CYTOTOXIC T LYMPHOCYTE RESPONSE TO INFLUENZA VIRUS

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A critical early step in the host response to invading microorganisms is the presentation of microbial proteins to the immune system. This proposal is designed to investigate the mechanism of viral antigen processing and presentation to T lymphocytes. It is a continuation of our ongoing efforts to understand in molecular terms viral antigen recognition by MHC class I restricted CD8+ T lymphocytes and MHC class II restricted CD4+ T lymphocytes in the mouse using the type A influenza viruses as a model system. The proposal focuses on two areas: the analysis of the contribution of residues within and outside of an antigenic site in the formation of the antigenic moiety recognized by T lymphocytes in an infected cell and the definition of the intracellular compartment(s) in which newly synthesized viral polypeptides are processed and presented to T lymphocytes. The experimental approach employs cloned populations of cytolytic CD8+ and CD4+ T lymphocytes and synthetic minigenes along with mutant viral polypeptides to probe processing and presentation events in the recognition of the influenza hemagglutinin (HA) and nucleocapsid (NP) proteins. The specific aims of this proposal are: i) to characterize the antigenic moieties in the influenza HA recognized by CD8+ T lymphocytes; ii) to examine the pathway by which newly synthesized influenza virus polypeptides are processed and presented to CD4+ T lymphocytes. This investigation should provide basic information on the immune response to an important human pathogen. In addition, these studies should help to elucidate the molecular mechanisms involved in the formation of antigenic epitopes recognized by T lymphocytes and thereby provide a framework for future vaccine design.