Influenza A, B and C viruses (IAV, IBV, ICV) circulate globally and infect humans, with IAV/IBV causing most severe disease. While CD8 + T-cells confer cross-protection against different IAV strains, CD8 + T-cell responses to IBV/ICV are understudied. We dissected the CD8 + T-cell cross-reactome against influenza viruses and provided the first evidence of CD8 + T-cell cross-reactivity across IAV, IBV and ICV. Using immunopeptidomics, we identified immunodominant CD8 + T-cell epitopes from IBV, protective in mice, and found prominent memory CD8 + T-cells towards both universal and influenza type-specific epitopes in blood and lungs of healthy humans, with lung-derived CD8 + T-cells displaying a tissue-resident phenotype. Importantly, effector CD38 + Ki67 + CD8 + T-cells against novel epitopes were readily detected in IAV-and IBV-infected pediatric and adult patients. Our study introduces a new paradigm, whereby CD8 + T-cells confer unprecedented cross-reactivity across all influenza viruses, a key finding for designing universal vaccines.

Highlights d Analyses of 184 immune features define kinetics of immune responses to SARS-CoV-2 d Circulating T FH 1 cells in acute COVID-19 correlate with antibodies d sIL-6R levels are elevated in severe COVID-19 but do not correlate with IL-6 d Elevated IL-6 and IL-18 correlate with immune cell hyperactivation