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.
- Ana Angulo
- Pablo Engel
- Stipan Jonjic
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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.
- John W Schoggins, University of Texas Southwestern Medical Center, United States
© 2021, Angulo et al.
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