Human CD8⁺ T cell cross-reactivity across influenza A, B and C viruses

Influenza A, B and C viruses (IAV, IBV and ICV, respectively) circulate globally and infect humans, with IAV and IBV causing the most severe disease. CD8⁺ T cells confer cross-protection against IAV strains, however the responses of CD8⁺ T cells to IBV and ICV are understudied. We investigated the breadth of CD8⁺ T cell cross-recognition and provide evidence of CD8⁺ T cell cross-reactivity across IAV, IBV and ICV. We identified immunodominant CD8⁺ T cell epitopes from IBVs that were protective in mice and found memory CD8⁺ T cells directed against universal and influenza-virus-type-specific epitopes in the blood and lungs of healthy humans. Lung-derived CD8⁺ T cells displayed tissue-resident memory phenotypes. Notably, CD38⁺Ki67⁺CD8⁺ effector T cells directed against novel epitopes were readily detected in IAV- or IBV-infected pediatric and adult subjects. Our study introduces a new paradigm whereby CD8⁺ T cells confer unprecedented cross-reactivity across all influenza viruses, a key finding for the design of universal vaccines.