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

Abstract

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.

Figure 1.. Effector functions of bystander activated CD8 T_mem.

(A) Proinflammatory cytokines including type I IFN or combinations of IL-12, IL-15, and/or IL-18 activate CD8 T_mem to become bystander activated and express IFNγ and/or granzyme B (GzmB). (B) IFNγ could signal in an autocrine and paracrine manner. Both non-immune cells, such as stromal and parenchymal cells, and leukocytes, such as CD8 T cells, APCs, and neutrophils can be activated by IFNγ. (C) Engagement of NKG2D on bystander activated CD8 T_mem with stress-induced NKG2D ligands (NKG2DLs) on targets coordinates the delivery of cytotoxic GzmB granules to target cells. (D) IFNγ secretion has pleiotropic effects which result in a heightened immune state. (E) Direct NKG2D-mediated and indirect IFNγ-mediated responses ultimately converge to result in target cell death.

Figure 2.. Site-specific bystander activation results in localized bystander-mediated effector responses.

(A) Localized infection will lead to the generation of proinflammatory cytokines that can bystander activate CD8 T_RM in situ. (B) CXCR3 ligands (CXCR3L), including CXCL9 and CXCL10, are produced at sites of early immune activation. Circulating bystander CD8 T_mem are recruited in a CXCR3-dependent manner to these sites, at where they encounter bystander-activating cytokines. (A and B) Both result in localized bystander activation and bystander-mediated effector responses.