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

View ORCID ProfileRebecca A Porritt, Lisa Paschold, View ORCID ProfileMagali Noval Rivas, View ORCID ProfileMary Hongying Cheng, Lael M Yonker, Harsha Chandnani, Merrick Lopez, Donjete Simnica, Christoph Schultheiß, Chintda Santiskulvong, View ORCID ProfileJennifer Van Eyk, View ORCID ProfileAlessio Fasano, View ORCID ProfileIvet Bahar, View ORCID ProfileMascha Binder, View ORCID ProfileMoshe Arditi
doi: https://doi.org/10.1101/2020.11.09.372169
Rebecca A Porritt
1Departments of Pediatrics, Division of Infectious Diseases and Immunology, Infectious and Immunologic Diseases Research Center (IIDRC) and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Lisa Paschold
3Department of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany
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Magali Noval Rivas
1Departments of Pediatrics, Division of Infectious Diseases and Immunology, Infectious and Immunologic Diseases Research Center (IIDRC) and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
4Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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Mary Hongying Cheng
5Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
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Lael M Yonker
6Mucosal Immunology and Biology Research Center and Department of Pediatrics, Boston, Massachusetts General Hospital, MA, USA
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Harsha Chandnani
7Department of Pediatrics, Loma Linda University Hospital, CA, USA
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Merrick Lopez
7Department of Pediatrics, Loma Linda University Hospital, CA, USA
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Donjete Simnica
3Department of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany
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Christoph Schultheiß
3Department of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany
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Chintda Santiskulvong
8Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Jennifer Van Eyk
9Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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  • ORCID record for Jennifer Van Eyk
Alessio Fasano
6Mucosal Immunology and Biology Research Center and Department of Pediatrics, Boston, Massachusetts General Hospital, MA, USA
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Ivet Bahar
5Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
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Mascha Binder
3Department of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), Germany
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Moshe Arditi
1Departments of Pediatrics, Division of Infectious Diseases and Immunology, Infectious and Immunologic Diseases Research Center (IIDRC) and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
4Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
9Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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  • For correspondence: moshe.arditi@cshs.org
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Summary

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 P681RRAR in the SAg-like motif of SARS-CoV-2 spike

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Identification of a unique TCR repertoire, consistent with a superantigen selection process in Children with Multi-system Inflammatory Syndrome
Rebecca A Porritt, Lisa Paschold, Magali Noval Rivas, Mary Hongying Cheng, Lael M Yonker, Harsha Chandnani, Merrick Lopez, Donjete Simnica, Christoph Schultheiß, Chintda Santiskulvong, Jennifer Van Eyk, Alessio Fasano, Ivet Bahar, Mascha Binder, Moshe Arditi
bioRxiv 2020.11.09.372169; doi: https://doi.org/10.1101/2020.11.09.372169
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Identification of a unique TCR repertoire, consistent with a superantigen selection process in Children with Multi-system Inflammatory Syndrome
Rebecca A Porritt, Lisa Paschold, Magali Noval Rivas, Mary Hongying Cheng, Lael M Yonker, Harsha Chandnani, Merrick Lopez, Donjete Simnica, Christoph Schultheiß, Chintda Santiskulvong, Jennifer Van Eyk, Alessio Fasano, Ivet Bahar, Mascha Binder, Moshe Arditi
bioRxiv 2020.11.09.372169; doi: https://doi.org/10.1101/2020.11.09.372169

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