TY - JOUR TI - Soluble PD-L1 generated by endogenous retroelement exaptation is a receptor antagonist AU - Ng, Kevin W AU - Attig, Jan AU - Young, George R AU - Ottina, Eleonora AU - Papamichos, Spyros I AU - Kotsianidis, Ioannis AU - Kassiotis, George A2 - Chang, Howard Y A2 - Rath, Satyajit A2 - Chang, Howard Y VL - 8 PY - 2019 DA - 2019/11/15 SP - e50256 C1 - eLife 2019;8:e50256 DO - 10.7554/eLife.50256 UR - https://doi.org/10.7554/eLife.50256 AB - 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. KW - PD-L1 KW - LINE KW - retroelement KW - receptor antagonist JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -