T lymphocytes must be produced throughout life to replenish losses from cellular senescence, trauma, and antigen-induced activation. Stem cells for this process emigrate from the bone marrow and home to the thymus via the blood, after which they undergo extensive proliferation to generate a pool of cells for TCR/MHC-mediated selection. T lineage commitment is induced by signals found within the thymus, because early intrathymic precursors maintain non-T lineage potential. Stromal cells, mainly epithelial cells and fibroblasts, are believed to be the primary source of such signals. However, the molecular nature of interactions between lymphoid progenitors and stromal cells is poorly understood, and very few of the signals required for lineage commitment and proliferation have been identified. The goal of this project is to define the molecular signals by which thymic stromal cells induce T lineage commitment and proliferation of multipotent precursors from bone marrow. The three-phase approach involves 1) isolation of mRNA from thymocytes at defined stages of development, followed by microarray screening for genes encoding receptors that function in lineage commitment or proliferation; 2) in situ localization of the corresponding ligands in the thymus; and 3) in vivo analysis of mutant cells deficient in the interactions predicted by the first two phases. These studies are expected to reveal the molecular nature of signals by which the thymus induces T lineage commitment and proliferation in the steady-state. A better understanding of this process may also help to predict new strategies for treating age-related deficiencies of thymic stroma, including the prolonged inability to produce T cells that frequently follows hematopoietic reconstitution after myeloablative therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI053739-03
Application #
6797899
Study Section
Immunobiology Study Section (IMB)
Program Officer
Macchiarini, Francesca
Project Start
2003-09-15
Project End
2005-03-31
Budget Start
2004-09-01
Budget End
2005-03-31
Support Year
3
Fiscal Year
2004
Total Cost
$165,135
Indirect Cost
Name
University of Miami School of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
052780918
City
Miami
State
FL
Country
United States
Zip Code
33146
Huang, Jiaxue; Garrett, Karla P; Pelayo, Rosana et al. (2005) Propensity of adult lymphoid progenitors to progress to DN2/3 stage thymocytes with Notch receptor ligation. J Immunol 175:4858-65
Prockop, Susan E; Petrie, Howard T (2004) Functional assessment of alphaEbeta7/E-cadherin interactions in the steady state postnatal thymus. Clin Dev Immunol 11:135-41
Tabrizifard, Sahba; Olaru, Alexandru; Plotkin, Jason et al. (2004) Analysis of transcription factor expression during discrete stages of postnatal thymocyte differentiation. J Immunol 173:1094-102
Prockop, Susan E; Petrie, Howard T (2004) Regulation of thymus size by competition for stromal niches among early T cell progenitors. J Immunol 173:1604-11
Porritt, Helen E; Rumfelt, Lynn L; Tabrizifard, Sahba et al. (2004) Heterogeneity among DN1 prothymocytes reveals multiple progenitors with different capacities to generate T cell and non-T cell lineages. Immunity 20:735-45
Plotkin, Jason; Prockop, Susan E; Lepique, Ana et al. (2003) Critical role for CXCR4 signaling in progenitor localization and T cell differentiation in the postnatal thymus. J Immunol 171:4521-7