Antiviral lung resident memory T cell maintenance and reinvigoration

PROJECT SUMMARY Seasonal influenza A (IAV) and other airborne viral pathogens such as SARS-CoV-2 represent a substantial burden on global public health. While sterilizing immunity can be attained through neutralizing antibodies, seasonal antigenic drift permits viral evasion of humoral immunity, which necessitates annual reformulation of the seasonal influenza vaccine. It has previously been shown, that cross-reactive CD8+ T cells can provide heterosubtypic non-sterilizing immunity to IAV. However, this cross-protection is relatively short-lived in the context of a singular antigen exposure. Our lab has shown that lung tissue resident memory T cells (lung Trm) contribute to this strain transcending cross-protection and that the waning in numbers of IAV-specific Trm strongly correlate with this loss of IAV cross-protection. Importantly, we have found that multiple exposures to the same IAV antigens (boosting) can extend the longevity of these lung Trm populations, and as a result, provide extended heterosubtypic immunity. There still exists a substantial knowledge gap regarding why lung Trm cells are so short lived when they are clearly important for protection. Addressing this question remains a critical step in the rational design of universal influenza vaccines. Our long-term goal is to understand the biology that underlies the waning of lung Trm cells and to harness this information to aid in the development of broadly protective influenza vaccines. We will address this long-term goal with the following specific aims: Aim 1: Determine the molecular T cell intrinsic factors that permit extended longevity and functionality of lung Trm following multiple antigen exposures. Aim 2: Define the optimal priming and boosting vaccination strategies to maximize Trm generation, re- invigoration, and function.