Project Summary/Abstract: Despite the availability of a seasonal vaccine, influenza virus remains a critical burden to human health, infecting millions worldwide every year. The limited efficacy of current influenza vaccine strategies is largely due to antigenic shift, which allows the virus to evade established antibody responses. Thus, developing new strategies to elicit broadly protective responses that can recognize diverse influenza strains is of great importance. One potential strategy is to develop a T-cell based vaccine that could recognize conserved internal epitopes and provide protective immunity across many influenza strains. While cellular immunity cannot prevent influenza infection, pre-existing antiviral T cells can limit viral replication and disease severity. Lung tissue-resident memory CD8 T cells (CD8 TRM) are a critical subset of memory T cells that are established following primary respiratory infection and remain localized within the lung tissue, where they provide rapid protection against subsequent respiratory challenge. However, whereas CD8 TRM identified in other barrier tissues such as the skin and gut have been shown to remain stable and provide long-lasting protection, CD8 TRM in the lung gradually decline over time. Importantly, our preliminary studies show that the loss of lung CD8 TRM correlates with a decline in cellular immunity to respiratory infection, including influenza. Currently, our knowledge of the mechanisms governing the maintenance of tissue-resident memory CD8 T cells in the lung remains limited. Our group has also identified several strategies, including immunization with a recombinant adenovirus vector and a prime-boost approach with recombinant influenza viruses, which result in the long- term maintenance of influenza-specific CD8 TRM in the lungs of mice. Our major objective is to identify the mechanisms responsible for the enhanced longevity of CD8 lung TRM observed following these infection/immunization strategies. The results of this study will inform future design of cell-mediated influenza vaccines by providing valuable insight into the maintenance of lung TRM, and thus, the durability of cellular immunity to respiratory pathogens.

Project Narrative: Lung tissue-resident memory T cells are crucial mediators of cellular immunity against respiratory pathogens such as influenza viruses, but the number of these cells in the lung tissue gradually declines over time. This proposal seeks to understand the mechanisms that are important for the long-term maintenance of lung- resident memory T cells following novel vaccination platforms, such as recombinant adenovirus and prime- boost strategies. Our results will identify mechanisms that enhance the durability of cellular immunity in the lung and may guide future cell-mediated vaccine strategies against respiratory pathogens.