Triphasic production of IFNγ by innate and adaptive lymphocytes following influenza A virus infection

Abstract

Interferon gamma (IFN{gamma}) 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{gamma} and where they are located at different stages of an infection are limited. We have used reporter mice to investigate in vivo expression of IFN{gamma} in the lung and secondary lymphoid organs during and following influenza A virus (IAV) infection. We observed a triphasic production of IFN{gamma} expression. Unconventional T cells and innate lymphoid cells, particularly NK cells, were the dominant producers of early IFN{gamma}, 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 produce IFN{gamma} in the lungs and draining lymph node. Interestingly, IFN{gamma} production by lymph node Natural Killer (NK), NKT and innate lymphoid 1 cells also continued to be above naive levels, suggesting memory-like phenotypes for these cells. Analysis of the localisation of IFN{gamma}+ 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{gamma} while CD4 T cells in the draining lymph node increased their IFN{gamma} response. Together, these data suggest that IFN{gamma} production fluctuates based on cellular source and location, both of which could impact subsequent immune responses.