Universally cross-reactive CD8+ T cell immunity across influenza A, B and C viruses

Koutsakos M, Illing P, Nguyen THO, Mifsud NA, Crawford JC, Rizzetto S, Eltahla, Clemens EB, Sant S, Chua BY, Wong CY, Allen EK, Teng D, Dash P, Grzelak L, Zeng W, Hurt A, Barr IG, Rockman S, Jackson DC, Kotsimbos TC, Cheng AC, Richard M, Westall GP, Wakim LM, Rossjohn J, Vijaykrishna D, Luciani F, Thomas PG, Gras S, Purcell AW, Kedzierska K. . Nature Immunology 20:613-625


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.