Work

Bystander activation proceeds independently of TCR machinery and co-inhibitory pathways but is regulated by the cell-extrinsic cytokine milieu 2483

Year: 2025

Type: article

Abstract: Description Memory CD8 T cells lacking TCR specificity for an infection can become activated into cytotoxic effectors despite their lack of cognate recognition. This phenomenon, called bystander activation, is dependent on inflammation (IL-12, -15, and -18 in tandem) and leads to functional changes including IFNγ secretion, direct cytotoxicity, and PD-1 upregulation, that parallel the outcomes of TCR activation. But it remains controversial as to whether bystander activation requires some level of TCR expression or basal signaling to proceed. Using inhibitors and genetic ablation of TCR components, we find that bystander activation proceeds independent of TCR. We targeted PD-1 with biologics and gene ablation to determine that PD-1 signaling selectively restrains TCR-mediated functions, but spares bystander activation. Though independent of TCR and PD-1, we show IL-4:STAT6 signaling modulates bystander activation by downregulating IL-18Rα expression, consequently blunting IFNγ expression in bystander T cells. Curbing IFNγ in bystander T cells with IL-4 compromises bystander-mediated pathogen control. Sources of IL-4, including cytokine therapy and helminth infection, hindered protective IFNγ responses by bystander T cells. Together, we show bystander activation is independent of TCR and co-inhibitory pathways that likely evolved to exclusively control TCR activation, but that cell-extrinsic factors like IL-4 can modulate bystander activation by regulating cytokine receptor expression. Funding Sources Supported by NIH/NCI K00 CA245735; NIH/NIAID R01 AI038903, K22 AI177360; Damon Runyon Cancer Res. Fndn. DRG-2427-21. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.395