Sequence and Structural Analyses Reveal Distinct and Highly Diverse Human CD8 + TCR Repertoires to Immunodominant Viral Antigens

Cell Rep. 2017 Apr 18;19(3):569-583. doi: 10.1016/j.celrep.2017.03.072.

Abstract

A diverse T cell receptor (TCR) repertoire is essential for controlling viral infections. However, information about TCR repertoires to defined viral antigens is limited. We performed a comprehensive analysis of CD8+ TCR repertoires for two dominant viral epitopes: pp65495-503 (NLV) of cytomegalovirus and M158-66 (GIL) of influenza A virus. The highly individualized repertoires (87-5,533 α or β clonotypes per subject) comprised thousands of unique TCRα and TCRβ sequences and dozens of distinct complementary determining region (CDR)3α and CDR3β motifs. However, diversity is effectively restricted by preferential V-J combinations, CDR3 lengths, and CDR3α/CDR3β pairings. Structures of two GIL-specific TCRs bound to GIL-HLA-A2 provided a potential explanation for the lower diversity of GIL-specific versus NLV-specific repertoires. These anti-viral TCRs occupied up to 3.4% of the CD8+ TCRβ repertoire, ensuring broad T cell responses to single epitopes. Our portrait of two anti-viral TCR repertoires may inform the development of predictors of immune protection.

Keywords: CD8 T cells; TCR repertoire; TCR-pMHC structure; human; αβ TCRs for CMV-NLV; αβ TCRs for IAV-GIL.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Antibody Affinity / immunology
  • Antigens, Viral / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Clone Cells
  • Complementarity Determining Regions / immunology
  • Consensus Sequence
  • Cytomegalovirus / immunology
  • HLA-A2 Antigen / immunology
  • Humans
  • Immunodominant Epitopes / immunology*
  • Influenza A virus / immunology
  • Peptides / chemistry
  • Peptides / metabolism
  • Protein Binding
  • Receptors, Antigen, T-Cell / chemistry*
  • Receptors, Antigen, T-Cell / immunology*
  • Species Specificity

Substances

  • Antigens, Viral
  • Complementarity Determining Regions
  • HLA-A2 Antigen
  • Immunodominant Epitopes
  • Peptides
  • Receptors, Antigen, T-Cell