Soluble PD-L1 generated by endogenous retroelement exaptation is a receptor antagonist

  1. Kevin W Ng
  2. Jan Attig
  3. George R Young
  4. Eleonora Ottina
  5. Spyros I Papamichos
  6. Ioannis Kotsianidis
  7. George Kassiotis  Is a corresponding author
  1. The Francis Crick Institute, United Kingdom
  2. Democritus University of Thrace Medical School, Greece

Abstract

Immune regulation is a finely balanced process of positive and negative signals. PD-L1 and its receptor PD-1 are critical regulators of autoimmune, anti-viral and anti-tumoural T cell responses. Although the function of its predominant membrane-bound form is well-established, the source and biological activity of soluble PD-L1 (sPD-L1) remain incompletely understood. Here, we show that sPD-L1 in human healthy tissues and tumours is produced by exaptation of an intronic LINE-2A (L2A) endogenous retroelement in the CD274 gene, encoding PD-L1, which causes omission of the transmembrane domain and the regulatory sequence in the canonical 3' untranslated region. The alternatively spliced CD274-L2A transcript forms the major source of sPD-L1 and is highly conserved in hominids, but lost in mice and a few related species. Importantly, CD274-L2A-encoded sPD-L1 lacks measurable T cell inhibitory activity. Instead, it functions as a receptor antagonist, blocking the inhibitory activity of PD-L1 bound on cellular or exosomal membranes.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure 1G, Figure 1-figure supplement 3, and Figure 3B.

The following previously published data sets were used

Article and author information

Author details

  1. Kevin W Ng

    Retroviral Immunology, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1635-6768
  2. Jan Attig

    Retroviral Immunology, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2159-2880
  3. George R Young

    Retrovirus-Host Interactions, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Eleonora Ottina

    Retroviral Immunology, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Spyros I Papamichos

    Department of Haematology, Democritus University of Thrace Medical School, Alexandroupolis, Greece
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7119-0647
  6. Ioannis Kotsianidis

    Department of Haematology, Democritus University of Thrace Medical School, Alexandroupolis, Greece
    Competing interests
    The authors declare that no competing interests exist.
  7. George Kassiotis

    Retroviral Immunology, The Francis Crick Institute, London, United Kingdom
    For correspondence
    george.kassiotis@crick.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8457-2633

Funding

Francis Crick Institute (10099)

  • Kevin W Ng
  • Jan Attig
  • George R Young
  • Eleonora Ottina
  • George Kassiotis

Wellcome (102898/B/13/Z)

  • George Kassiotis

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

Reviewing Editor

  1. Howard Y Chang, Stanford University, United States

Ethics

Animal experimentation: All animal experiments were approved by the ethical committee of the Francis Crick Institute and conducted according to local guidelines and UK Home Office regulations under the Animals Scientific Procedures Act 1986 (ASPA) (licence number: PCD77C6D0)

Human subjects: This study was reviewed and approved by The Francis Crick Institute's Human Ethics Group and all experiments were carried out in accordance with the United Kingdom's Human Tissue Act (2004). All participants provided written informed consent prior to participation in the study.

Version history

  1. Received: July 16, 2019
  2. Accepted: November 13, 2019
  3. Accepted Manuscript published: November 15, 2019 (version 1)
  4. Version of Record published: November 25, 2019 (version 2)

Copyright

© 2019, Ng 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. Kevin W Ng
  2. Jan Attig
  3. George R Young
  4. Eleonora Ottina
  5. Spyros I Papamichos
  6. Ioannis Kotsianidis
  7. George Kassiotis
(2019)
Soluble PD-L1 generated by endogenous retroelement exaptation is a receptor antagonist
eLife 8:e50256.
https://doi.org/10.7554/eLife.50256

Share this article

https://doi.org/10.7554/eLife.50256

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