Homologous peptides derived from influenza A, B and C viruses induce variable CD8 (+) T cell responses with cross‐reactive potential

OBJECTIVE: Influenza A, B and C viruses (IAV, IBV and ICV, respectively) circulate globally, infecting humans and causing widespread morbidity and mortality. Here, we investigate the T cell response towards an immunodominant IAV epitope, NP(265‐273,) and its IBV and ICV homologues, presented by HLA‐A*03:01 molecule expressed in ~ 4% of the global population (~ 300 million people). METHODS: We assessed the magnitude (tetramer staining) and quality of the CD8(+) T cell response (intracellular cytokine staining) towards NP(265‐IAV) and described the T cell receptor (TCR) repertoire used to recognise this immunodominant epitope. We next assessed the immunogenicity of NP(265‐IAV) homologue peptides from IBV and ICV and the ability of CD8(+) T cells to cross‐react towards these homologous peptides. Furthermore, we determined the structures of NP(265‐IAV) and NP(323‐IBV) peptides in complex with HLA‐A*03:01 by X‐ray crystallography. RESULTS: Our study provides a detailed characterisation of the CD8(+) T cell response towards NP(265‐IAV) and its IBV and ICV homologues. The data revealed a diverse repertoire for NP(265‐IAV) that is associated with superior anti‐viral protection. Evidence of cross‐reactivity between the three different influenza virus strain‐derived epitopes was observed, indicating the discovery of a potential vaccination target that is broad enough to cover all three influenza strains. CONCLUSION: We show that while there is a potential to cross‐protect against distinct influenza virus lineages, the T cell response was stronger against the IAV peptide than IBV or ICV, which is an important consideration when choosing targets for future vaccine design.