The mucosal surfaces are covered by a thin epithelium which is adapted for selective adsorption of essential nutrients, but is a weak physical barrier against the outside environment. Because this epithelium can be easily breached many infectious agents use the mucosal tissues as gateways into the body. These pathogens include several highly pathogenic respiratory viruses which pose a constant threat to human health. The fragile membranes ofthe alveoli make the lungs particulariy vulnerable to immune damage. We will use a heterosubtypic reinfection model to examine the mechanisms that help protect the lungs from these infections. Previous studies have shown that local populations of cytotoxic T lymphocytes (CTL) and IgA antibodies in the respiratory tract can provide immunity between different stains of influenza virus. Our data indicate that these mechanisms are facilitated by mild antigen-driven inflammation, which helps pathogen-specific CTL stay near the mucosal surface between repeated viral infections and augments local antibody production. The goals ofthe current study are to investigate how a tightly regulated cytokine response promotes enduring T and B cell mediated heterosubtypic immunity. We will focus on the cytokines that trigger innate immune activation, as well as long-term TGF-beta production which plays a pivotal role in immune regulation in the lungs. RELEVANCE (See instructions): Influenza viruses are highly contagious pathogens that are in constant circulation in human populations. High death tolls make these infections a top priority for mass vaccination programs but accumulating data indicate that the current vaccination approaches are not optimized to generate enduring immunity. Our data indicate that T cell mediated immunity in the lungs can be prolonged by a mild inflammatory response.