THYMIC ENVIRONMENT AND T CELL DIFFERENTIATION

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DESCRIPTION (Adapted from the Investigator's abstract): 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.