HLA-G5 expression by trophoblast cells: the facts.

The non-classical HLA Class I molecule HLA-G was discovered at the fetal–maternal interface, but over the past few years, the tissue distribution of HLA-G in normal tissues has been found to be broader than originally reported: (i) HLA-G molecules have been detected from oocyte to blastocyst stage, then in invasive trophoblast, amniotic cells and fluid, endothelial cells from the chorionic villi and erythroid cells in all organs sustaining primitive to definitive erythropoiesis and (ii) in adult tissues, HLA-G antigens have been detected in thymic epithelial cells, in the epithelium, endothelium and keratocytes from cornea and in cells of the erythropoietic lineage from bone marrow. Additionally, HLA-G ectopic expression was demonstrated in various pathological situations such as cancer, transplantation, viral infection, inflammation and auto-immune diseases (reviewed in Carosella et al., 2003). Concerning soluble HLA-G, both shed HLA-G1 and HLA-G5 proteins have been detected in various body fluids, such as amniotic fluid and serum from pregnant women (Hamai et al. The function of the non-classical HLA Class I molecule HLA-G was initially described in the context of fetal–maternal tolerance where HLA-G expression by classical HLA Class I-negative cytotro-phoblast protects this fetal tissue against destruction by natural killer (NK) cells of the mother (Rouas-Freiss et al., 1997a,b). Since then, the capability of HLA-G to inhibit immune responses has been broadened to inhibition of peripheral NK cells and CTLs (Rouas-Freiss and Kirszenbaum et al.regulation of inhibitory receptor expression (LeMaoult et al., 2005) and inhibition of dendritic cell maturation (Ristich et al., 2005). This has positioned HLA-G as a molecule capable of significantly contributing to tolerance of allografts (Lila et al. These immuno-suppressive properties are shared by the HLA-G1 and the secreted HLA-G5 proteins. In addition, the soluble HLA-G isoforms (i.e. both shed HLA-G1 and HLA-G5) can induce apoptosis of activated CD8 + T and NK cells through ligation with CD8 (Carosella et al., 2003). In a recent article (this issue of Mol Hum Reprod), Blaschitz et al. have reinvestigated what was the nature of the soluble HLA-G molecules that were expressed by human trophoblasts and claim that the only soluble form of HLA-G that is produced by trophoblast is the shed HLA-G1 and not the secreted isoform, HLA-G5. There are several structures of soluble HLA-G proteins: (i) shed, i.e. derived from the release of membrane bound HLA-G isoforms, such as HLA-G1 (HLA-G1s for HLA-G1 shedding) and (ii) secreted, i.e. directly expressed as soluble isoforms, …