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Clin Transl Immunology . Characterisation of novel influenza-derived HLA-B*18:01-restricted epitopes

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  • Clin Transl Immunology . Characterisation of novel influenza-derived HLA-B*18:01-restricted epitopes

    Clin Transl Immunology

    . 2024 May 10;13(5):e1509.
    doi: 10.1002/cti2.1509. eCollection 2024. Characterisation of novel influenza-derived HLA-B*18:01-restricted epitopes

    Samuel Liwei Leong 1 2 , Lawton Murdolo 1 2 , Janesha C Maddumage 1 2 , Marios Koutsakos 3 , Katherine Kedzierska 3 , Anthony W Purcell 4 , Stephanie Gras 1 2 4 , Emma J Grant 1 2 4


    Objectives: Seasonal influenza viruses cause roughly 650 000 deaths annually despite available vaccines. CD8+ T cells typically recognise influenza-derived peptides from internal structural and non-structural influenza proteins and are an attractive avenue for future vaccine design as they could reduce the severity of disease following infection with diverse influenza strains. CD8+ T cells recognise peptides presented by the highly polymorphic Human Leukocyte Antigens class I molecules (HLA-I). Each HLA-I variant has distinct peptide binding preferences, representing a significant obstacle for designing vaccines that elicit CD8+ T cell responses across broad populations. Consequently, the rational design of a CD8+ T cell-mediated vaccine would require the identification of highly immunogenic peptides restricted to a range of different HLA molecules.
    Methods: Here, we assessed the immunogenicity of six recently published novel influenza-derived peptides identified by mass-spectrometry and predicted to bind to the prevalent HLA-B*18:01 molecule.
    Results: Using CD8+ T cell activation assays and protein biochemistry, we showed that 3/6 of the novel peptides were immunogenic in several HLA-B*18:01+ individuals and confirmed their HLA-B*18:01 restriction. We subsequently compared CD8+ T cell responses towards the previously identified highly immunogenic HLA-B*18:01-restricted NP219 peptide. Using X-ray crystallography, we solved the first crystal structures of HLA-B*18:01 presenting immunogenic influenza-derived peptides. Finally, we dissected the first TCR repertoires specific for HLA-B*18:01 restricted pathogen-derived peptides, identifying private and restricted repertoires against each of the four peptides.
    Conclusion: Overall the characterisation of these novel immunogenic peptides provides additional HLA-B*18:01-restricted vaccine targets derived from the Matrix protein 1 and potentially the non-structural protein and the RNA polymerase catalytic subunit of influenza viruses.

    Keywords: CD8+ T cells; HLA‐B*18:01; immunodominance hierarchy; immunogenic; influenza.