T cells in thymus develop from hematopoietic stem cells (HSCs) in bone marrow (BM), but the cellular intermediates linking HSCs in BM via blood to early T lineage progenitors in thymus remain poorly defined. The long-term goal of the proposed work is to elucidate the cellular and molecular basis for early T cell development. It has recently been determined that early T lineage progenitors (ETPs) in thymus derive from a BM progenitor population distinct from previously described common lymphoid progenitors (CLPs), and that the pathways leading to T and B cells diverge earlier than had been previously appreciated. Experiments are proposed to further define and characterize the intermediate populations that lead from multipotent progenitors in BM, through a circulating progenitor cell in blood, eventually leading to ETPs and their downstream T lineage progeny within the thymus. While cytokines and Notch signals are known to be critical for early T cell development, the cellular intermediates receiving and integrating these multiple signals are largely uncharacterized. Notch signals are probably received by blood-borne hematopoietic progenitors shortly after thymic colonization, but ETP subsets within which these signals operate to result in T lineage commitment are also not characterized. Our goal is to identify a complete lineage of cells leading from HSCs in bone marrow to T lineage cells in thymus. An understanding of the key cellular intermediates in T lineage development is necessary to understand disorders in this process, and will be of basic and critical use in a wide variety of diagnostic and therapeutic endeavors. Hence understanding the T cell defects in aging, the process of malignant transformation in T lineage cells, and gene therapy to correct defects of T cell development and function all require that the steps of hematopoiesis linking HSCs to T cells be understood.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI059621-04
Application #
7186688
Study Section
Immunobiology Study Section (IMB)
Program Officer
Deckhut Augustine, Alison M
Project Start
2004-03-01
Project End
2009-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
4
Fiscal Year
2007
Total Cost
$338,145
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Yang, Qi; Li, Fengyin; Harly, Christelle et al. (2015) TCF-1 upregulation identifies early innate lymphoid progenitors in the bone marrow. Nat Immunol 16:1044-50
De Obaldia, Maria Elena; Bhandoola, Avinash (2015) Transcriptional regulation of innate and adaptive lymphocyte lineages. Annu Rev Immunol 33:607-42
Rupp, Levi J; Brady, Brenna L; Carpenter, Andrea C et al. (2014) The microRNA biogenesis machinery modulates lineage commitment during αβ T cell development. J Immunol 193:4032-42
De Obaldia, Maria Elena; Bell, J Jeremiah; Bhandoola, Avinash (2013) Early T-cell progenitors are the major granulocyte precursors in the adult mouse thymus. Blood 121:64-71
De Obaldia, Maria Elena; Bell, J Jeremiah; Wang, Xinxin et al. (2013) T cell development requires constraint of the myeloid regulator C/EBP-α by the Notch target and transcriptional repressor Hes1. Nat Immunol 14:1277-84
Yang, Qi; Monticelli, Laurel A; Saenz, Steven A et al. (2013) T cell factor 1 is required for group 2 innate lymphoid cell generation. Immunity 38:694-704
Bhandoola, Avinash; Artis, David (2012) Immunology. Rebuilding the thymus. Science 336:40-1
Zhang, Shirley L; Bhandoola, Avinash (2012) Losing TREC with age. Immunity 36:163-5
Sultana, Dil Afroz; Zhang, Shirley L; Todd, Sarah P et al. (2012) Expression of functional P-selectin glycoprotein ligand 1 on hematopoietic progenitors is developmentally regulated. J Immunol 188:4385-93
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

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