Broad CD8+ T cell cross-recognition of distinct influenza A strains in humans

Emma J. Grant, Tracy M. Josephs, Liyen Loh, E. Bridie Clemens, Sneha Sant, Mandvi Bharadwaj, Weisan Chen, Jamie Rossjohn, Stephanie Gras, Katherine Kedzierska

Research output: Contribution to journalArticleResearchpeer-review

54 Citations (Scopus)

Abstract

Newly-emerged and vaccine-mismatched influenza A viruses (IAVs) result in a rapid global spread of the virus due to minimal antibody-mediated immunity. In that case, established CD8+ T-cells can reduce disease severity. However, as mutations occur sporadically within immunogenic IAV-derived T-cell peptides, understanding of T-cell receptor (TCRαβ) cross-reactivity towards IAV variants is needed for a vaccine design. Here, we investigate TCRαβ cross-strain recognition across IAV variants within two immunodominant human IAV-specific CD8+ T-cell epitopes, HLA-B*37:01-restricted NP338-346 (B37-NP338) and HLA-A*01:01-restricted NP44-52 (A1-NP44). We find high abundance of cross-reactive TCRαβ clonotypes recognizing distinct IAV variants. Structures of the wild-type and variant peptides revealed preserved conformation of the bound peptides. Structures of a cross-reactive TCR-HLA-B37-NP338 complex suggest that the conserved conformation of the variants underpins TCR cross-reactivity. Overall, cross-reactive CD8+ T-cell responses, underpinned by conserved epitope structure, facilitates recognition of distinct IAV variants, thus CD8+ T-cell-targeted vaccines could provide protection across different IAV strains.

Original languageEnglish
Article number5427
Number of pages16
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 21 Dec 2018

Keywords

  • immunological memory
  • influenza virus
  • translational immunology
  • x-ray crystallography
  • ARC Centre of Excellence in Advanced Molecular Imaging

    Whisstock, J. (Primary Chief Investigator (PCI)), Abbey, B. (Chief Investigator (CI)), Nugent, K. A. (Chief Investigator (CI)), Quiney, H. M. (Chief Investigator (CI)), Godfrey, D. I. (Chief Investigator (CI)), Heath, W. (Chief Investigator (CI)), Fairlie, D. P. (Chief Investigator (CI)), Chapman, H. (Partner Investigator (PI)), Peele, A. (Partner Investigator (PI)), Davey, J. (Partner Investigator (PI)) & Wittmann, A. (Project Manager)

    30/06/1431/03/21

    Project: Research

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