38