The goal of this research effort is to understand how an important type of white blood cell, called a T lymphocyte, recognizes the presence of a microorganism or cancer cell in the body, or inappropriately recognizes a normal component of the body (an ?auto-antigen?). This research tries to provide a detailed understanding of how the substances (antigens) making up these microorganisms, cancer cells, or normal self-components, are made visible to the defending T cells or the auto-reactive T cells. We have examined the structure and function of special cellular proteins called major histocompatibility complex (MHC) molecules that are essential for antigens to be recognized by T cells. Specific questions involve understanding how structural differences in the MHC molecules of different individuals affect the ability of these proteins to stimulate T cells and the exact nature of the antigens bound to the MHC molecules. Our work has described the events within a cell that bring the antigen and MHC molecule and the cellular distribution of antigenic complexes within the body (antigen processing and presentation). By understanding these events, we will be able to identify the most important components of microorganisms or cancer cells to use in protective or therapeutic vaccines and how best deliver these substances to stimulate an effective immune response. We have made several advances in the past year. The actual target for MHC class II antigen binding was shown to be large protein fragments rather than peptides. This explains why MHC class II molecules have open ends to their binding site ? they need to be able to accommodate these larger protein chains. We have utilized novel reagents produced in our laboratory to visualize specific peptide:MHC molecule complexes on various cells in intact lymphoid organs and to quantitate such complexes on these cells. We have uncovered a key role for microbial signals in enhancing antigen processing by dendritic cells and increasing their contact with T cells in secondary lymphoid tissue. Experiments on DNA vaccines has revealed a major role for directly transduced dendritic cells in the success of this immunization procedure. Very recent experiments have revealed a putative receptor- mediated system for uptake of heat shock protein-associated antigens. We have also defined two intracellular pathways for presentation of these bound antigens by MHC class I molecules. This could play a key role in enhancing CD8+ T cell responses to infectious agents. Finally, methods for highly efficient retroviral transduction of dendritic cells grown ex vivo have been developed and are being employed to modify the function of these key antigen presenting cells to promote either tolerance or immunity. - Antigen processing; antigen presentation; adjuvants; dendritic cells; Hsp; DNA vaccination.
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