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.
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.
Next generation sequencing of human immune cell subsets across diseasesEuropean Nucleotide Archive, SRP045500.
The Cancer Genome AtlasTCGA.
- Kevin W Ng
- Jan Attig
- George R Young
- Eleonora Ottina
- George Kassiotis
- George Kassiotis
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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.
- Howard Y Chang, Stanford University, United States
© 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.