T Cells: Ready and waiting to go

Some T cells that have been activated by a herpesvirus can also respond to SARS-CoV-2, even if the original herpesvirus infection happened before the COVID-19 pandemic.
  1. Laura Rivino
  2. Linda Wooldridge  Is a corresponding author
  1. School of Cellular and Molecular Medicine, Faculty of Life Sciences, University of Bristol, United Kingdom
  2. Bristol Veterinary School, Faculty of Health Sciences, University of Bristol, United Kingdom

Cells called T cells play an important role in protecting the body against infection by removing pathogens that may cause harm. Two major types of T cell are involved in the response to a viral infection. Both become activated when their receptors recognize short peptides from viral proteins called ‘epitopes’: CD8 T cells directly attack infected cells, whereas CD4 T cells help other immune cells (called B cells) to produce antibodies. Once the infection has been eliminated, some of these CD8 and CD4 T cells survive in the body as long-lived memory T cells which can immediately respond if the virus invades again.

Previous studies found that some blood samples taken before the COVID-19 pandemic already contained T cells that could recognize the SARS-CoV-2 virus (Grifoni et al., 2020; Le Bert et al., 2020). However, researchers still do not fully understand how these T cells arose, or how they impact immunity and disease outcomes for COVID-19 patients.

One possibility is that these pre-existing T cells arose due to a phenomenon called heterologous immunity (Welsh et al., 2010). This is when CD4 and CD8 T cells activated by a specific pathogen ‘cross-react’ and respond to epitopes from a different virus (Mason, 1998). It was previously thought that coronaviruses already circulating in the population before the pandemic were responsible for the existence of some T cells that could recognise SARS-CoV-2 (Grifoni et al., 2020; Swadling et al., 2022). Now, in eLife, Cilia Pothast (Leiden University Medical Center), Mirjam Heemskerk (also at Leiden) and colleagues report that another group of viruses may have also been involved (Pothast et al., 2022).

The team hypothesised that some of the T cells specific to SARS-CoV-2 had been activated by a herpesvirus called human cytomegalovirus (HCMV). This pathogen is highly prevalent in the population and has also been linked to changes in the severity of COVID-19 symptoms (Alanio et al., 2022). To investigate, they stimulated pre-pandemic blood samples with different segments of SARS-CoV-2 proteins. This led them to discover a population of ‘cross-reactive’ CD4 and CD8 T cells that can recognize epitopes from both SARS-CoV-2 and HCMV (Figure 1).

Infection with human cytomegalovirus (HCMV) can stimulate T cells that can recognise SARS-CoV-2.

When individuals are infected with HCMV (virus shown in pink), the population of T cells that can detect this virus expands (T cells shown here in purple). Cross-reactivity is a well-known feature of the immune response. Through this process, HCMV infection can activate T cells (shown here in green) that can recognise both HCMV and another pathogen – including the SARS-CoV-2 virus, even if the HCMV infection happened before the COVID-19 pandemic. These cross-reactive T cells may be able to contribute to the immunity of an individual to SARS-CoV-2, as well as to how COVID-19 affects their body.

Image credit: Created with BioRender.com.

Pothast et al. found that this cross-reactivity was due to a T cell receptor that is expressed in multiple individuals. However, there are very few similarities between the amino acid sequences of the SARS-CoV-2 and the HCMV epitopes, bringing into question how this T cell receptor can detect both viruses. It may be possible to explain the molecular basis for this observation by solving crystal structures of this T cell receptor in complex with either the presented HCMV or SARS-CoV-2 epitopes.

Further experiments then revealed that the cross-reactive T cells limit the replication of SARS-CoV-2 in vitro when the virus is present at low levels. However, the cross-reactive T cells did not appear to have an activated phenotype in patients with severe COVID-19. This might be because individuals included in this study were over 60 years of age, and HCMV-specific T cells do not work as well as people get older (Ouyang et al., 2004).

It has been suggested that heterologous immunity may play a beneficial role in protective immunity (Welsh et al., 2010). This is consistent with a recent study showing that T cells which cross-react with SARS-CoV-2 are associated with abortive infections (when the virus fails to spread to other cells) and asymptomatic cases of COVID-19 (Swadling et al., 2022). These pre-existing T cells may also enhance a person’s response to vaccines (Loyal et al., 2021). However, heterologous immunity is a double-edged sword, as it can also increase the severity of some viral infections. For example, in dengue infections, cross-reactive antibodies and T cells can result in an immune response that is harmful to the body (Welsh et al., 2010; Screaton et al., 2015).

Further studies are needed to establish whether other pathogens (including bacteria) can stimulate T cells capable of recognising epitopes from SARS-CoV-2. In addition, studies with larger cohorts of vaccinated individuals and patients with mild or severe COVID-19 are required to define the role that these cross-reactive T cells play in protective immunity, in response to vaccination, and in disease pathology.

References

Article and author information

Author details

  1. Laura Rivino

    Laura Rivino is in the School of Cellular and Molecular Medicine, Faculty of Life Sciences, University of Bristol, Bristol, United Kingdom

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6213-9794
  2. Linda Wooldridge

    Linda Wooldridge is in the Bristol Veterinary School, Faculty of Health Sciences, University of Bristol, Bristol, United Kingdom

    For correspondence
    Linda.Wooldridge@bristol.ac.uk
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6213-347X

Publication history

  1. Version of Record published: January 6, 2023 (version 1)

Copyright

© 2023, Rivino and Wooldridge

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

Metrics

  • 417
    Page views
  • 44
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Laura Rivino
  2. Linda Wooldridge
(2023)
T Cells: Ready and waiting to go
eLife 12:e85080.
https://doi.org/10.7554/eLife.85080
  1. Further reading

Further reading

    1. Immunology and Inflammation
    Oksana Tsyklauri, Tereza Chadimova ... Ondrej Stepanek
    Research Article

    Regulatory T cells (Tregs) are indispensable for maintaining self-tolerance by suppressing conventional T cells. On the other hand, Tregs promote tumor growth by inhibiting anti-cancer immunity. In this study, we identified that Tregs increase the quorum of self-reactive CD8+ T cells required for the induction of experimental autoimmune diabetes in mice. Their major suppression mechanism is limiting available IL-2, an essential T-cell cytokine. Specifically, Tregs inhibit the formation of a previously uncharacterized subset of antigen-stimulated KLRK1+ IL7R+ (KILR) CD8+ effector T cells, which are distinct from conventional effector CD8+ T cells. KILR CD8+ T cells show a superior cell killing abilities in vivo. The administration of agonistic IL-2 immunocomplexes phenocopies the absence of Tregs, i.e., it induces KILR CD8+ T cells, promotes autoimmunity, and enhances anti-tumor responses in mice. Counterparts of KILR CD8+ T cells were found in the human blood, revealing them as a potential target for immunotherapy.

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Justin L Roncaioli, Janet Peace Babirye ... Russell E Vance
    Research Advance Updated

    Bacteria of the genus Shigella cause shigellosis, a severe gastrointestinal disease driven by bacterial colonization of colonic intestinal epithelial cells. Vertebrates have evolved programmed cell death pathways that sense invasive enteric pathogens and eliminate their intracellular niche. Previously we reported that genetic removal of one such pathway, the NAIP–NLRC4 inflammasome, is sufficient to convert mice from resistant to susceptible to oral Shigella flexneri challenge (Mitchell et al., 2020). Here, we investigate the protective role of additional cell death pathways during oral mouse Shigella infection. We find that the Caspase-11 inflammasome, which senses Shigella LPS, restricts Shigella colonization of the intestinal epithelium in the absence of NAIP–NLRC4. However, this protection is limited when Shigella expresses OspC3, an effector that antagonizes Caspase-11 activity. TNFα, a cytokine that activates Caspase-8-dependent apoptosis, also provides potent protection from Shigella colonization of the intestinal epithelium when mice lack both NAIP–NLRC4 and Caspase-11. The combined genetic removal of Caspases-1, -11, and -8 renders mice hyper-susceptible to oral Shigella infection. Our findings uncover a layered hierarchy of cell death pathways that limit the ability of an invasive gastrointestinal pathogen to cause disease.