1. Immunology and Inflammation
Download icon

Cytomegalovirus restricts ICOSL expression on antigen presenting cells disabling T cell co-stimulation and contributing to immune evasion

  1. Guillem Angulo
  2. Jelena Zeleznjak
  3. Pablo Martínez-Vicente
  4. Joan Puñet-Ortiz
  5. Hartmut Hengel
  6. Martin Messerle
  7. Annette Oxenius
  8. Stipan Jonjic
  9. Astrid Krmpotic
  10. Pablo Engel
  11. Ana Angulo  Is a corresponding author
  1. University of Barcelona, Spain
  2. University of Rijeka, Croatia
  3. Albert-Ludwigs-Universität Freiburg, Faculty of Medicine, Germany
  4. Hannover Medical School, Germany
  5. ETH Zürich, Switzerland
  6. Faculty of Medicine and Health Sciences, University of Barcelona, Spain
Research Article
  • Cited 2
  • Views 678
  • Annotations
Cite this article as: eLife 2021;10:e59350 doi: 10.7554/eLife.59350

Abstract

Viral infections are controlled, and very often cleared, by activated T lymphocytes. The inducible co-stimulator (ICOS) mediates its functions by binding to its ligand ICOSL, enhancing T-cell activation and optimal germinal center (GC) formation. Here, we show that ICOSL is heavily downmodulated during infection of antigen presenting cells by different herpesviruses. We found that, in murine cytomegalovirus (MCMV), the immunoevasin m138/fcr-1 physically interacts with ICOSL, impeding its maturation and promoting its lysosomal degradation. This viral protein counteracts T-cell responses, in an ICOS-dependent manner, and limits virus control during the acute MCMV infection. Additionally, we report that blockade of ICOSL in MCMV-infected mice critically regulates the production of MCMV-specific antibodies due to a reduction of T follicular helper and GC B cells. Altogether, these findings reveal a novel mechanism evolved by MCMV to counteract adaptive immune surveillance, and demonstrates a role of the ICOS:ICOSL axis in the host defense against herpesviruses.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files

Article and author information

Author details

  1. Guillem Angulo

    Biomedical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7086-9754
  2. Jelena Zeleznjak

    Center for Proteomics / Department of Histology and Embryology, University of Rijeka, Rijeka, Croatia
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6619-3675
  3. Pablo Martínez-Vicente

    Biomedical Sciences, School of Medicine, University of Barcelona, Barcelona, Spain
    Competing interests
    No competing interests declared.
  4. Joan Puñet-Ortiz

    Biomedical Sciences, University of Medicine, University of Barcelona, Barcelona, Spain
    Competing interests
    No competing interests declared.
  5. Hartmut Hengel

    Institute of Virology, Albert-Ludwigs-Universität Freiburg, Faculty of Medicine, Freiburg, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3482-816X
  6. Martin Messerle

    Institute of Virology, Hannover Medical School, Hannover, Germany
    Competing interests
    No competing interests declared.
  7. Annette Oxenius

    Institute of Microbiology, Department of Biology, ETH Zürich, Zürich, Switzerland
    Competing interests
    No competing interests declared.
  8. Stipan Jonjic

    Deparment of Histology and Embryology, University of Rijeka, Rijeka, Croatia
    Competing interests
    Stipan Jonjic, Reviewing editor, eLife.
  9. Astrid Krmpotic

    Department of Histology and Embryology, University of Rijeka, Rijeka, Croatia
    Competing interests
    No competing interests declared.
  10. Pablo Engel

    Immunology Unit, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
    Competing interests
    No competing interests declared.
  11. Ana Angulo

    Biomedical Sciences, School of Medicine, University of Barcelona, Barcelona, Spain
    For correspondence
    aangulo@ub.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5792-1164

Funding

Ministerio de Economía y Competitividad (SAF 2017-87688)

  • Ana Angulo

Ministerio de Economía y Competitividad (RTI2018-094440-B-I00)

  • Pablo Engel

European Regional Development Fund (KK.01.1.1.01.0006)

  • Stipan Jonjic

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

Ethics

Animal experimentation: All procedures involving animals and their care were approved (protocol number CEEA 308/12) by the Ethics Committee of the University of Barcelona (Spain) and the Animal Welfare Committee at the University of Rijeka (Croatia) and were conducted in compliance with institutional guidelines as well as with national (Generalitat de Catalunya decree 214/1997, DOGC 2450) and international (Guide for the Care and Use of Laboratory Animals, National Institutes of Health, 85-23, 1985) laws and policies.

Human subjects: Human blood was obtained from healthy volunteer donors through the Blood and Tissue Bank of the Catalan Department of Health (Barcelona, Spain). Utilization of blood products for the experiments conducted was approved by the Ethics Committee of the Hospital Clinic of Barcelona (Barcelona, Spain), and according to the principles of the Declaration of Helsinki.

Reviewing Editor

  1. John W Schoggins, University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: May 27, 2020
  2. Accepted: January 15, 2021
  3. Accepted Manuscript published: January 18, 2021 (version 1)
  4. Version of Record published: January 27, 2021 (version 2)
  5. Version of Record updated: February 25, 2021 (version 3)

Copyright

© 2021, Angulo 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.

Metrics

  • 678
    Page views
  • 115
    Downloads
  • 2
    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)

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

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

Further reading

    1. Immunology and Inflammation
    Marie Ghraichy et al.
    Research Article

    Several human B-cell subpopulations are recognized in the peripheral blood, which play distinct roles in the humoral immune response. These cells undergo developmental and maturational changes involving VDJ recombination, somatic hypermutation and class switch recombination, altogether shaping their immunoglobulin heavy chain (IgH) repertoire. Here, we sequenced the IgH repertoire of naïve, marginal zone, switched and plasma cells from 10 healthy adults along with matched unsorted and in silico separated CD19+ bulk B cells. Using advanced bioinformatic analysis and machine learning, we show that sorted B cell subpopulations are characterised by distinct repertoire characteristics on both the individual sequence and the repertoire level. Sorted subpopulations shared similar repertoire characteristics with their corresponding in silico separated subsets. Furthermore, certain IgH repertoire characteristics correlated with the position of the constant region on the IgH locus. Overall, this study provides unprecedented insight over mechanisms of B cell repertoire control in peripherally circulating B cell subpopulations.

    1. Immunology and Inflammation
    Veronika Lang et al.
    Research Article

    Local circadian clocks are active in most cells of our body. However, their impact on circadian physiology is still under debate. Mortality by endotoxic (LPS) shock is highly time-of-day dependent and local circadian immune function such as the cytokine burst after LPS challenge has been assumed to be causal for the large differences in survival. Here, we investigate the roles of light and myeloid clocks on mortality by endotoxic shock. Strikingly, mice in constant darkness (DD) show a three-fold increased susceptibility to LPS as compared to mice in light-dark conditions. Mortality by endotoxic shock as a function of circadian time is independent of light-dark cycles as well as myeloid CLOCK or BMAL1 as demonstrated in conditional knockout mice. Unexpectedly, despite the lack of a myeloid clock these mice still show rhythmic patterns of pro- and anti-inflammatory cytokines such as TNF,α MCP-1, IL-18 and IL-10 in peripheral blood as well as time-of-day and site dependent traffc of myeloid cells. We speculate that systemic time-cues are sufficient to orchestrate innate immune response to LPS by driving immune functions such as cell traffcking and cytokine expression.