T cells are only activated by antigen after it has been processed into small peptides, stably associated with major histocompatibility complex (MHC) molecules., and displayed at the cell surface of antigen presenting cells (APC). In addition to T cell receptor recognition of the antigen-MHC ligand, T cell activation requires engagement of one or more accessory or costimulatory molecules expression on the cell surface of APC. A number of cell surface proteins have been suggested to play a role in T cell adhesion and activation events, but the precise role of each of these molecules and the relateive ability of these molecules to selectively activate particular T cell subsets have not been fully established. Furthermore, engagement of the T cell receptor in the absence of costimulation can lead to the induction of a long lived state of T cell unresponsiveness, termed clonal anergy. Thus, the magnitude and nature of an immune response may be regulated the differential expression of costimulatory molecules that selectively activate or anergize certain T cell subsets. This regulation is thought to be critical in the maintenance of self tolerance and its breakdown may contribute to the induction of autoimmune disease. This proposal is directed at understanding the role of costimulation in the generation of T cell responses, in the regulation of self tolerance, and in the induction of autoimmunity.
Specific Aim 1. Determine the ability to specific costimulatory molecules to activate naive T cells and to select for T cell subsets. We will utilize a gene transfer system and T cell receptor transgenic mice to examine the role of specific costimulatory molecules in the induction of naive T cells, the propagation of T cell responses, the selection of T cell subsets, and the induction of T cell anergy.
Specific Aim 2. Characterize the novel costimulatory molecule, FSX. We have recently identified a novel costimulatory activity expressed on the surface of a fibrosarcoma that fulfills many of the same functions as B7 (for example, costimulate Th1 cells through an independent signal from the T cell receptor and protect against anergy induction), but is not in the B7 family. We propose to identify and genetically clone this molecule(s), examine its expression in conventional antigen presenting cells, and determine its role in T cell activation and the regulation of autoimmunity.
Specific Aim 3. Determine the role of a subset selection and anergy induction in the regulation of T cell responses to islet cells. We will utilize two T cell receptor transgenic systems to analyze the role of T cell subset skewing in the development of autoimmune diabetes. One system is specific for an islet-specific antigen presented in the of host antigen presenting cells and the second is specific for a target antigen expressed exclusively on islet cells.
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