Insulin dependent diabetes mellitus (IDDM) results from autoimmune destruction of pancreatic beta cells. Although islet cells appear to be the targets of specific T cell cytolysis, the role of beta cells in the initiation of the response is not dear. It has been suggested that the induction of MHC class II molecules on islet cell during IDDM is an important step in the initiation of diabetes. However, analyses of transgenic mouse models and in vitro antigen presentation assays suggest that islet cells fail to activate T cells. In fact, interaction of T cells and islet cells often leads to the induction of T cell nonresponsiveness, raising the possibility that the induction of Class II on islet cells during IDDM may downregulate autoimmune responses. This project contains three Specific Aims: 1. Determine whether Class H MHC expression on islet cells is sufficient to induce IDDM. Recent results in our laboratory have emphasized the importance of invariant chain in the conformation and immunological recognition of Class H molecules. We will address whether co-expression on Class II and invariant chain on islet cells will effect T cell responsiveness. In addition, we will utilize an inducible expression system to determine if induction of Class II expression of islet cells in immunologically mature animals will induce T cell tolerance or autoimmunity. 2. Analyze the expression and importance of accessory molecules in the activation of T cells by islet cells. Efficient activation of T cells by antigen presenting cells requires the involvement of several cell-cell interaction molecules, independent of T cell receptor engagement. To address the role of accessory molecule expression by islet cells in the development of IDDM, we will determine the expression level of these accessory molecules by normal and diabetic islet cells. 3. Define the ability of islet cells to present endogenous antigens to Class I-restricted T cells in vivo. We will utilize transgenic mice that express known cellular antigens on islet cells to determine the ability of islet cell to generate immunogenic complexes of these antigens with Class I molecules and the immunological consequence of expression of these complexes. The overall goals of this proposal are to define the ability of islets cells to serve as antigen presenting cells for the activation of T cells and to determine the role islet cells play in the initiation and development of IDDM.
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| Anderson, M S; Miller, J (1992) Invariant chain can function as a chaperone protein for class II major histocompatibility complex molecules. Proc Natl Acad Sci U S A 89:2282-6 |
