CD4+ T Cells Recognize Conserved Influenza A Epitopes through Shared Patterns of V-Gene Usage and Complementary Biochemical Features

• Published in: Cell reports (Cambridge) Vol. 32; no. 2; p. 107885
• Main Authors: Greenshields-Watson, Alexander, Attaf, Meriem, MacLachlan, Bruce J., Whalley, Thomas, Rius, Cristina, Wall, Aaron, Lloyd, Angharad, Hughes, Hywel, Strange, Kathryn E., Mason, Georgina H., Schauenburg, Andrea J., Hulin-Curtis, Sarah L., Geary, James, Chen, Yuan, Lauder, Sarah N., Smart, Kathryn, Vijaykrishna, Dhanasekaran, Grau, Miguel L., Shugay, Mikhail, Andrews, Robert, Dolton, Garry, Rizkallah, Pierre J., Gallimore, Awen M., Sewell, Andrew K., Godkin, Andrew J., Cole, David K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.07.2020; Cell Press; Elsevier
• Subjects: Adult; Amino Acid Motifs; Amino Acid Sequence; Animals; biochemistry; Birds - virology; CD4 T cells; CD4-Positive T-Lymphocytes - immunology; clonotyping; Complementarity Determining Regions - chemistry; Conserved Sequence; Epitopes - chemistry; Epitopes - immunology; Female; Germ Cells - metabolism; HLA class II; HLA-DR1 Antigen - immunology; Humans; Immunodominant Epitopes - chemistry; Immunodominant Epitopes - immunology; Immunoglobulin Variable Region - genetics; immunology; influenza; Influenza A virus - immunology; Male; Middle Aged; peptide epitopes; Peptides - chemistry; Peptides - immunology; pHLA mutlimer; Receptors, Antigen, T-Cell - metabolism; Swine - virology; T cell receptor; Tissue Donors; Viral Proteins - immunology; X-ray crystallography; Young Adult; Zoonoses - immunology; Zoonoses - virology; influenza; X-ray crystallography; peptide epitopes; T cell receptor; clonotyping; pHLA mutlimer; biochemistry; HLA class II; CD4 T cells; immunology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.107885

T cell recognition of peptides presented by human leukocyte antigens (HLAs) is mediated by the highly variable T cell receptor (TCR). Despite this built-in TCR variability, individuals can mount immune responses against viral epitopes by using identical or highly related TCRs expressed on CD8+ T cells. Characterization of these TCRs has extended our understanding of the molecular mechanisms that govern the recognition of peptide-HLA. However, few examples exist for CD4+ T cells. Here, we investigate CD4+ T cell responses to the internal proteins of the influenza A virus that correlate with protective immunity. We identify five internal epitopes that are commonly recognized by CD4+ T cells in five HLA-DR1+ subjects and show conservation across viral strains and zoonotic reservoirs. TCR repertoire analysis demonstrates several shared gene usage biases underpinned by complementary biochemical features evident in a structural comparison. These epitopes are attractive targets for vaccination and other T cell therapies. [Display omitted] •Conserved influenza epitopes are recognized in multiple HLA-DR1+ donors•Shared TRAV-gene usage underpins epitope-specific responses in vitro•Structural analysis identifies biochemical features associated with V-gene selection•CDR3 motifs and enrichments are evident in several shared “public” CDR3 sequences CD4+ T cells orchestrate protection from severe influenza. However, knowledge of epitopes and the molecular patterns associated with recognition across the population is lacking. Greenshields-Watson et al. identify several influenza epitopes from internal proteins and use them to explore the biochemical features that underpin CD4+ T cell responses to influenza.