Structural basis of biased T cell receptor recognition of an immunodominant HLA-A2 epitope of the SARS-CoV-2 spike protein

J Biol Chem. 2021 Sep;297(3):101065. doi: 10.1016/j.jbc.2021.101065. Epub 2021 Aug 10.


CD8+ T cells play an important role in vaccination and immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although numerous SARS-CoV-2 CD8+ T cell epitopes have been identified, the molecular basis underpinning T cell receptor (TCR) recognition of SARS-CoV-2-specific T cells remains unknown. The T cell response directed toward SARS-CoV-2 spike protein-derived S269-277 peptide presented by the human leukocyte antigen (HLA)-A∗02:01 allomorph (hereafter the HLA-A2S269-277 epitope) is, to date, the most immunodominant SARS-CoV-2 epitope found in individuals bearing this allele. As HLA-A2S269-277-specific CD8+ T cells utilize biased TRAV12 gene usage within the TCR α-chain, we sought to understand the molecular basis underpinning this TRAV12 dominance. We expressed four TRAV12+ TCRs which bound the HLA-A2S269-277 complex with low micromolar affinity and determined the crystal structure of the HLA-A2S269-277 binary complex, and subsequently a ternary structure of the TRAV12+ TCR complexed to HLA-A2S269-277. We found that the TCR made extensive contacts along the entire length of the S269-277 peptide, suggesting that the TRAV12+ TCRs would be sensitive to sequence variation within this epitope. To examine this, we investigated cross-reactivity toward analogous peptides from existing SARS-CoV-2 variants and closely related coronaviruses. We show via surface plasmon resonance and tetramer studies that the TRAV12+ T cell repertoire cross-reacts poorly with these analogous epitopes. Overall, we defined the structural basis underpinning biased TCR recognition of CD8+ T cells directed at an immunodominant epitope and provide a framework for understanding TCR cross-reactivity toward viral variants within the S269-277 peptide.

Keywords: COVID-19; HLA-A2; SARS-CoV-2; T cell receptor recognition; spike protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Epitopes, T-Lymphocyte / chemistry*
  • HLA-A2 Antigen / metabolism*
  • Humans
  • Immunodominant Epitopes / metabolism*
  • Protein Conformation
  • Receptors, Antigen, T-Cell / chemistry
  • Receptors, Antigen, T-Cell / metabolism*
  • Spike Glycoprotein, Coronavirus / metabolism*


  • Epitopes, T-Lymphocyte
  • HLA-A2 Antigen
  • Immunodominant Epitopes
  • Receptors, Antigen, T-Cell
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2