Memory CD8 T cell localization and protection from influenza

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Influenza infection is a recurring public health burden and our current strategies of seasonal influenza vaccination provide suboptimal protection. Thus, it is critical to provide basic, mechanistic insights into the possibility of universal influenza vaccines and much work is devoted to strategies to induce broadly neutralizing antibodies. However, in the absence of neutralizing antibodies, the presence of IAV-specific memory CD8 T cells targeting conserved viral proteins such as NP or M2, which are maintained systemically as well as in the lung correlate with control of viral titers and reduction of disease symptoms in humans. Mouse models suggest it is the lung resident memory CD8 T cells (Trm) that enable swift and robust protection against IAV infection. Thus, establishing a robust long-term Trm population in the lung may be an important goal for an IAV vaccine with broad coverage. Recent evidence from our laboratories shows that repetitive encounter with influenza infection to generate quaternary (4M) memory in the lung profoundly improves the durability of lung Trm and heterosubtypic immunity compared to primary (1M) memory Trm. Our long-term goal is to understand the biology of IAV-induced Trm and how these cells can be manipulated to enhance immunity to aid in development of universal influenza vaccines. We will address this long-term goal with the following specific aims: Specific Aim 1. Determine the mechanisms underlying improved durability of 4M vs 1M IAV-specific lung Trm Specific Aim 2. Determine if IAV-specific 4M lung Trm provide better per cell protection than 1M lung Trm Specific Aim 3. Dissect the role of 4M vs 1M IAV-specific CD69+CD103+ LN populations