This application addresses broad Challenge Area (11) Regenerative Medicine, and specific Challenge Topic, 1-HL-101*: Develop cell-based therapies for cardiovascular, lung, and blood diseases. Engineering hematopoietic progenitors for efficient migration to the thymus T cells develop in a specialized organ, the thymus. They derive from hematopoietic progenitors that colonize the thymus from the blood. Many different progenitors in the bone marrow (BM) possess T lineage potential and will make T cells in experimental circumstances. However, our recent work has shown that the process of thymic settling is selective and regulated. Our hypothesis is that physiological T cell progenitors differ from other progenitors with T lineage potential chiefly in their ability to migrate to the thymus. More specifically, we hypothesize that the chemokine receptors CCR7 and CCR9 cooperate to mediate recruitment of rare BM- derived progenitors to the thymus. In this challenge grant proposal, we present our preliminary data indicating CCR7 and CCR9 are selectively expressed on key hematopoietic progenitors, and are important for migration to the thymus. We propose to establish the role of CCR7 and CCR9 in thymic homing, and to identify and characterize the physiologically relevant progenitors that express these homing molecules and so contribute to T lymphopoiesis. We present data suggesting that the generation of thymic homing progenitors is deficient in aged mice. As this may contribute to the loss of thymic cellularity and immunosuppression seen with aging, we propose to determine whether ectopic expression of CCR7 and CCR9 improves T lymphopoiesis, and confers T lineage competence on aged progenitors that are otherwise incompetent to generate T cells. These studies will provide new understanding into the molecular underpinnings of early T cell development. Understanding the mechanisms of thymic settling in mice is an essential stepping-stone towards developing new clinical interventions for individuals with diminished T cell numbers. Our findings may have application for boosting T cell numbers after bone marrow transplantation.

Public Health Relevance

T cells develop in the thymus from hematopoietic progenitors. The identity of molecules that allow progenitor cells to migrate to the thymus is not well known. We propose to identify molecules that support trafficking of progenitors to the thymus, to identify and characterize physiological T cell progenitors that express these trafficking molecules, and to determine whether the ectopic expression of these molecules will allow a broader range of blood progenitors to migrate to the thymus and improve T lymphopoiesis

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
NIH Challenge Grants and Partnerships Program (RC1)
Project #
5RC1HL099758-02
Application #
7940946
Study Section
Special Emphasis Panel (ZRG1-VH-D (58))
Program Officer
Thomas, John
Project Start
2009-09-30
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$498,904
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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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
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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
Zlotoff, Daniel A; Bhandoola, Avinash (2011) Hematopoietic progenitor migration to the adult thymus. Ann N Y Acad Sci 1217:122-38
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Zlotoff, Daniel A; Sambandam, Arivazhagan; Logan, Theodore D et al. (2010) CCR7 and CCR9 together recruit hematopoietic progenitors to the adult thymus. Blood 115:1897-905
Sultana, Dil Afroz; Bell, J Jeremiah; Zlotoff, Daniel A et al. (2010) Eliciting the T cell fate with Notch. Semin Immunol 22:254-60