Molecular Basis of a Dominant SARS-CoV-2 Spike-Derived Epitope Presented by HLA-A*02:01 Recognised by a Public TCR

  1. Christopher Szeto
  2. Andrea T. Nguyen
  3. Christian A. Lobos
  4. Demetra S. M. Chatzileontiadou
  5. Dhilshan Jayasinghe
  6. Emma J. Grant
  7. Alan Riboldi-Tunnicliffe
  8. Corey Smith
  9. Stephanie Gras

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Abstract

The data currently available on how the immune system recognises the SARS-CoV-2 virus is growing rapidly. While there are structures of some SARS-CoV-2 proteins in complex with antibodies, which helps us understand how the immune system is able to recognise this new virus; however, we lack data on how T cells are able to recognise this virus. T cells, especially the cytotoxic CD8+ T cells, are critical for viral recognition and clearance. Here we report the X-ray crystallography structure of a T cell receptor, shared among unrelated individuals (public TCR) in complex with a dominant spike-derived CD8+ T cell epitope (YLQ peptide). We show that YLQ activates a polyfunctional CD8+ T cell response in COVID-19 recovered patients. We detail the molecular basis for the shared TCR gene usage observed in HLA-A*02:01+ individuals, providing an understanding of TCR recognition towards a SARS-CoV-2 epitope. Interestingly, the YLQ peptide conformation did not change upon TCR binding, facilitating the high-affinity interaction observed.

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  1. Version published to 10.3390/cells10102646
  2. ScreenIT

    SciScore for 10.1101/2021.08.15.456333: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line AuthenticationAuthentication: The final models have been validated and deposited using the wwPDB OneDep System and the final refinement statistics, PDB codes are summarized in Table 3.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Sequence alignment: The full spike proteins from the five different coronaviruses were aligned using the online alignment software Rhône-Alpes Bioinformatics Center (PRABI http://www.prabi.fr/) multiple sequence alignment CLUSTALW (29).
    PRABI
    suggested: (PRABI, RRID:SCR_010522)
    CLUSTALW
    suggested: (ClustalW, RRID:SCR_017277)
    Briefly, CD8+ T cell lines were stimulated with cognate peptide pools or 10µM individual peptides (Genscript) and incubated for 5 hours in the presence of GolgiPlug (BD Biosciences), GolgiStop (BD Biosciences) and anti-CD107a-AF488 (BD Biosciences/eBioscience).
    BD Biosciences
    suggested: (BD Biosciences, RRID:SCR_013311)
    BD Biosciences/eBioscience
    suggested: None
    Cells were acquired on a BD LSRFortessa with FACSDiva software.
    FACSDiva
    suggested: (BD FACSDiva Software, RRID:SCR_001456)
    Analysis was performed using FlowJo software where cytokine levels identified in the R0 control condition were subtracted from corresponding test conditions.
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    Manual model building was conducted using COOT (37) followed by refinement with BUSTER (38).
    COOT
    suggested: (Coot, RRID:SCR_014222)
    BUSTER
    suggested: (BUSTER, RRID:SCR_015653)
    All molecular graphics representations were created using PyMOL (Schrodinger, LLC, v1.7.6.3)
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)
    Fluorescence intensity data was normalised and plotted using GraphPad Prism 9 (version 9.0.0).
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Kinetics data was analysed using the T200 BiaE-valuation software, whilst steady state values were extracted using T200 BiaEvaluation software, plotted and fitted into a one-site specific binding non-linear regression using Graphpad Prism (version 9.0).
    BiaEvaluation
    suggested: (BIAevaluation Software, RRID:SCR_015936)
    Graphpad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 4. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  3. Version published to 10.1101/2021.08.15.456333v1 on bioRxiv