This interdisciplinary program in autoimmune disease brings together three investigators who will utilize common transgenic models in which antigens are expressed in pancreatic islets to study the dynamic relationship that exists between antigen presenting cells, autoimmune T cells and target tissue. First, we will consider the avidity and affinity of T cell-APC interaction as it modulates expression of key molecules required for lymphocyte migration and islet cell infiltration, and affects the phenotype of the activated T cell. Next, we will consider the dynamic situation that exists within the pancreas in which the potential for islet damage is counter-balanced by the potential for islet regeneration. Our overall goal is to identify key variables determinative of disease prevention vs. progression. PROJECT 1 will investigate the role of ligand density and the affinity of T-APC interactions in determining the activation status and pathogenic potential of CD4 T cells. By utilizing TCR transgenic T cells with specificity for proteins expressed as transgenes on the beta cells in the islets, these populations can be used in Project 3 to study the correlation between the form of activation and the potential for insulitis and diabetes. PROJECT 2 will focus on the repertoire of CD8 T cells that is available for recognition of antigens expressed in the islets. Particular emphasis will be placed on the role of TCR affinity in determining the fate of the cell in response to self or foreign antigens. TCR transgenics with different receptor affinities for the same ligand will be used to investigate the correlation between TCR affinity and the immune potential of the CD8 T cell, as monitored by expression of key molecules, and by potential for islet infiltration and tissue destruction. PROJECT 3 will address the dynamic interaction between T cell infiltrates and pancreatic tissue in modulating progression towards diabetes. Utilizing CD4 and CD8 T cells with different phenotypes, as obtained in Projects 1 and 2, this project will test the hypothesis that under certain circumstances the interaction of T cells with islets is able to elicit growth factors that can mediate islet cell neogenesis. In addition, the effect of localized production of IL4 in the islets will be tested in two different transgenic models of spontaneous autoimmune diabetes, one dependent on CD4 and the other on CD8 T cells, to determine if disease progression can be prevented. Taken together, these projects represent an integrated approach to test the influence of a variety of variables that affect the activation status and phenotype of the T cell on the potential for progression or prevention of autoimmune diabetes.
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