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 () and Katherine Kedzierska ()
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Emma J. Grant: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Tracy M. Josephs: Biomedicine Discovery Institute, Monash University
Liyen Loh: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
E. Bridie Clemens: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Sneha Sant: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Mandvi Bharadwaj: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Weisan Chen: La Trobe University
Jamie Rossjohn: Biomedicine Discovery Institute, Monash University
Stephanie Gras: Biomedicine Discovery Institute, Monash University
Katherine Kedzierska: The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07815-5

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