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

Andrea T Nguyen; Hiu Ming Peter Lau; Hannah Sloane; Dhilshan Jayasinghe; Nicole A Mifsud; Demetra Sm Chatzileontiadou; Emma J Grant; Christopher Szeto; Stephanie Gras

doi:10.1002/cti2.1422

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

Clin Transl Immunology. 2022 Oct 19;11(10):e1422. doi: 10.1002/cti2.1422. eCollection 2022.

Authors

Andrea T Nguyen^{1

2}, Hiu Ming Peter Lau¹, Hannah Sloane^{1

2}, Dhilshan Jayasinghe^{1

2}, Nicole A Mifsud¹, Demetra Sm Chatzileontiadou^{1

2}, Emma J Grant^{1

2}, Christopher Szeto^{1

2}, Stephanie Gras^{1

2}

Affiliations

¹ Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute Monash University Clayton VIC Australia.
² Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science La Trobe University Bundoora VIC Australia.

Abstract

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.

Keywords: CD8+ T cell; HLA; Influenza; cross‐reactivity; immune response; immunodominant epitope.