This proposal is designed to examine the mechanism by which cytosolic proteins in the pulmonary parenchyma are processed and presented to the murine immune system at the same time the research program described herein will serve as a vehicle for the applicant to obtain basic training in modem molecular and cellular immunology, as well as molecular biology. He will be highly qualified to apply these skills in the analysis of local immune responses in the lung and in the study of autoimmune mechanisms o The proposal focuses on two viral polypeptides, the type A influenza nucelocapsid protein (NP) and the nonstructural protein ic proteins transiently expressed in respiratory epithelial cells. The experimental approach will utilize clonal populations of CD4+ and CD8+ T lymphocytes to examine the mechanisms by which these proteins are processed and presented in association with Class I and Class II MHC molecules on tumor cell targets and populations of isolated respiratory epithelia in vitro. The pathways of intracellular targeting of these molecules will be explored as will the in vivo function of CD4+ and CD8+ T cells directed to these proteins in the host response to pulmonary viral infection. This will lead to studies which will examine immune recognition of one or both of these proteins expressed as transgenes in mice where the viral protein is specifically expressed in the lungs off of lung specific promotors, as a model for autoimmune lung injury. In addition to experimental bench research the applicant will take didactic courses in cell biology, modem biochemistry, virology, and molecular immunology. The applicant win have an advisory committee for this work consisting of the sponsor, a highly skilled molecular biologist, and a cell biologist. The program outlined in this proposal will not only provide a focus for future research in lung immunology and mechanisms of immune mediated pulmonary injury, but also give the applicant extensive training in the modem research skills and techniques required for his future development as a fully independent investigator.
