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

• Published in: Nature communications Vol. 9; no. 1; pp. 5427 - 16
• Main Authors: Grant, Emma J., Josephs, Tracy M., Loh, Liyen, Clemens, E. Bridie, Sant, Sneha, Bharadwaj, Mandvi, Chen, Weisan, Rossjohn, Jamie, Gras, Stephanie, Kedzierska, Katherine
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.12.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/31; 631/1647/2258/1266; 631/250/2152/1566/1571; 631/250/2520; 631/250/255/1578; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Conformation; Cross-reactivity; Epitopes; Histocompatibility antigen HLA; HLA-A1 Antigen - immunology; HLA-B37 Antigen - immunology; Humanities and Social Sciences; Humans; Immunity; Immunogenicity; Influenza; Influenza A; Influenza A virus - immunology; Lymphocytes; Lymphocytes B; Lymphocytes T; multidisciplinary; Mutation; Peptides; Recognition; Science; Science (multidisciplinary); Strain analysis; Strains (organisms); T cell receptors; Vaccines; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-07815-5

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 NP 338-346 (B37-NP 338 ) and HLA-A*01:01-restricted NP 44-52 (A1-NP 44 ). 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-NP 338 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. Mutations within immunological epitope containing regions of influenza A virus can impair the established immune response between influenza strains and could impact rational vaccine design. Here Grant et al. examine the presence, structural impact and cross reactivity of two human immunodominant influenza epitope variants.