T lymphocytes play a primary role in recovery from viral infections and in antiviral immunity. Although this general concept has been well recognized for many years, there is little information available on the mechanism(s) of action of T lymphocytes in viral immunity,. This proposal is designed to examine the role of specific subsets of MHC class II restricted T lymphocytes and their cytokine products in the immune response to and recovery from experimental influenza virus infection in mice. This project builds on recent evidence indicating the existance of distinct subsets of class II restricted T lymphocytes in mice. These T lymphocyte subsets appear to have different cytokine profiles and may exhibit different functional activity in vivo. The experiments outlined in this proposal will examine the effect of clonal populations of T lymphocytes directed against type A influenza virus corresponding to these subsets on recovery from experimental influenza infection in adoptive transfer experiments. We will then examine specific T cell gene products, e.g. specific cytokines, which play a role in mediating recovery from infection. Finally, we will attempt to manipulate expression of these genes in clonal populations to further examine their respective roles. These experiments should provide further information on the role of CD4 positive cells in the recovery from viral infection and provide information on the role of specific T cell products in mediating the antiviral effect of T cells. GRANTS=K04AI01051 This award will provide salary support that will significantly reduce the teaching load of the candidate and therefore will allow much more effort to be devoted to research on solution structural studies of RNAs. Specifically, the award will cut the teaching load of the candidate in half from the normal two (3 credit) courses per year to a single course. This reduced teaching load means that the candidate can take full advantage of unique search opportunities that the University of Colorado at Boulder offers for studies of RNA structure. Boulder has eight research groups that are extremely active in the areas of RNA biochemistry and molecular biology. The candidate moved to Boulder in 1988 to take advantage of this environment and since that time has set up a research effort in nuclear magnetic resonance (NMR) structural studies of RNA. This work complements the previous research by the candidate in the areas of NMR studies of DNA and antimicrobial peptides. The increased time that be devoted to research by this reduction of teaching load will allow the next phase of the NMR structural studies of RNA to proceed at an accelerated pace. This phase will involve application of heteronuclear multi-dimensional NMR experiments to the structure determination of biologically active RNAs. The heteronuclear NMR experiments are presently revolutionizing solution structure determinations of proteins, but these techniques have yet to be applied to studies of RNAs. The RNAs that will be studied include: i) two RNA enzymes, the self-cleaving hammerhead and hairpin RNA domains, both of which have potentially important in vivo applications as site-specific RNA endonucleases which can be designed to specifically cleave a target MRNA or the genome of an RNA virus such as HIV; ii) a yeast tRNAPhe system that will serve as a model system for developing techniques for identification of tertiary interactions in RNAs; and iii) several RNA structural motifs including a set of unusually stable and naturally occurring RNA hairpins that contain tetranucleotide loops. The structural information provided by the NMR experiments will be combined with additional biological and biochemical data in order to improve structure-activity relationships for RNAs.
| Esser, M T; Dinglasan, R D; Krishnamurthy, B et al. (1997) IL-2 induces Fas ligand/Fas (CD95L/CD95) cytotoxicity in CD8+ and CD4+ T lymphocyte clones. J Immunol 158:5612-8 |
| Graham, M B; Braciale, T J (1997) Resistance to and recovery from lethal influenza virus infection in B lymphocyte-deficient mice. J Exp Med 186:2063-8 |
| Graham, M B; Braciale, V L; Braciale, T J (1994) Influenza virus-specific CD4+ T helper type 2 T lymphocytes do not promote recovery from experimental virus infection. J Exp Med 180:1273-82 |
