Respiratory virus infections are a significant source of annual morbidity and mortality, constituting a major human health problem worldwide. Memory T cell responses are critical for quickly limiting viral replication and mitigating unnecessary inflammation responsible for immunopathology. Acting as sentinels capable of quickly organizing a secondary immune response upon pathogen challenge, resident memory CD8 T (TRM) populations are initially primed by microenvironment cues and antigen presenting cell (APC) licensing following acute infection of peripheral tissues. Despite their capacity for heterologous protection against influenza virus challenge, scant knowledge exists as to factors necessary to establish and maintain airway and lung parenchymal (LP) CD8 TRM cells. This body of work focuses on 1) the regulation of CD8 TRM cell establishment and maintenance in the LP and airways and 2) the protection conveyed by airway and LP CD8 TRM cells. In the absence of antibody protection, antigen-specific T cell responses, generated following previous influenza virus infection, reduce murine morbidity and mortality during lethal H7N9 influenza virus challenge. Airway CD8 TRM cells are alone sufficient to mediate protection upon heterologous challenge, working in concert with LP CD8 TRM cells to produce effector cytokines and kill infected cells, respectively. Furthermore, this work demonstrates that, in contrast to mechanisms described for other tissues, lung CD8 TRM cell establishment requires cognate antigen recognition once systemic effector T cells are recruited to the lung by local inflammation. Priming with local antigen and inflammation or native intranasal infection conveys equal protection upon heterologous challenge, while priming with local inflammation alone does not confer protection. This combination of local antigen and inflammation formed long-lasting TRM populations in the LP and airways that highly express the chemokine receptor CXCR6 and adhesion molecule CD49a, which uniquely characterize these two populations. Importantly, we demonstrate that CXCR6 is necessary for robust formation of virus-specific airway and LP CD8 TRM cells. These findings have identified novel mechanisms regulating the establishment and protective efficacy of lung CD8 TRM populations. Applying these findings may aid in the development of a new vaccination strategy for enhanced CD8 TRM cell establishment and protection.
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