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

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.