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

Chaurasia, Priyanka, Nguyen, Thi H.O., Rowntree, Louise C., Juno, Jennifer A., Wheatley, Adam K., Kent, Stephen J., Kedzierska, Katherine, Rossjohn, Jamie and Petersen, Jan 2021. Structural basis of biased T cell receptor recognition of an immunodominant HLA-A2 epitope of the SARS-CoV-2 spike protein. Journal of Biological Chemistry 297 (3) , 101065. 10.1016/j.jbc.2021.101065

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: his is an open access article under the CCBY-NC-ND license (
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Date of First Compliant Deposit: 23 November 2021
Date of Acceptance: 2 August 2021
Last Modified: 23 Nov 2021 14:15

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