Prompt Antiviral Action of Pulmonary CD8+ TRM Cells Is Mediated by Rapid IFN-γ Induction and Its Downstream ISGs in the Lung
Lang Jiang, Lu Liu, Miaomiao Zhang, Linxia Zhang, Cuisong Zhu, Qian He, Lilin Ye, Chen Zhao, Zejun Li, Jianqing Xu, Xiaoyan Zhang
Abstract
Growing lines of evidence supported the importance of CD8+ lung tissue resident memory T (T RM ) 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+ T RM cells. By simultaneously interrogating transcriptional dynamics in lung CD8+ T RM cells and surrounding tissues during the early course of infection, we demonstrated that lung CD8+ T RM 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+ T RM 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.