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.