Phenotypically distinct populations of thymic epithelial cells (TE) support different aspects of thymocyte development, with cortical TE contributing to prothymocyte 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 and cortical TE in particular. The first is concerned with the cellular mechanisms involved in thymus organogenesis involving the interactions between epithelial cells and between epithelial cells and immigrant T cell progenitors which lead to the development of the cortical thymic environment. In vitro models of thymus organogenesis will examine the involvement of selected adhession molecules in the establishment of a functional TE compartment with particular emphasis on the cortical TE population and the differentiation potential of T cell progenitors. The second is directed at understanding the role of cortical TE in positive selection and other poximal aspects of thymocyte development. In these studies, advantage will be taken of novel cellular reagents which phenotypically and functionally resemble cortical TE and are used in an in vitro co-culture system to reproduce some aspects of cortical TE function in vitro. This in vitro approach to thymocyte development will be used to define the TE cell surface molecules and soluble products that affect T cell development. As part of this effort, the functional properties of a novel cytokine produced by these TE cells will be further characterized and basic information regarding the expression pattern of this cytokine and it's receptor will be determined. Understanding the interplay between thymocyte and TE that regulate the development and maintenance of 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 and may be useful in designing approaches to retard age-related loss of thymic function. Defining the molecules and cell interactions that regulate normal lymphocyte development also provides the knowledge necessary for an understanding of the dysregulation of these processes that contribute to autoimmune disease.
Showing the most recent 10 out of 48 publications
