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

Elife. 2021 Jan 18:10: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.

Keywords: antigen presenting cells; cd275; cytomegalovirus; herpesvirus; icosl; immunology; inflammation; mouse; t-cell co-stimulation; viral immune evasion; virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Herpesviridae Infections / virology*
  • Immune Evasion*
  • Inducible T-Cell Co-Stimulator Ligand / metabolism*
  • Inducible T-Cell Co-Stimulator Protein / metabolism*
  • Mice
  • Muromegalovirus / physiology*
  • T-Lymphocytes / immunology*

Substances

  • Inducible T-Cell Co-Stimulator Ligand
  • Inducible T-Cell Co-Stimulator Protein

Grants and funding

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