T cells develop in the thymus from hematopoietic progenitors. We have previously shown that normal migration of progenitors to the thymus uses two homing molecules, CCR7 and CCR9. However, we have now found that progenitor migration to the thymus after conditioning irradiation during bone marrow transplantation is independent of CCR7 and CCR9. Unexpectedly, we find that inhibition of other homing molecules can dramatically improve thymic reconstitution after bone marrow transplantation. We propose to identify and characterize progenitors homing both the normal thymus and after bone marrow transplantation, to identify and characterize the homing molecules that are used by progenitors for thymic homing after irradiation. Further, we will determine whether the ectopic expresion or inhibition of homing molecules will allow a broader range of blood progenitors to migrate to the thymus and improve T lymphopoiesis after bone marrow transplantation, and understand what the underlying mechanisms might be. !

Public Health Relevance

The identity of progenitors homing to the thymus, and the homing molecules used by cells to get to the thymus, is not well understood. In this proposal, we will identify the cells homing to the thymus normally and after bone marrow transplantation. We will identify and characterize the molecules that are for thymic homing, and determine whether the ectopic expression of homing molecules will allow a broader range of blood progenitors to migrate to the thymus and improve T lymphopoiesis after bone marrow transplantation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL110741-02
Application #
8305559
Study Section
Special Emphasis Panel (ZRG1-IMM-G (03))
Program Officer
Thomas, John
Project Start
2011-08-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$389,567
Indirect Cost
$139,567
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; Bhandoola, Avinash (2013) Early T-cell progenitors are the major granulocyte precursors in the adult mouse thymus. Blood 121:64-71
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
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