Triphasic production of IFN γ by innate and adaptive lymphocytes following influenza A virus infection.

Interferon gamma (IFN γ ) is a potent antiviral cytokine that can be produced by many innate and adaptive immune cells during infection. Currently, our understanding of which cells produce IFN γ and where they are located at different stages of an infection is limited. We have used reporter mice to investigate in vivo expression of Ifn γ mRNA in the lung and secondary lymphoid organs during and following influenza A virus (IAV) infection. We observed a triphasic production of Ifn γ expression. Unconventional T cells and innate lymphoid cells, particularly NK cells, were the dominant producers of early Ifn γ , while CD4 and CD8 T cells were the main producers by day 10 post-infection. Following viral clearance, some memory CD4 and CD8 T cells continued to express Ifn γ in the lungs and draining lymph node. Interestingly, Ifn γ production by lymph node natural killer (NK), NKT, and innate lymphoid type 1 cells also continued to be above naïve levels, suggesting memory-like phenotypes for these cells. Analysis of the localization of Ifn γ + memory CD4 and CD8 T cells demonstrated that cytokine+ T cells were located near airways and in the lung parenchyma. Following a second IAV challenge, lung IAV-specific CD8 T cells rapidly increased their expression of Ifn γ while CD4 T cells in the draining lymph node increased their Ifn γ response. Together, these data suggest that Ifn γ production fluctuates based on cellular source and location, both of which could impact subsequent immune responses.