Mangeney Marianne, Renard Martial, Schlecht-Louf Géraldine, Bouallaga Isabelle, Heidmann Odile, Letzelter Claire, Richaud Aurélien, Ducos Bertrand, Heidmann Thierry
Unité des Rétrovirus Endogènes et Eléments Rétroïdes des Eucaryotes Supérieurs, Unité Mixte de Recherche 8122, Centre National de la Recherche Scientifique, Institut Gustave Roussy, F-94805 Villejuif, France.
Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20534-9. doi: 10.1073/pnas.0707873105. Epub 2007 Dec 12.
We have previously demonstrated that the envelope proteins of a murine and primate retrovirus are immunosuppressive in vivo. This property was manifested by the ability of the proteins, when expressed by allogeneic tumor cells normally rejected by engrafted mice, to have the env-expressing cells escape (at least transiently) immune rejection. Here, we analyzed the immunosuppressive activity of the human and murine syncytins. These are envelope genes from endogenous retroviruses independently coopted by ancestral hosts, conserved in evolution, specifically expressed in the placenta, and with a cell-cell fusogenic activity likely contributing to placenta morphogenesis. We show that in both humans and mice, one of the two syncytins (human syncytin-2 and mouse syncytin-B) is immunosuppressive and, rather unexpectedly, the other (human syncytin-1 and mouse syncytin-A) is not (albeit able to induce cell-cell fusion). Delineation of the immunosuppressive domain by deletion analysis, combined with a comparison between immunosuppressive and nonimmunosuppressive sequences, allowed us to derive a mutation rule targeted to specific amino acids, resulting in selective switch from immunosuppressive to nonimmunosuppressive envelope proteins and vice versa. These results unravel a critical function of retroviral envelopes, not necessarily "individually" selected for in the retrovirus endogenization process, albeit "tandemly" conserved in evolution for the syncytin pairs in primates and Muridae. Selective inactivation of immunosuppression, under conditions not affecting fusogenicity, should be important for understanding the role of this function in placental physiology and maternofetal tolerance.
我们之前已经证明，一种鼠类和灵长类逆转录病毒的包膜蛋白在体内具有免疫抑制作用。这种特性表现为，当这些蛋白由移植小鼠通常会排斥的同种异体肿瘤细胞表达时，能使表达env的细胞逃避（至少是短暂地）免疫排斥。在此，我们分析了人类和鼠类合胞素的免疫抑制活性。这些是来自内源性逆转录病毒的包膜基因，被祖先宿主独立地加以利用，在进化过程中得以保留，在胎盘中特异性表达，并且具有可能有助于胎盘形态发生的细胞间融合活性。我们发现，在人类和小鼠中，两种合胞素之一（人类合胞素-2和小鼠合胞素-B）具有免疫抑制作用，而另一种（人类合胞素-1和小鼠合胞素-A）则没有（尽管能够诱导细胞间融合）。通过缺失分析确定免疫抑制结构域，并将免疫抑制序列与非免疫抑制序列进行比较，使我们能够得出针对特定氨基酸的突变规则，从而实现从免疫抑制性包膜蛋白到非免疫抑制性包膜蛋白的选择性转换，反之亦然。这些结果揭示了逆转录病毒包膜的一项关键功能，该功能不一定是在逆转录病毒内源性过程中“单独”选择的，尽管在灵长类动物和鼠科动物的合胞素对的进化过程中是“串联”保留的。在不影响融合性的条件下选择性灭活免疫抑制作用，对于理解该功能在胎盘生理学和母胎耐受性中的作用应该很重要。
