Immunoregulation of Anti-Listerial Immunity

The development of a cellular immune response is required to control infection caused by the intracellular parasite Listeria monocytogenes. This bacterium has the capacity to enter into many different cells of the body including macrophages and because of the subsequent production of an array of virulence factors is capable of growing freely within the infected- cell's cytoplasm. The cellular immune mechanism used to identify Listeria-infected cells depends in part on a signaling process by which MHC Class I molecules associate with an unknown array of Listeria- derived peptides and maintain this association during transport and final expression of the molecular complex at the infected-cell surface. This molecular complex of the MHC Class I molecule and Listeria-derived peptide is the target of specific cytotoxic T cells that are generated in the immune response to L. monocytogenes. The expression of specific antilisterial immunity can be shown to be mediated exclusively by these cytotoxic T cells which belong to the CD4-,CD8+ T cell subset. The recognition of a L. monocytogenes-infected cell by specific antilisterial CD8 T cells results in the lysis of the infected cell and the production of macrophage activating-gamma interferon. The CD8 T cells are responsible for both the lytic event and the production of this and other lymphokines. The transport of Listeria peptide by MHC Class I molecules in the murine model has been established to occur through the interaction of peptide with the H2-K region encoded molecules.
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Recent findings in the P.I.'s laboratory have indicated that a relatively nonpolymorphic MHC Class lb molecule encoded by the H2-T region of the mouse H2 complex also can present Listeria peptides for cytotoxic T cell recognition. This application proposes studies to define the array of Listeria peptides and the restricting MHC Class I molecules which are important in vivo to mounting a protective immune response to Listeria. Specifically, T cell clones will be developed with specificity to Listeria peptides presented by MHC Class la and Class Ib molecules. These T-cell clones will be used to investigate the role of MHC Class I molecules in antilisterial immunity- and to determine if T-cell recognition of Listeria peptides in the context of MHC Class lb in vivo is sufficient for the expression of adoptively-transferred immunity, to L. monocytogenes.
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Additional studies using an array of mutant strains of L. monocytogenes, will attempt to determine the influence of 5 different virulence factors in the development and expression of antilisterial immunity. The final series of experiments proposed in this application will determine the significance of peptide immunodominance in antilisterial immunity. The results of these experiments will be informative as to the specificity of a cellular immune response to an intracellular pathogen in terms of the array of relevant protective epitopes and restricting MHC molecules. These studies of T-cell- specific responses to Listeria-derived peptides will also provide a test of the use of haplotype-associated peptide binding motifs for MHC Class I molecules as a means to select relevant protective peptides for vaccine development.