The respiratory tract is one of the most important sites of entry for pathogens including many potential bioterrorism agents such as influenza virus. Although local innate and early adaptive immune defenses are known to be crucial for limiting initial pathogen spread, the mechanisms underlying mucosal immunity in the respiratory tract are still poorly defined. Lung tissue dendritic cells (DC) are key components of the innate immune system that regulate adaptive immunity by migrating to the regional lymph nodes to present antigens to T cells. Preliminary data suggest that contrary to current dogma, DC can also activate immune responses in the lung tissue itself. The objective of this application is to determine the mechanisms by which respiratory tract DC activated by influenza virus-infection regulate local virus-specific T and B cell responses and to test how application of inactivated virus (as a prototype vaccine) affects their functions. The central hypothesis underlying this study is that infection of lung tissue DC is critical for their ability to present antigen to B cells and to regulate virus-specific CD4 T cell responses. The following Specific Aims are proposed:
Specific Aim #1 is to fully characterize respiratory tract DC responses following sublethal infection of mice with influenza A/PR8, by studying the phenotype of DC and their viral- and host-gene expression ex vivo and to determine the mechanisms by which they regulate virus-specific T-dependent and/or T-independent B cell responses.
Specific Aim #2 will determine the ability of lung tissue and draining lymph node DC to regulate the induction and/or quality of virus-specific effector CD4 T cell responses, by measuring cytokine profiles and clonal burst sizes of naive and activated CD4+T cells in co-cultures with virus-stimulated respiratory tract DC and in vivo following adoptive transfer of DC.
Specific Aim #3 is to determine whether application of inactivated virus induces local DC populations that differ in phenotype, gene expression profile or effector function from those induced by live virus infection; thus whether differences in the quality of the DC responses induced to live and inactivated virus could underlie the often disappointing levels of protection achieved with inactivated virus vaccines compared to those obtained after active infection. In summary, this study will provide a detailed understanding of respiratory tract DC biology, particularly their role in regulating early local responses at the site of pathogen entry. This information could help the development of novel interventions that utilize early respiratory tract defenses for immune protection. ? ?
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