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

Human memory CD8⁺ T cells can undergo T cell receptor (TCR)-independent activation by interleukin-15 (IL-15) in a bystander manner. Bystander-activated CD8⁺ T cells contribute to host tissue injury through natural killer (NK)-like cytotoxicity during viral infections. However, detailed mechanisms underlying IL-15-induced bystander activation remain to be elucidated. In this study, we investigated the molecular regulation of bystander activation and NK-like cytotoxicity of human CCR7⁻ memory CD8⁺ T cells. We found that TCR signals suppressed characteristic features of IL-15-induced CD8⁺ T cell activation. Ionomycin also suppressed IL-15-induced expression of NKG2D and NK cytotoxicity genes, indicating that Ca²⁺-calcineurin signaling suppressed bystander activation. Mechanistically, NFATc1 bound to AP-1, limiting its ability to induce expression of NK cytotoxicity-related genes. We also defined an IL-15-induced bystander activation gene set, which was validated in bystander CD8⁺ T cells from patients with hepatitis A virus infection. Our findings open avenues for investigating bystander CD8⁺ T cell activation and its regulation in pathological conditions.