This is a competitive renewal of a long-standing R01 by Dr. Thomas Braciale at the University of Virginia, Charlottesville to investigate the role of T lymphocytes in recovery from influenza virus infection and in the development associated immunopathology. The proposal focuses on the contribution of the perforin and fas-ligand (CD95L) effector pathways to viral clearance and in the development of alveolar damage in a transgenic mouse model. The experimental design primarily employs defined clonal populations of type A influenza virus-specific murine CD8+ T lymphocyte effectors of wild type or mutant origin. These CD8+ effectors are adoptively transferred into lethally infected syngeneic recipient mice to assess the role of cell associated or soluble CD8+ T Lymphocyte activities in virus clearance and recovery. The contribution of CD8+ T lymphocytes and specific effector activities to the development of pulmonary inflammation and injury and the consequences of this injury on lung function will be evaluated in transgenic mice expressing the type A influenza hemagglutinin gene selectively in alveolar type II cells of the lung. Addition, studies will extend the investigator's recent observation that CD8+ CTL effectors directed to a subdominant Class I MHC restricted viral epitope produce enhanced lethal injury after transfer into hemagglutinin transgene positive recipients. Studies are proposed to determine the mechanism of enhanced injury produced by this sub population of virus specific CD8+ T lymphocyte effectors.
The specific aims of the proposal are to (i) define the contribution of specific T lymphocyte effector mechanisms in virus clearance and recovery from experimental murine Type A influenza virus infection, and (ii) to characterize the mechanisms and outcomes of T lymphocyte mediated pulmonary injury. These studies should provide new information on the contribution of specific CTL effector mechanisms to the process of recovery from pulmonary virusinfection. The proposed analysis of CD8+ T cell mediated injury should likewise provide new insight into the type of injury produced in the lung by CD8+ T lymphocytes and the impact of injury on pulmonary function in infectious and auto immune lung diseases.
Showing the most recent 10 out of 69 publications
