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

Content Provider	Europe PMC
Author	Chaurasia, Priyanka Nguyen, Thi H.O. Rowntree, Louise C. Juno, Jennifer A. Wheatley, Adam K. Kent, Stephen J. Kedzierska, Katherine Rossjohn, Jamie Petersen, Jan
Copyright Year	2021
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.
ISSN	00219258
Volume Number	297
PubMed Central reference number	PMC8352664
Issue Number	3
PubMed reference number	34384783
Journal	The Journal of Biological Chemistry [J. Biol. Chem]
e-ISSN	1083351X
DOI	10.1016/j.jbc.2021.101065
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2021-08-10
Access Restriction	Open
Rights License	This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). © 2021 The Authors
Subject Keyword	COVID-19 SARS-CoV-2 HLA-A2 T cell receptor recognition spike protein BSA, buried surface area HLA, human leukocyte antigen PBMCs, peripheral blood monocular cells pHLA, peptide-HLA SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 SPR, surface plasmon resonance TCR, T cell receptor VDW, van der Waals
Content Type	Text
Resource Type	Article
Subject	Cell Biology Molecular Biology Biochemistry