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 ORCID: https://orcid.org/0000-0002-2020-7522 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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Abstract

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 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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:	11 May 2023 07:48
URI:	https://orca.cardiff.ac.uk/id/eprint/145606

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