TCR signaling via NFATc1 constrains IL-15-induced NK-like activation of human memory CD8+T cells

Summary Here we investigated the regulatory mechanisms of TCR-independent bystander activation and NK-like cytotoxicity of human memory CD8 + T cells. We found that TCR signals suppressed characteristic features of IL-15-induced CD8 + T-cell activation, including increased NKG2D expression and upregulation of genes related to NK cytotoxicity and IFN response. Moreover, ionomycin suppressed IL-15-induced bystander activation and NK-like cytotoxicity, indicating that Ca 2+ -calcineurin signaling is responsible for TCR-mediated suppression of IL-15-induced bystander activation. In detail, NFATc1 suppressed IL-15-induced bystander activation via binding to AP-1 that is necessary for the IL-15-induced upregulation of NK cytotoxicity-related genes. Consistent with these results, calcineurin inhibitors enhanced IL-15-induced NKG2D expression in the presence of TCR signals. Additionally, we defined genes upregulated by IL-15 and downregulated by concurrent TCR signals as an IL-15-induced bystander activation gene set, and found that this gene signature was upregulated in bystander CD8 + T cells from patients with hepatitis A virus infection. This study paves the way for further investigation of bystander CD8 + T-cell activation in various pathological conditions, and its regulation. Graphical abstract Highlights TCR signaling downregulates IL-15-induced transcriptomic features related to NK-like bystander activation of human memory CD8 + T cells via the Ca 2+ -calcineurin pathway. NFATc1 suppresses IL-15-induced bystander activation via binding to AP-1, which is responsible for IL-15-induced NK-like cytotoxic activity. Calcineurin inhibitors cannot suppress IL-15-induced bystander CD8 + T-cell activation, and paradoxically increase IL-15-induced NKG2D expression in the presence of TCR signals. Genes upregulated by IL-15 and downregulated by concurrent TCR signals define the gene set of bystander CD8 + T-cell activation, which was validated in disease contexts.