Retroviral Immunology, The Francis Crick Institute, London, United Kingdom.
Retrovirus-Host Interactions, The Francis Crick Institute, London, United Kingdom.
Elife. 2019 Nov 15;8:e50256. doi: 10.7554/eLife.50256.
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 () endogenous retroelement in the gene, encoding PD-L1, which causes omission of the transmembrane domain and the regulatory sequence in the canonical 3' untranslated region. The alternatively spliced transcript forms the major source of sPD-L1 and is highly conserved in hominids, but lost in mice and a few related species. Importantly, -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.
免疫调节是正向和负向信号的精细平衡过程。PD-L1 及其受体 PD-1 是自身免疫、抗病毒和抗肿瘤 T 细胞反应的关键调节剂。尽管其主要膜结合形式的功能已经得到很好的确立，但可溶性 PD-L1（sPD-L1）的来源和生物学活性仍不完全清楚。在这里，我们表明人类健康组织和肿瘤中的 sPD-L1 是由 PD-L1 基因内含子中的内源性逆转录元件（）外适应产生的，该元件导致跨膜结构域和规范的 3'非翻译区中的调节序列缺失。 剪接的 转录本形成 sPD-L1 的主要来源，在人类中高度保守，但在小鼠和一些相关物种中丢失。重要的是，编码的 sPD-L1 缺乏可测量的 T 细胞抑制活性。相反，它作为受体拮抗剂发挥作用，阻断细胞或外泌体膜上结合的 PD-L1 的抑制活性。
