Human Placenta Expresses and Secretes NKG2D Ligands via Exosomes that Down-Modulate the Cognate Receptor Expression: Evidence for Immunosuppressive Function
Human Placenta Expresses and Secretes NKG2D Ligands via Exosomes that Down-Modulate the Cognate Receptor Expression: Evidence for Immunosuppressive Function
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DOI：
10.4049/jimmunol.0803477
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发表时间：
2009-07-01
影响因子：
4.4
通讯作者：
Mincheva-Nilsson, Lucia
中科院分区：
文献类型：
--
作者：
Hedlund, Malin;Stenqvist, Ann-Christin;Mincheva-Nilsson, Lucia
在哺乳动物妊娠期间，母胎耐受涉及胎盘产生的许多免疫抑制因子。近年来，胎盘来源的外泌体已成为母体免疫耐受中新的免疫调节剂。外泌体是具有限定形态的膜纳米囊泡，其在与质膜融合后从内体多囊体（MVB）分泌。以前，我们报道了MHC I类链相关（MIC）蛋白A和B，活化NK细胞受体NKG 2D的人配体，由胎盘表达，分选到合体滋养层的MVB，并可能通过携带MIC的外泌体释放。在这份报告中，我们表明，第二个家庭的人NKG 2D配体，UL-16结合蛋白（ULBP），也表达胎盘。重要的是，这种表达不是由于胎盘CMV感染。免疫电镜显示ULBP 1 -5产生并保留在微泡/外泌体上的合胞体滋养层的MVB中。使用人胎盘外植体培养物和不同的测定，我们证明携带NKG 2D配体的外泌体由人胎盘释放。分离的胎盘外泌体在其表面携带ULBP 1 -5和MIC，并诱导NK、CD 8（+）和γ δ T细胞上的NKG 2D受体下调，导致其体外细胞毒性降低，而不影响穿孔素介导的裂解途径。胎盘NKG 2D配体的释放;通过外来体是产生这些配体的生物活性可溶形式的替代机制。这些发现强调了携带NKG 2D配体的胎盘外泌体在胎儿免疫逃逸中的作用，并支持胎盘作为独特免疫抑制器官的观点。免疫学杂志，2009，183：340-351。
During mammalian pregnancy maternal-fetal tolerance involves a number of immunosuppressive factors produced by placenta. Recently, placenta-derived exosomes have emerged as new immune regulators in the maternal immune tolerance. Exosomes are membrane nanovesicles with defined morphology, which are secreted from endosomal multivesicular bodies (MVB) upon fusion with the plasma membrane. Previously, we reported that the MHC class I chain-related (MIC) proteins A and B, human ligands of the activating NK cell receptor NKG2D, are expressed by placenta, sorted to MVB of syncytiotrophoblast and probably released via MIC-bearing exosomes. In this report, we show that the second family of human NKG2D ligands, the UL-16 binding proteins (ULBP), is also expressed by placenta. Importantly, this expression was not due to placental CMV infection. Immunoelectron microscopy disclosed that ULBP1-5 are produced and retained in MVB of the syncytiotrophoblast on microvesicles/exosomes. Using human placenta explant cultures and different assays, we demonstrate that exosomes bearing NKG2D ligands are released by human placenta. Isolated placental exosomes carried ULBP1-5 and MIC on their surface and induced down-regulation of the NKG2D receptor on NK, CD8(+), and gamma delta T cells, leading to reduction of their in vitro cytotoxicity without affecting the perforin-mediated lytic pathway. Release of placental NKG2D ligands; via exosomes is an alternative mechanism for generation of bioactive soluble form of these ligands. These findings highlight a role for NKG2D ligand-bearing placental exosomes in the fetal immune escape and support the view of placenta as a unique immunosuppressive organ. The Journal of Immunology, 2009, 183: 340-351.