The earliest described progenitors in the adult mouse thymus are termed early thymic progenitors (ETPs). They derive from rare circulating hematopoietic progenitors, whose identity was previously unknown. Our work in the previous funding period established that a population of progenitors termed early lymphoid progenitors (ELPs) circulates, and physiologically settles the thymus. In our current proposal, we wish to understand how rare ELPs settling the thymus give rise to ETPs and other downstream populations from which mature, immunocompetent T cells are ultimately derived. We hypothesize that tremendous proliferation occurs right after thymic settling, by which rare ELPs that settle the thymus generate large numbers of early thymic progenitors (ETPs). Indeed, we think that more proliferation may occur immediately after thymic settling than at any subsequent stage of T lymphopoiesis. One goal of our current proposal is to quantify this proliferation, and to determine how it is regulated. As ELPs settling the thymus possess lineage potentials for multiple cell types, another goal is to address the question of how alternative lineage fates and in particular the myeloid fate are constrained after thymic settling. Notch is a cell surface receptor involved in multiple cell fate decisions, and we wish to probe the role of Notch signaling in these critical early events. Further, we wish to determine the molecular mechanisms by which Notch co-ordinates T lineage commitment and lineage progression. Together, these studies will allow us to piece together a lineage of cells that extends from hematopoietic stem cells in the bone marrow to ETPs within the thymus, and to understand the signals that guide cells down the T cell developmental pathway.
Our specific Aims are:
Specific Aim 1 : To measure proliferation between thymic settling and the generation of ETPs.
Specific Aim 2 : To determine the function of Notch signaling in ETPs.
Specific Aim 3 : To determine the mechanism by which Notch signals result in T lineage progression and commitment.

Public Health Relevance

We propose to characterize proliferative and differentiative events at the earliest stages of intrathymic T cell development. Notch plays a critical role at this earliest stage, and we propose to elucidate the function of Notch signaling in early T cell development, and to determine the mechanisms by which it co-ordinates early T lineage progression and commitment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI059621-10
Application #
8423805
Study Section
Special Emphasis Panel (ZRG1-IMM-H (02))
Program Officer
Prabhudas, Mercy R
Project Start
2004-03-01
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$354,406
Indirect Cost
$124,082
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
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
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
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
Love, Paul E; Bhandoola, Avinash (2011) Signal integration and crosstalk during thymocyte migration and emigration. Nat Rev Immunol 11:469-77
Weber, Brittany Nicole; Chi, Anthony Wei-Shine; Chavez, Alejandro et al. (2011) A critical role for TCF-1 in T-lineage specification and differentiation. Nature 476:63-8
Yang, Qi; Saenz, Steven A; Zlotoff, Daniel A et al. (2011) Cutting edge: Natural helper cells derive from lymphoid progenitors. J Immunol 187:5505-9
Zlotoff, Daniel A; Bhandoola, Avinash (2011) Hematopoietic progenitor migration to the adult thymus. Ann N Y Acad Sci 1217:122-38
Yang, Qi; Jeremiah Bell, J; Bhandoola, Avinash (2010) T-cell lineage determination. Immunol Rev 238:12-22

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