Abstract
Growing lines of evidence supported the importance of CD8+ lung tissue resident memory T (TRM) cells in protection against respiratory viruses, exemplified by influenza A virus. However, the underlying in vivo mechanism remains largely undetermined. Here, we used mouse infection models to dissect in vivo cross-protective activity of lung CD8+ TRM cells. By simultaneously interrogating transcriptional dynamics in lung CD8+ TRM cells and surrounding tissues during the early course of infection, we demonstrated that lung CD8+ TRM cells react to antigen re-exposure within hours, manifested by IFN-γ upregulation, and a tissue-wide interferon-stimulated gene (ISG) program is subsequently elicited. Using antibody-mediated IFN-γ neutralization and IFN-γ receptor knockout mice, we could show that the induction of several important antiviral ISGs required IFN-γ signaling, so did the suppression of key inflammatory cytokines. Interestingly, there were also examples of ISGs unaffected in the absence of IFN-γ activity. Collectively, focusing on in situ characterization of lung CD8+ TRM cells during very early stage of infection, a critical period of host antiviral defense that has been poorly investigated, our studies highlight that these cells, once triggered by antigen re-exposure, are programmed to produce IFN-γ expeditiously to promote a lung-wide antiviral response for effective virus control.
Highlights
Influenza A viruses (IAVs) continued to be a serious public threat and vaccination is considered as the major, if not the only, means for its control at the population level [1]
Two sequential models were employed in the study: in one model, naïve C57BL/6J mice were first intranasally (i.n.) infected with 150 TCID50 of H9N2 and, after an interval as indicated, i.n. exposed to 1×104 TCID50 of H7N9 virus; in the other model, 5×104 P14 CD8+ T cells were isolated from P14 CD45.1 transgenic mouse and seeded into naïve C57BL/6J mice, which were i.n. primed with 50 TCID50 of PR/8 H1N1 (PR8)/PR8-gp33 1 day later and after waiting for 30 days, subjected to intranasal challenge with 2×105 plaque-forming units (PFU) of lymphocytic choriomeningitis virus (LCMV) Armstrong
During our course of exploration of vaccination strategy against H7N9 infection, we found in a mouse model that prior infection with low pathogenic, nondisease-causing H9N2 strain could confer a cross-protection against heterologous H7N9 challenge
Summary
Influenza A viruses (IAVs) continued to be a serious public threat and vaccination is considered as the major, if not the only, means for its control at the population level [1]. The major currently used IAV vaccine works by inducing neutralizing antibody against the head domain of viral hemagglutinin protein (HA), which is responsible for virus entry by binding to sialic acid receptors on cell surface [2, 3]. The virus composition of seasonal flu vaccine is determined based on surveillance data of currently circulating viruses, which was used to predict the virus strains with the greatest likelihood of circulating during the coming season. The emergency of mismatched epidemic and pandemic influenza variants driven by antigenic drift or shift posed further challenge for neutralizing an antibody-based IAV vaccine [2]. A possible solution to this conundrum is exploration of more conserved HA stalk as immunogen for vaccine design
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