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

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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

1. Linsley et al
(2014) Next generation sequencing of human immune cell subsets across diseases
European Nucleotide Archive, SRP045500.

https://www.ebi.ac.uk/ena/data/view/PRJNA258216
1. The Cancer Genome Atlas
(2017) The Cancer Genome Atlas
TCGA.

https://portal.gdc.cancer.gov/
1. The Genotype-Tissue Expression
(2017) The Genotype-Tissue Expression
GTEx.

https://gtexportal.org/home/datasets
1. Broad Institute Cancer Cell Line Encyclopedia
(2017) Broad Institute Cancer Cell Line Encyclopedia
CCLE.

https://portals.broadinstitute.org/ccle

Article and author information

Author details

Kevin W Ng

Retroviral Immunology, The Francis Crick Institute, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1635-6768
Jan Attig

Retroviral Immunology, The Francis Crick Institute, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-2159-2880
George R Young

Retrovirus-Host Interactions, The Francis Crick Institute, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Eleonora Ottina

Retroviral Immunology, The Francis Crick Institute, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Spyros I Papamichos

Department of Haematology, Democritus University of Thrace Medical School, Alexandroupolis, Greece

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7119-0647
Ioannis Kotsianidis

Department of Haematology, Democritus University of Thrace Medical School, Alexandroupolis, Greece

Competing interests
The authors declare that no competing interests exist.
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.

"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.

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.

Copyright

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.