Soluble PD-L1 generated by endogenous retroelement exaptation is a receptor antagonist
Immune regulation is a finely balanced process of positive and negative signals. PD-L1 and its receptor PD-1 are critical regulators of autoimmune, antiviral and antitumoural T cell responses. Although the function of its predominant membrane-bound form is well established, the source and biological...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2019-11-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/50256 |
| _version_ | 1811202792275050496 |
|---|---|
| author | Kevin W Ng Jan Attig George R Young Eleonora Ottina Spyros I Papamichos Ioannis Kotsianidis George Kassiotis |
| author_facet | Kevin W Ng Jan Attig George R Young Eleonora Ottina Spyros I Papamichos Ioannis Kotsianidis George Kassiotis |
| author_sort | Kevin W Ng |
| collection | DOAJ |
| description | Immune regulation is a finely balanced process of positive and negative signals. PD-L1 and its receptor PD-1 are critical regulators of autoimmune, antiviral and antitumoural 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. |
| first_indexed | 2024-04-12T02:44:38Z |
| format | Article |
| id | doaj.art-c6668738cc98470da90a0b9c9b22d6a0 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:44:38Z |
| publishDate | 2019-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-c6668738cc98470da90a0b9c9b22d6a02022-12-22T03:51:14ZengeLife Sciences Publications LtdeLife2050-084X2019-11-01810.7554/eLife.50256Soluble PD-L1 generated by endogenous retroelement exaptation is a receptor antagonistKevin W Ng0https://orcid.org/0000-0003-1635-6768Jan Attig1https://orcid.org/0000-0002-2159-2880George R Young2Eleonora Ottina3Spyros I Papamichos4https://orcid.org/0000-0001-7119-0647Ioannis Kotsianidis5George Kassiotis6https://orcid.org/0000-0002-8457-2633Retroviral Immunology, The Francis Crick Institute, London, United KingdomRetroviral Immunology, The Francis Crick Institute, London, United KingdomRetrovirus-Host Interactions, The Francis Crick Institute, London, United KingdomRetroviral Immunology, The Francis Crick Institute, London, United KingdomDepartment of Haematology, Democritus University of Thrace Medical School, Alexandroupolis, GreeceDepartment of Haematology, Democritus University of Thrace Medical School, Alexandroupolis, GreeceRetroviral Immunology, The Francis Crick Institute, London, United Kingdom; Department of Medicine, Faculty of Medicine, Imperial College London, London, United KingdomImmune regulation is a finely balanced process of positive and negative signals. PD-L1 and its receptor PD-1 are critical regulators of autoimmune, antiviral and antitumoural 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.https://elifesciences.org/articles/50256PD-L1LINEretroelementreceptor antagonist |
| spellingShingle | Kevin W Ng Jan Attig George R Young Eleonora Ottina Spyros I Papamichos Ioannis Kotsianidis George Kassiotis Soluble PD-L1 generated by endogenous retroelement exaptation is a receptor antagonist eLife PD-L1 LINE retroelement receptor antagonist |
| title | Soluble PD-L1 generated by endogenous retroelement exaptation is a receptor antagonist |
| title_full | Soluble PD-L1 generated by endogenous retroelement exaptation is a receptor antagonist |
| title_fullStr | Soluble PD-L1 generated by endogenous retroelement exaptation is a receptor antagonist |
| title_full_unstemmed | Soluble PD-L1 generated by endogenous retroelement exaptation is a receptor antagonist |
| title_short | Soluble PD-L1 generated by endogenous retroelement exaptation is a receptor antagonist |
| title_sort | soluble pd l1 generated by endogenous retroelement exaptation is a receptor antagonist |
| topic | PD-L1 LINE retroelement receptor antagonist |
| url | https://elifesciences.org/articles/50256 |
| work_keys_str_mv | AT kevinwng solublepdl1generatedbyendogenousretroelementexaptationisareceptorantagonist AT janattig solublepdl1generatedbyendogenousretroelementexaptationisareceptorantagonist AT georgeryoung solublepdl1generatedbyendogenousretroelementexaptationisareceptorantagonist AT eleonoraottina solublepdl1generatedbyendogenousretroelementexaptationisareceptorantagonist AT spyrosipapamichos solublepdl1generatedbyendogenousretroelementexaptationisareceptorantagonist AT ioanniskotsianidis solublepdl1generatedbyendogenousretroelementexaptationisareceptorantagonist AT georgekassiotis solublepdl1generatedbyendogenousretroelementexaptationisareceptorantagonist |