PMID- 34384783 OWN - NLM STAT- MEDLINE DCOM- 20211013 LR - 20211013 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 297 IP - 3 DP - 2021 Sep TI - Structural basis of biased T cell receptor recognition of an immunodominant HLA-A2 epitope of the SARS-CoV-2 spike protein. PG - 101065 LID - S0021-9258(21)00868-1 [pii] LID - 10.1016/j.jbc.2021.101065 [doi] LID - 101065 AB - 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. CI - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Chaurasia, Priyanka AU - Chaurasia P AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. FAU - Nguyen, Thi H O AU - Nguyen THO AD - Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia. FAU - Rowntree, Louise C AU - Rowntree LC AD - Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia. FAU - Juno, Jennifer A AU - Juno JA AD - Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia. FAU - Wheatley, Adam K AU - Wheatley AK AD - Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, University of Melbourne, Melbourne, Victoria, Australia. FAU - Kent, Stephen J AU - Kent SJ AD - Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, University of Melbourne, Melbourne, Victoria, Australia. FAU - Kedzierska, Katherine AU - Kedzierska K AD - Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia. Electronic address: kkedz@unimelb.edu.au. FAU - Rossjohn, Jamie AU - Rossjohn J AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia; Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia; Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom. Electronic address: Jamie.rossjohn@monash.edu. FAU - Petersen, Jan AU - Petersen J AD - Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia; Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia. Electronic address: jan.petersen@monash.edu. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210810 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (HLA-A2 Antigen) RN - 0 (Immunodominant Epitopes) RN - 0 (Receptors, Antigen, T-Cell) RN - 0 (Spike Glycoprotein, Coronavirus) RN - 0 (spike protein, SARS-CoV-2) SB - IM MH - Epitopes, T-Lymphocyte/*chemistry MH - HLA-A2 Antigen/*metabolism MH - Humans MH - Immunodominant Epitopes/*metabolism MH - Protein Conformation MH - Receptors, Antigen, T-Cell/chemistry/*metabolism MH - Spike Glycoprotein, Coronavirus/*metabolism PMC - PMC8352664 OTO - NOTNLM OT - COVID-19 OT - HLA-A2 OT - SARS-CoV-2 OT - T cell receptor recognition OT - spike protein COIS- Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. EDAT- 2021/08/14 06:00 MHDA- 2021/10/14 06:00 PMCR- 2021/08/10 CRDT- 2021/08/13 05:55 PHST- 2021/06/10 00:00 [received] PHST- 2021/08/02 00:00 [revised] PHST- 2021/08/06 00:00 [accepted] PHST- 2021/08/14 06:00 [pubmed] PHST- 2021/10/14 06:00 [medline] PHST- 2021/08/13 05:55 [entrez] PHST- 2021/08/10 00:00 [pmc-release] AID - S0021-9258(21)00868-1 [pii] AID - 101065 [pii] AID - 10.1016/j.jbc.2021.101065 [doi] PST - ppublish SO - J Biol Chem. 2021 Sep;297(3):101065. doi: 10.1016/j.jbc.2021.101065. Epub 2021 Aug 10.