The Ugly Duckling Turned to Swan: A Change in Perception of Bystander-Activated Memory CD8 T Cells

Memory T cells (T mem ) rapidly mount Ag-specific responses during pathogen reencounter. However, T mem also respond to inflammatory cues in the absence of an activating TCR signal, a phenomenon termed bystander activation. Although bystander activation was first described over 20 years ago, the physiological relevance and the consequences of T cell bystander activation have only become more evident in recent years. In this review, we discuss the scenarios that trigger CD8 T mem bystander activation including acute and chronic infections that are either systemic or localized, as well as evidence for bystander CD8 T mem within tumors and following vaccination. We summarize the possible consequences of bystander activation for the T cell itself, the subsequent immune response, and the host. We highlight when T cell bystander activation appears to benefit or harm the host and briefly discuss our current knowledge gaps regarding regulatory signals that can control bystander activation.