Phenotypically distinct populations of thymic epithelial cells (TE) support different aspects of thymocyte development, with cortical TE contributing to pro-thymocyte expansion and positive selection, and medullary TE participating in negative selection. The basis for this TE heterogeneity, the interactions that mediate the establishment these functional and morphologically distinct epithelial compartments are ill defined and the nature of their interactions with thymocytes remain poorly understood. Studies proposed here will examine two related aspects of the thymic environment: first, that selected members of the fibroblast growth factor (FGF) family profoundly affect the growth/differentiation of TE subsets and second, as an intrathymic source of these mediators, thymocytes directly affect these processes. This latter hypothesis would account for the alterations in the thymic architecture observed in murine models where thymocyte differentiation is arrested. Studies proposed in this application will provide new information regarding the temporal and spatial patterns of selected FGF family members and the receptors for these ligands within the thymic environment and identify the cellular source of these mediators within the thymus. Other studies will define the effects on the functional activity of FGFs on phenotypic and functional properties of TE cell lines and primary TE cultures and on the phenotype and functional integrity of fetal thymus organ cultures. Several mutant and transgenic mice with altered levels of these FGFs or bearing dominant-negative forms of the FGF receptor will also be used to test this hypothesis. Understanding the interplay between thymocyte and TE that regulate the development and maintenance of thymic epithelial heterogeneity and hence the lymphopoietic environment has important clinical relevance and may lead to therapeutic modalities that would be beneficial in reversing the effects of primary or acquired immunodeficiencies affecting T-cell production. In addition, the information may help us understand mechanisms underlying age-related thymic senescence and to design approaches to retard age-related losses of thymic function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI024137-13A1
Application #
6200065
Study Section
Immunobiology Study Section (IMB)
Program Officer
Ridge, John P
Project Start
1986-12-01
Project End
2005-05-31
Budget Start
2000-06-01
Budget End
2001-05-31
Support Year
13
Fiscal Year
2000
Total Cost
$266,000
Indirect Cost
Name
University of Washington
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Dooley, James; Erickson, Matthew; Larochelle, William J et al. (2007) FGFR2IIIb signaling regulates thymic epithelial differentiation. Dev Dyn 236:3459-71
Gillard, Geoffrey O; Dooley, James; Erickson, Matthew et al. (2007) Aire-dependent alterations in medullary thymic epithelium indicate a role for Aire in thymic epithelial differentiation. J Immunol 178:3007-15
Dooley, James; Erickson, Matthew; Gillard, Geoffrey O et al. (2006) Cervical thymus in the mouse. J Immunol 176:6484-90
Gillard, Geoffrey O; Farr, Andrew G (2006) Features of medullary thymic epithelium implicate postnatal development in maintaining epithelial heterogeneity and tissue-restricted antigen expression. J Immunol 176:5815-24
Fontenot, Jason D; Dooley, James L; Farr, Andrew G et al. (2005) Developmental regulation of Foxp3 expression during ontogeny. J Exp Med 202:901-6
Rodriguez-Galan, Maria Cecilia; Bream, Jay H; Farr, Andrew et al. (2005) Synergistic effect of IL-2, IL-12, and IL-18 on thymocyte apoptosis and Th1/Th2 cytokine expression. J Immunol 174:2796-804
Dooley, James; Erickson, Matt; Farr, Andrew G (2005) An organized medullary epithelial structure in the normal thymus expresses molecules of respiratory epithelium and resembles the epithelial thymic rudiment of nude mice. J Immunol 175:4331-7
Dooley, James; Erickson, Matthew; Roelink, Henk et al. (2005) Nude thymic rudiment lacking functional foxn1 resembles respiratory epithelium. Dev Dyn 233:1605-12
Cooper, Cristine J; Turk, Gail L; Sun, Mingyi et al. (2004) Cutting edge: TCR revision occurs in germinal centers. J Immunol 173:6532-6

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