Identification of a unique TCR repertoire, consistent with a superantigen selection process in Children with Multi-system Inflammatory Syndrome

  1. Rebecca A Porritt
  2. Lisa Paschold
  3. Magali Noval Rivas
  4. Mary Hongying Cheng
  5. Lael M Yonker
  6. Harsha Chandnani
  7. Merrick Lopez
  8. Donjete Simnica
  9. Christoph Schultheiß
  10. Chintda Santiskulvong
  11. Jennifer Van Eyk
  12. Alessio Fasano
  13. Ivet Bahar
  14. Mascha Binder
  15. Moshe Arditi

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Abstract

Multisystem Inflammatory Syndrome in Children (MIS-C), a hyperinflammatory syndrome associated with SARS-CoV-2 infection, shares many clinical features with toxic shock syndrome, which is triggered by bacterial superantigens. The superantigen specificity for binding different Vβ-chains results in Vβ-skewing, whereby T cells with specific Vβ-chains and diverse antigen specificity are overrepresented in the TCR repertoire. Here, we characterized the TCR repertoire of MIS-C patients and found a profound expansion of TCR Beta Variable gene (TRBV)11-2. Furthermore, TRBV11-2 skewing was remarkably correlated with MIS-C severity and serum cytokine levels. Further analysis of TRBJ gene usage and CDR3 length distribution of MIS-C expanding TRBV11-2 clones revealed extensive junctional diversity, indicating a superantigen-mediated selection process for TRBV expansion. In silico modelling indicates that polyacidic residues in TCR Vβ11-2 engage in strong interactions with the superantigen-like motif of SARS-CoV-2 spike glycoprotein. Overall, our data indicate that the immune response in MIS-C is consistent with superantigenic activation.

Highlights

  • Multisystem Inflammatory Disease in Children (MIS-C) patients exhibit T cell receptor (TCR) repertoire skewing, with expansion of T cell Receptor Beta Variable gene (TRBV)11-2

  • TRBV11-2 skewing correlates with MIS-C severity and cytokine storm

  • J gene/CDR3 diversity in MIS-C patients is compatible with a superantigen selection process

  • In silico modelling indicates TCR Vβ11-2 engages in CDR3-independent interactions with the polybasic insert P 681 RRAR in the SAg-like motif of SARS-CoV-2 spike

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    SciScore for 10.1101/2020.11.09.372169: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: Cedars Sinai Medical Center (Los Angeles), Loma Linda University Hospital (Loma Linda) and Martin-Luther-University Halle-Wittenberg, (Halle, Saale; Germany) under Ethics committee approval and informed consent.
    Consent: Cedars Sinai Medical Center (Los Angeles), Loma Linda University Hospital (Loma Linda) and Martin-Luther-University Halle-Wittenberg, (Halle, Saale; Germany) under Ethics committee approval and informed consent.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Bubble diagrams, which depict the clonal distribution of repertoires, were generated using packages packcircles (Bedward et al., 2018) and ggplot2 (Wickham, 2016).
    ggplot2
    suggested: (ggplot2, RRID:SCR_014601)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    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: We did not find any issues relating to colormaps.

    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.

    About SciScore

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  2. Version published to 10.1101/2020.11.09.372169v1 on bioRxiv