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

Cell Rep. 2020 Jul 14;32(2):107885. 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.

Keywords: CD4 T cells; HLA class II; T cell receptor; X-ray crystallography; biochemistry; clonotyping; immunology; influenza; pHLA mutlimer; peptide epitopes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Birds / virology
  • CD4-Positive T-Lymphocytes / immunology*
  • Complementarity Determining Regions / chemistry
  • Conserved Sequence
  • Epitopes / chemistry
  • Epitopes / immunology*
  • Female
  • Germ Cells / metabolism
  • HLA-DR1 Antigen / immunology
  • Humans
  • Immunodominant Epitopes / chemistry
  • Immunodominant Epitopes / immunology
  • Immunoglobulin Variable Region / genetics*
  • Influenza A virus / immunology*
  • Male
  • Middle Aged
  • Peptides / chemistry
  • Peptides / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Swine / virology
  • Tissue Donors
  • Viral Proteins / immunology
  • Young Adult
  • Zoonoses / immunology
  • Zoonoses / virology


  • Complementarity Determining Regions
  • Epitopes
  • HLA-DR1 Antigen
  • Immunodominant Epitopes
  • Immunoglobulin Variable Region
  • Peptides
  • Receptors, Antigen, T-Cell
  • Viral Proteins