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Science immunology
03 04, 2021;6 (57):

SARS-CoV-2 mutations in MHC-I-restricted epitopes evade CD8 T cell responses.

Benedikt Agerer, Maximilian Koblischke, Venugopal Gudipati, Luis Fernando Montaño-Gutierrez, Mark Smyth, Alexandra Popa, Jakob-Wendelin Genger, Lukas Endler, David M Florian, Vanessa Mühlgrabner, Marianne Graninger, Stephan W Aberle, Anna-Maria Husa, Lisa Ellen Shaw, Alexander Lercher, Pia Gattinger, Ricard Torralba-Gombau, Doris Trapin, Thomas Penz, Daniele Barreca, Ingrid Fae, Sabine Wenda, Marianna Traugott, Gernot Walder, Winfried F Pickl, Volker Thiel, Franz Allerberger, Hannes Stockinger, Elisabeth Puchhammer-Stöckl, Wolfgang Weninger, Gottfried Fischer, Wolfgang Hoepler, Erich Pawelka, Alexander Zoufaly, Rudolf Valenta, Christoph Bock, Wolfgang Paster, René Geyeregger, Matthias Farlik, Florian Halbritter, Johannes B Huppa, Judith H Aberle, Andreas Bergthaler
Author Information
  1. Benedikt Agerer: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. ORCID
  2. Maximilian Koblischke: Center for Virology, Medical University of Vienna, Vienna, Austria. ORCID
  3. Venugopal Gudipati: Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria. ORCID
  4. Luis Fernando Montaño-Gutierrez: St. Anna Children´s Cancer Research Institute (CCRI), Vienna, Austria. ORCID
  5. Mark Smyth: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. ORCID
  6. Alexandra Popa: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. ORCID
  7. Jakob-Wendelin Genger: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. ORCID
  8. Lukas Endler: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. ORCID
  9. David M Florian: Center for Virology, Medical University of Vienna, Vienna, Austria.
  10. Vanessa Mühlgrabner: Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
  11. Marianne Graninger: Center for Virology, Medical University of Vienna, Vienna, Austria.
  12. Stephan W Aberle: Center for Virology, Medical University of Vienna, Vienna, Austria.
  13. Anna-Maria Husa: St. Anna Children´s Cancer Research Institute (CCRI), Vienna, Austria. ORCID
  14. Lisa Ellen Shaw: Department of Dermatology, Medical University of Vienna, Vienna, Austria. ORCID
  15. Alexander Lercher: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. ORCID
  16. Pia Gattinger: Department of Pathophysiology and Allergy Research, Division of Immunopathology, Medical University of Vienna, Vienna, Austria. ORCID
  17. Ricard Torralba-Gombau: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. ORCID
  18. Doris Trapin: Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
  19. Thomas Penz: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  20. Daniele Barreca: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. ORCID
  21. Ingrid Fae: Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria. ORCID
  22. Sabine Wenda: Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria. ORCID
  23. Marianna Traugott: Department of Medicine 4, Clinic Favoriten, Vienna, Austria. ORCID
  24. Gernot Walder: Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
  25. Winfried F Pickl: Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
  26. Volker Thiel: Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland.
  27. Franz Allerberger: Austrian Agency for Health and Food Safety (AGES), Vienna, Austria. ORCID
  28. Hannes Stockinger: Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria. ORCID
  29. Elisabeth Puchhammer-Stöckl: Center for Virology, Medical University of Vienna, Vienna, Austria.
  30. Wolfgang Weninger: Department of Dermatology, Medical University of Vienna, Vienna, Austria.
  31. Gottfried Fischer: Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria. ORCID
  32. Wolfgang Hoepler: Department of Medicine 4, Clinic Favoriten, Vienna, Austria. ORCID
  33. Erich Pawelka: Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria. ORCID
  34. Alexander Zoufaly: Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria.
  35. Rudolf Valenta: Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
  36. Christoph Bock: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. ORCID
  37. Wolfgang Paster: St. Anna Children´s Cancer Research Institute (CCRI), Vienna, Austria. ORCID
  38. René Geyeregger: St. Anna Children´s Cancer Research Institute (CCRI), Vienna, Austria. ORCID
  39. Matthias Farlik: Department of Dermatology, Medical University of Vienna, Vienna, Austria. ORCID
  40. Florian Halbritter: St. Anna Children´s Cancer Research Institute (CCRI), Vienna, Austria. ORCID
  41. Johannes B Huppa: Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria. ORCID
  42. Judith H Aberle: Center for Virology, Medical University of Vienna, Vienna, Austria.
  43. Andreas Bergthaler: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. abergthaler@cemm.oeaw.ac.at. ORCID
PMID: 33664060 DOI: 10.1126/sciimmunol.abg6461

Abstract

CD8 T cell immunity to SARS-CoV-2 has been implicated in COVID-19 severity and virus control. Here, we identified nonsynonymous mutations in MHC-I-restricted CD8 T cell epitopes after deep sequencing of 747 SARS-CoV-2 virus isolates. Mutant peptides exhibited diminished or abrogated MHC-I binding in a cell-free in vitro assay. Reduced MHC-I binding of mutant peptides was associated with decreased proliferation, IFN-γ production and cytotoxic activity of CD8 T cells isolated from HLA-matched COVID-19 patients. Single cell RNA sequencing of ex vivo expanded, tetramer-sorted CD8 T cells from COVID-19 patients further revealed qualitative differences in the transcriptional response to mutant peptides. Our findings highlight the capacity of SARS-CoV-2 to subvert CD8 T cell surveillance through point mutations in MHC-I-restricted viral epitopes.

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Grants

  1. 679146/European Research Council

MeSH Term

CD8-Positive T-Lymphocytes
COVID-19
Cell Proliferation
Epitopes, T-Lymphocyte
HLA-A Antigens
High-Throughput Nucleotide Sequencing
Humans
Immunity, Cellular
Interferon-gamma
Mutation
Peptides
SARS-CoV-2

Chemicals

Epitopes, T-Lymphocyte
HLA-A Antigens
IFNG protein, human
Peptides
Interferon-gamma
Journal Article Research Support, Non-U.S. Gov't

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