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

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posted on 22.01.2020 by Kevin W Ng, Jan Attig, George R Young, Eleonora Ottina, Spyros I Papamichos, Ioannis Kotsianidis, George Kassiotis
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.

Funding

Crick (Grant ID: 10099, Grant title: Kassiotis FC001099) Wellcome Trust (Grant ID: 102898/B/13/Z, Grant title: WT 102898/B/13/Z)

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