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

Memory T cells (Tmem) rapidly mount Ag-specific responses during pathogen reencounter. However, Tmem 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 Tmem bystander activation including acute and chronic infections that are either systemic or localized, as well as evidence for bystander CD8 Tmem 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.