The respiratory tract serves as a significant entry point for pathogens including many potential bioweapons. Among these pathogens, Influenza virus represents a serious public health threat not only with regard to epidemic influenza but also because of the increasing threat of pandemic outbreaks. Previous studies have shown that protection from lethal influenza virus infections is mediated in part by CDS T cell killing of influenza-infected cells. The induction, magnitude, and effector phenotype of this T cell response in turn is generally thought to be intimately linked to the dendritic cell (DC) response to virus challenge. However our current understanding of how DC specifically regulate respiratory T cell responses in general and responses to lethal (highly virulent) and sub-lethal influenza virus infections in particular is quite limited. Therefore our long-term goal is to understand the mechanisms through which DC regulate, dependent upon the nature of the pulmonary challenge, the CDS T cell response to pulmonary infections. Through such regulation, DC appear to ultimately determine the outcome of virulent influenza virus infections as our preliminary results show that influenza-specific CDS T cell responses are inhibited during lethal dose influenza virus infections. This inhibition is dependent upon FasL expression by lymph node DC (LNDC) and LNDC driven apoptosis of the developing T cell response. Therefore in this proposal we will continue to utilize our mouse model of influenza virus infection to determine how DC regulate influenza-specific CDS T cells responses following lethal and sublethal influenza virus infections in the following Specific Aims: 1) Determine which LNDC subset(s) mediate LNDC elimination of virus-specific CDS T cell responses following lethal influenza virus infections and if this elimination is antigen-specific 2) Determine the mechanisms regulating IL-12p40 dependent LNDC FasL expression 3) Determine the role of DC in the initiation of virus-specific CDS effector responses during lethal and sublethal influenza infections. This proposal will elucidate how DC regulate and control the influenza-specific CDS T cell response during lethal and sublethal influenza virus infections. Furthermore it will yield important insights into the DC regulatory mechanisms that will need to be inhibited during vaccinations and treatments aimed at enhancing protective pulmonary immunity, particularly during lethal influenza virus infections and vaccinations.
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