SARS-CoV-2-specific CD4+ and CD8+ T cell responses can originate from cross-reactive CMV-specific T cells

Abstract

Detection of SARS-coronavirus-2 (SARS-CoV-2) specific CD4+ and CD8+ T cells in SARS-CoV-2-unexposed donors has been explained by the presence of T cells primed by other coronaviruses. However, based on the relative high frequency and prevalence of cross-reactive T cells, we hypothesized CMV may induce these cross-reactive T cells. Stimulation of pre-pandemic cryo-preserved PBMCs with SARS-CoV-2 peptides revealed that frequencies of SARS-CoV-2-specific T cells were higher in CMV-seropositive donors. Characterization of these T cells demonstrated that membrane-specific CD4+ and spike-specific CD8+ T cells originate from cross-reactive CMV-specific T cells. Spike-specific CD8+ T cells recognize SARS-CoV-2 spike peptide FVSNGTHWF (FVS) and dissimilar CMV pp65 peptide IPSINVHHY (IPS) presented by HLA-B*35:01. These dual IPS/FVS-reactive CD8+ T cells were found in multiple donors as well as severe COVID-19 patients and shared a common T cell receptor (TCR), illustrating that IPS/FVS-cross-reactivity is caused by a public TCR. In conclusion, CMV-specific T cells cross-react with SARS-CoV-2, despite low sequence homology between the two viruses, and may contribute to the pre-existing immunity against SARS-CoV-2.

Data availability

Figure 1 - Source data 1 contains percentages underlying figure 1C-F. Figure 4 - Source data 1 contains the sequence data used to generate figures and the data have been deposited in SRA (NCBI) database under BioProjectID PRJNA891934.

The following data sets were generated

Article and author information

Author details

  1. Cilia R Pothast

    Department of Hematology, Leiden University Medical Center, Leiden, Netherlands
    For correspondence
    c.r.pothast@lumc.nl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9761-3123
  2. Romy C Dijkland

    Department of Hematology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  3. Melissa Thaler

    Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5590-4918
  4. Renate S Hagedoorn

    Department of Hematology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  5. Michel GD Kester

    Department of Hematology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  6. Anne K Wouters

    Department of Hematology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  7. Pieter S Hiemstra

    Department of Pulmonology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  8. Martijn J van Hemert

    Department of Medical Microbiology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  9. Stephanie Gras

    Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  10. JH Frederik Falkenburg

    Department of Hematology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  11. Mirjam HM Heemskerk

    Department of Hematology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    The authors declare that no competing interests exist.

Funding

Health~Holland (LSHM19088)

  • Mirjam HM Heemskerk

National Health and Medical Research Council (1159272)

  • Stephanie Gras

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Bio-banked PBMCs were cryopreserved after informed consent from the respective donors, in accordance with the declaration of Helsinki. The samples from COVID-19 patients were part of a trial (NL8589) registered in the Dutch Trial Registry and approved by Medical Ethical Committee Leiden-Den Haag-Delft (NL73740.058.20).

Reviewing Editor

  1. Gabrielle T Belz, University of Queensland, Australia

Publication history

  1. Received: July 21, 2022
  2. Accepted: November 13, 2022
  3. Accepted Manuscript published: November 21, 2022 (version 1)

Copyright

© 2022, Pothast et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Cilia R Pothast
  2. Romy C Dijkland
  3. Melissa Thaler
  4. Renate S Hagedoorn
  5. Michel GD Kester
  6. Anne K Wouters
  7. Pieter S Hiemstra
  8. Martijn J van Hemert
  9. Stephanie Gras
  10. JH Frederik Falkenburg
  11. Mirjam HM Heemskerk
(2022)
SARS-CoV-2-specific CD4+ and CD8+ T cell responses can originate from cross-reactive CMV-specific T cells
eLife 11:e82050.
https://doi.org/10.7554/eLife.82050
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