A mechanistic approach to T cell based influenza vaccines

Vaccination is the most effective way to prevent disease associated with influenza infection. However in susceptible hosts, a major contributing factor to host mortality is aberrant immune responses. In determining the causes of influenza related pathology, it was observed that excessive cytokine production, significant lung pathology, and a lack of viral clearance were key contributors to survival after a lethal infection. Therefore, both viral and host factors contribute to influenza related illness. Moreover, current influenza vaccines are suboptimal and the mechanistic insights into T cell based influenza immunity have not been fully described. The studies in this dissertation highlight the role of various pattern recognition receptors (PRRs) and antiviral transcription factors in the induction of effector and memory T cell responses to influenza. It was determined that toll-like receptor 9 (TLR9) deficiency contributed to impaired virus-specific memory T cell formation in secondary lymphoid tissue. Additionally, a novel role for interferon regulatory factor 3 (IRF3) in the expression of effector and cytotoxic proteins following primary and secondary influenza infections was defined. These studies suggest that signaling through host factors classically defined as innate immune proteins can contribute to protective T cell based immunity. Finally, a mucosally administered vaccine adjuvanted by a TLR9 agonist was developed, that induced vaccine-specific memory T cell responses and limited viral replication following a lethal influenza challenge. Together, these results suggest that signaling through PRRs is a viable vaccine strategy capable of inducing memory T cell responses to prevent against influenza related disease