TCR-independent unique signature of bystander-activated memory CD8+ T cells during influenza infection

Abstract

In bystander activation, pre-existing memory $CD8^+$ T cells unrelated to the infecting microbes are activated by cytokines without cognate antigens. The detailed mechanisms and unique gene signature of bystander activation remain to be elucidated. Here, I investigated bystander activation of OT-1 memory cells in a mouse model of influenza infection. I found that OT-1 memory cells are activated with upregulation of granzyme B and interferon- $ \gamma $, during A/Puerto Rico/8/1934 (PR8) infection, and IL-15 is a critical cytokine for bystander activation. In transcriptomic analysis, the interferon-induced gene signature was upregulated in bystander-activated OT-1 memory cells during PR8 infection but not in the presence of T cell receptor (TCR) stimulation. Among the interferon-induced genes, upregulation of interferon-induced transmembrane protein 3 (IFITM3) distinguished bystander-activated OT-1 memory cells from TCR-activated OT-1 memory cells. Moreover, the repeatedly reactivated OT-1 memory $CD8^+$ T cells showed protective bystander effect to reduce early viral load during PR8 infection. Through this study, I reveal that bystander-activated memory $CD8^+$ T cells have a unique transcriptomic feature compared to TCR-activated memory $CD8^+$ T cells and protective role during PR8 infection. In particular, IFITM3 upregulation, which is downregulated by calcium dependent signaling induced by TCR stimulation can be used as a marker of bystander-activated memory $CD8^+$ T cells at early phase of PR8 infection.