PROJECT SUMMARY / ABSTRACT Respiratory virus infection and intranasal immunization generates antigen-specific T cell and B cell memory throughout the respiratory tract. This includes a population of tissue-resident memory T cells (TRM) that are uniquely positioned within the mucosa to rapidly recognize and respond to re-exposure with a similar pathogen. Often these TRM are specific for highly conserved epitopes that are shared across many viral strains and can therefore provide protection against viral variants. While previous studies have shown that TRM can mediate protection by limiting viral replication and immunopathology following direct inoculation, it is not known whether TRM alone can effectively surveil the large surface area of the respiratory epithelium to rapidly identify and eliminate rare, infected cells during natural transmission events prior to propagation of the infection throughout the respiratory tract. Furthermore, the TRM antiviral mechanisms that are important for limiting transmission are unknown, and how these mechanisms impact local innate and epithelial cells inhibit viral propagation are not well characterized. To address these deficiencies, we have developed a murine model of Sendai virus transmission, and new experimental tools to establish Sendai virus-specific respiratory tract TRM without generating Sendai-specific antibody. Our preliminary data show that Sendai-specific respiratory tract CD8+ TRM protected mice from propagation of infection following transmission events, whereas mice with only circulating Sendai-specific CD8+ memory T cells were not protected. Finally, in collaboration with Dr. Anice Lowen (co-I), we have developed a guinea pig model of heterosubtypic influenza virus transmission to investigate the efficacy of T cell-mediated immunity in limiting transmission of a relevant human pathogen. This proposal will investigate the characteristics, durability, and molecular mechanisms of respiratory tract TRM that protect against natural respiratory transmission.