A herpesvirus encoded Qa-1 mimic inhibits natural killer cell cytotoxicity through CD94/NKG2A receptor engagement

Abstract

A recurrent theme in viral immune evasion is the sabotage of MHC-I antigen presentation, which brings virus the concomitant issue of 'missing-self' recognition by NK cells that use inhibitory receptors to detect surface MHC-I proteins. Here we report that rodent herpesvirus Peru (RHVP) encodes a Qa-1 like protein (pQa-1) via RNA splicing to counteract NK activation. While pQa-1 surface expression is stabilized by the same canonical peptides presented by murine Qa-1, pQa-1 is GPI-anchored and resistant to the activity of RHVP pK3, a ubiquitin ligase that targets MHC-I for degradation. pQa-1 tetramer staining indicates that it recognizes CD94/NKG2A receptors. Consistently, pQa-1 selectively inhibits NKG2A+ NK cells and expression of pQa-1 can protect tumor cells from NK control in vivo. Collectively these findings reveal an innovative NK evasion strategy wherein RHVP encodes a modified Qa-1 mimic refractory to MHC-I sabotage and capable of specifically engaging inhibitory receptors to circumvent NK activation.

Data availability

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

Article and author information

Author details

  1. Xiaoli Wang

    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States
    Competing interests
    No competing interests declared.
  2. Sytse J Piersma

    Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St Louis, United States
    Competing interests
    No competing interests declared.
  3. Nelson A Christopher

    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States
    Competing interests
    No competing interests declared.
  4. Ya-Nan Dia

    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States
    Competing interests
    No competing interests declared.
  5. Ted Christensen

    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States
    Competing interests
    No competing interests declared.
  6. Eric Lazear

    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States
    Competing interests
    No competing interests declared.
  7. Liping Yang

    Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St Louis, United States
    Competing interests
    No competing interests declared.
  8. Marjolein Sluijter

    Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    No competing interests declared.
  9. Thorbald van Hall

    Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9115-558X
  10. Ted H Hansen

    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States
    Competing interests
    No competing interests declared.
  11. Wayne M Yokoyama

    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States
    Competing interests
    Wayne M Yokoyama, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0566-7264
  12. Daved H Fremont

    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States
    For correspondence
    fremont@wustl.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8544-2689

Funding

National Institute of Allergy and Infectious Diseases (R01-AI109687)

  • Daved H Fremont

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#08-133) of the University of Arizona. The protocol was approved by the Committee on the Ethics of Animal Experiments of the University of Minnesota (Permit Number: 27-2956). All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.

Copyright

© 2018, Wang 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.

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  1. Xiaoli Wang
  2. Sytse J Piersma
  3. Nelson A Christopher
  4. Ya-Nan Dia
  5. Ted Christensen
  6. Eric Lazear
  7. Liping Yang
  8. Marjolein Sluijter
  9. Thorbald van Hall
  10. Ted H Hansen
  11. Wayne M Yokoyama
  12. Daved H Fremont
(2018)
A herpesvirus encoded Qa-1 mimic inhibits natural killer cell cytotoxicity through CD94/NKG2A receptor engagement
eLife 7:e38667.
https://doi.org/10.7554/eLife.38667

Share this article

https://doi.org/10.7554/eLife.38667

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