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Publication Abstract from PubMed

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 S(269-277) peptide presented by the human leukocyte antigen (HLA)-A *02:01 allomorph (hereafter the HLA-A2(S269-277) epitope) is, to date, the most immunodominant SARS-CoV-2 epitope found in individuals bearing this allele. As HLA-A2(S269-277)-specific CD8(+) T cells utilize biased TRAV12 gene usage within the TCR alpha-chain, we sought to understand the molecular basis underpinning this TRAV12 dominance. We expressed four TRAV12(+) TCRs which bound the HLA-A2(S269-277) complex with low micromolar affinity and determined the crystal structure of the HLA-A2(S269-277) binary complex, and subsequently a ternary structure of the TRAV12(+) TCR complexed to HLA-A2(S269-277). We found that the TCR made extensive contacts along the entire length of the S(269-277) 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 S(269-277) peptide.

Structural basis of biased T cell receptor recognition of an immunodominant HLA-A2 epitope of the SARS-CoV-2 spike protein.,Chaurasia P, Nguyen THO, Rowntree LC, Juno JA, Wheatley AK, Kent SJ, Kedzierska K, Rossjohn J, Petersen J J Biol Chem. 2021 Sep;297(3):101065. doi: 10.1016/j.jbc.2021.101065. Epub 2021 , Aug 10. PMID:34384783^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.