Structural basis of biased T cell receptor recognition of an immunodominant HLA-A2 epitope of the SARS-CoV-2 spike protein.
J Biol Chem
; 297(3): 101065, 2021 09.
Article
in English
| MEDLINE | ID: covidwho-1347684
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∗0201 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
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Receptors, Antigen, T-Cell
/
HLA-A2 Antigen
/
Immunodominant Epitopes
/
Epitopes, T-Lymphocyte
/
Spike Glycoprotein, Coronavirus
Type of study:
Randomized controlled trials
Topics:
Vaccines
/
Variants
Limits:
Humans
Language:
English
Journal:
J Biol Chem
Year:
2021
Document Type:
Article
Affiliation country:
J.jbc.2021.101065
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