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

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, 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 <i>LINE-2A</i> (<i>L2A</i>) endogenous retroelement in the <i>CD274</i> gene, encoding PD-L1, which causes omission of the transmembrane domain and the regulatory sequence in the canonical 3' untranslated region. The alternatively spliced <i>CD274-L2A</i> transcript forms the major source of sPD-L1 and is highly conserved in hominids, but lost in mice and a few related species. Importantly, <i>CD274-L2A</i>-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.