This proposal is a competitive renewal of the previous grant, AI 07289, a long term project supported by a ten year Merit Award.
The aims of this competitive renewal have been expanded from the original application to take advantage of progress in these investigations as well as in the field. These studies focus on the question of how foreign peptide epitopes are selected, and complexed by the MHC molecule for antigen presentation, and how the T cell receptor recognizes the peptide epitope in the context of MHC. The general aims are to use the techniques of immunobiology, biochemistry, molecular genetics and three dimensional structure analysis, (l) to understand the mechanism by which peptides of appropriate length and sequence are selected for and bound by the MHC presenting molecules and (2) to identify at the structural level, the features of the T cell receptor involved in recognizing these peptides in the MHC target molecules. Specifically, it is proposed to continue the studies begun in the previous grant period on the structural basis for the function of class I molecules in peptide presentation. These will include a series of related projects utilizing either three-dimensional structure analysis or in vitro, biochemical and physical-chemical procedures to probe the structural impact of MHC polymorphism, the mechanism for editing and binding peptides, and the role and interactions of chaperones in the proper folding of MHC class I complexes. These studies are relevant to peptide vaccine development. T-cell receptor function/structure analyses will be complemented by studies to determine the 3D structure of the T-cell receptor in order to understand the structural basis for the events of T-cell recognition of peptide presented by MHC, studies that are relevant to T-cell development, immunity to infectious diseases and autoimmunity.
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