In the United States alone influenza virus is a major health burden, hospitalizing 200,000, and resulting in 36,000 deaths per year. Pandemic influenza strains also have the potential to cause much more severe disease and mortality as in the case of the 1918 Spanish Flu. Given that the seasonality of infection is driven largely by antigenic shift to avoid established antibody responses, the creation of a broadly active T cell-based vaccine that recognizes highly conserved internal epitopes is an appropriate strategy to circumvent this issue. Lung tissue resident memory T cells (lung TRM) have already been found to be important in a protective heterosubtypic response to influenza, but the mechanisms by which they are established are still unknown. This project will use a mouse model of influenza infection to examine the role of monocytes and other antigen- presenting cell (APC) subsets in the generation of a protective lung TRM response. This will be accomplished using both genetic and antibody depletion approaches to eliminate specific APC subsets in order to investigate the role of these cells for the generation of tissue resident memory T cells. Using a combination of flow- cytometry and in vitro T cell stimulation, the goal of this proposal is to determine the contribution of individual APC subsets in establishing cellular immunity against a secondary influenza challenge. The knowledge gained in this study may guide future vaccine design against respiratory pathogens by defining the optimal APC targets for the delivery of antigen in order to generate lung TRM.
Cellular immunity to highly conserved epitopes on internal influenza virus proteins has the potential to provide broad protection against many different influenza strains and lessen clinical symptoms following influenza infection. However, to generate optimal cellular immunity against respiratory pathogens such as influenza virus we must first understand the mechanisms that regulate the establishment of antiviral T cells in the lung. This proposal will identify the pulmonary antigen presenting cell subsets that promote the establishment of virus-specific T cells in lung tissue, suggesting new vaccination strategies that will grant robust protection against many strains of influenza.
|McMaster, Sean R; Wein, Alexander N; Dunbar, Paul R et al. (2018) Pulmonary antigen encounter regulates the establishment of tissue-resident CD8 memory T cells in the lung airways and parenchyma. Mucosal Immunol 11:1071-1078|
|Wein, Alexander N; Dunbar, Paul R; McMaster, Sean R et al. (2018) IL-36? Protects against Severe Influenza Infection by Promoting Lung Alveolar Macrophage Survival and Limiting Viral Replication. J Immunol 201:573-582|