Shown in (A) is the experimental scheme. unaffected in the absence of IFN- activity. Collectively, focusing on 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- expeditiously to promote a lung-wide antiviral response for effective virus control. self-renewal, in line with the provision of a long-lived immune protection independently of enduring local antigen stimulation (11C14). Contrastingly, the number of lung TRM declined over Rabbit polyclonal to Smac time, and its maintenance may require continued replenishment from circulating memory T-cell pools (15C18). Although a number of murine studies have supported the importance of lung CD8+ TRM cells in memory recall response against IAV (19C24) and suggested its elicitation as a critical measurement of a vaccine effective in cross-subtype protection, the protective mechanism of lung TRM cells is not yet fully understood. CD8+ TRM cells might execute their antiviral function through directly killing the infected cells (25) or establishing an antiviral milieu through secretion of antiviral cytokines represented by IFN- (26). The second mechanism was proposed on the basis of functional characterization of mouse female reproductive tract (FRT) and skin TRM cells, positing that activation by reencountering cognate antigen triggers TRM to release IFN-, which induces expression of ISGs to establish a tissue-wide antiviral response (26, 27). Owing to the broad antiviral activities of some of the IFN–induced ISGs, Salmefamol this response is endowed with capacity to be cross-protective. In addition, IFN- may cooperate with other cytokines released by TRM to orchestrate maturation of dendritic cells (DCs) and natural killer (NK) cells, as well as recruitment Salmefamol of circulating memory T and B cell to fortify local antiviral immunity (27). Given the phenotype diversity among different TRM cells, the generality of the IFN- paradigm remains to be vindicated. In the case of lung TRM cells, only a few published reports explored the mechanistic aspect of their antiviral functions. McMaster et?al. initially showed by an intratracheal transfer approach that airway TRM cells were sufficient for mounting effective protection against influenza virus infection in an antigen-specific manner (20). The same study also characterized the responses of airway TRM cells to antigen stimulation and identified rapid production of IFN- with little cell proliferation as the major event, which was subsequently substantiated by the finding that viral control conveyed by Salmefamol transfer of airway IFN–deficient TRM cells was less effective than that achieved by wild-type TRM cells. According to our knowledge, there has been no published report on dynamics of lung TRM cells during an effective protective response. Here, we used mouse infection models to assess the protective potential of lung CD8+ TRM cells and interrogate their working mechanism by Salmefamol a combinatory approach. In particular, we probed the early action of activated lung CD8+ TRM cells by using microarray to analyze transcriptional changes in both these cells and the lung over the course of early phase of infection. This paralleled analysis, combined with following experimental corroborations, established rapid production of IFN- to induce a tissue-wide expression of ISGs while suppressing inflammation as the major, but not the only, mechanism utilized by lung TRM cells Salmefamol to exert their protective functions. Together, our work shed new insights into the biology of lung CD8+ TRM cells and thereby provided new mechanistic basis for their optimal exploitation to protect against respiratory viral infection as well as other diseases. Materials and Methods Mice C57BL/6J (B6) mice were originally purchased from the Jackson Laboratory; P14 CD45.1 transgenic mouse was a gift from Dr. Lilin Ye (Army Medical University, Chongqin); we obtained the.