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

  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

  • Curated by eLife

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    eLife assessment

    This is a very elegant study which clearly demonstrates the existence of CMV specific memory T cells in CMV+ pre-pandemic individuals that are capable of recognising epitopes from SARS-CoV-2. It provides new insights into the development of cross-reactive immune cells that was not anticipated. The study has been elegantly performed and presents important findings. In particular, the discovery of a public TCR which mediates the crossreactivity described is an important finding.

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Abstract

Detection of severe acute respiratory syndrome 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 relatively high frequency and prevalence of cross-reactive T cells, we hypothesized cytomegalovirus (CMV) may induce these cross-reactive T cells. Stimulation of pre-pandemic cryo-preserved peripheral blood mononuclear cells (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.

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  1. Version published to 10.7554/elife.82050 on eLife
  2. Version published to 10.1101/2022.07.31.502203v2 on bioRxiv
  3. eLife

    eLife assessment

    This is a very elegant study which clearly demonstrates the existence of CMV specific memory T cells in CMV+ pre-pandemic individuals that are capable of recognising epitopes from SARS-CoV-2. It provides new insights into the development of cross-reactive immune cells that was not anticipated. The study has been elegantly performed and presents important findings. In particular, the discovery of a public TCR which mediates the crossreactivity described is an important finding.

  4. eLife

    Reviewer #1 (Public Review):

    This is a very interesting study examining the possibility that high incidence of SARS-CoV2 reactive T cells in apparently COVID 19 naive individuals. While it has been assumed that these emerge as a consequence of cross-reactivity with other coronavirus, this study investigates an alternate possibility, that they may arise through cross-reactivity with unrelated viruses. The authors demonstrate that cross-reactivity between the two viruses is dictated by shared public TCR. This is broadly of interest to the field in understanding how T cell populations emerge in the context of different viral infections.

  5. eLife

    Reviewer #2 (Public Review):

    The authors hypothesized that T-cells capable of recognizing SARS-CoV-2 specific antigens might be present within the pre-existing CMV specific T cell memory pool in CMV+ individuals. In order to test this hypothesis, the authors used a collection of pre-pandemic samples from CMV+ and CMV- donors. Using the approach described in the manuscript, the authors were able to demonstrate the existence of CMV specific T cells capable of crossreacting with SARS-CoV-2 antigens. In addition they were able to show that this crossreactivity can be mediated by a public TCR. The findings warrant additional studies in larger cohorts of acutely infected individuals. This important finding expands our knowledge of T-cell crossreactivity and heterologous immunity. In addition, this study provides useful information regarding the origin of T-cells that crossreact with SARS-CoV-2.

  6. eLife

    Reviewer #3 (Public Review):

    Authors identified that HCMV specific T cells cross-react to SARS-CoV-2 epitopes. These cross-reactive CD4+ and CD8+ cells were identified in pre-pandemic healthy donors by stimulating with SARS-CoV-2 and HCMV protein peptide pools. The manuscript convincingly showed that HCMV specific T cells cross-react to SARS-CoV-2 peptides, which explains the detection of SARS-CoV-2 specific T cells in pre-pandemic PBMC samples. This highlights that T cells primed by highly prevalent pathogens, in addition to highly similar coronaviruses, are a potential source of cross-reactive T cells. Although these T cells showed relatively low affinity to SARS-CoV-2 epitopes, they showed potential to control SARS-CoV-2 replication in vitro. The detection of these T cells was limited to a small cohort of individuals with severe SARS-CoV-2. These initial observations from this study support the claim that cross-reactive T cells recognize the coronavirus epitopes, but detection in severe COVID-19 cohorts might point to the limited role of these cells in control of the SARS-CoV-2 infection, especially in the light of previous studies that report HCMV positivity as a potential risk factor for severe COVID-19 disease. Future studies should focus on explaining if other high prevalence virus, such as EBV or Influenza, specific T cell responses can also cross-react with SARS-CoV-2.

  7. Version published to 10.1101/2022.07.31.502203v1 on bioRxiv