IFITM3 Is Upregulated Characteristically in IL-15-Mediated Bystander-Activated CD8⁺ T Cells during Influenza Infection

In bystander activation, pre-existing memory CD8⁺ T cells unrelated to the infecting microbes are activated by cytokines without cognate Ags. The detailed mechanisms and unique gene signature of bystander activation remain to be elucidated. In this study, we investigated bystander activation of OT-1 memory cells in a mouse model of influenza infection. We found that OT-1 memory cells are activated with upregulation of granzyme B and IFN-γ, during PR8 (A/Puerto Rico/8/1934) infection, and IL-15 is a critical cytokine for bystander activation. In transcriptomic analysis, the IFN-induced gene signature was upregulated in bystander-activated OT-1 memory cells during PR8 infection but not in the presence of TCR stimulation. Among the IFN-induced genes, upregulation of IFN-induced transmembrane protein 3 (IFITM3) distinguished bystander-activated OT-1 memory cells from TCR-activated OT-1 memory cells. Therefore, we reveal that bystander-activated memory CD8⁺ T cells have a unique transcriptomic feature compared with TCR-activated memory CD8⁺ T cells. In particular, IFITM3 upregulation can be used as a marker of bystander-activated memory CD8⁺ T cells at early infection.