HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Hedlund, M. Articles by Mincheva-Nilsson, L. PubMed PubMed Citation Articles by Hedlund, M. Articles by Mincheva-Nilsson, L.

Human Placenta Expresses and Secretes NKG2D Ligands via Exosomes that Down-Modulate the Cognate Receptor Expression: Evidence for Immunosuppressive Function¹

Malin Hedlund^*, Ann-Christin Stenqvist^*, Olga Nagaeva^*, Lennart Kjellberg, Marianne Wulff, Vladimir Baranov^* and Lucia Mincheva-Nilsson^2,*

^* Department of Clinical Immunology and Department of Obstetrics and Gynecology, Umeå University, Umeå, Sweden

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 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 costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant CAN 2008/627, no. 08 0360 from the Swedish National Cancer Research Foundation Cancerfonden, Grant AMP 08-587 from Cancerforskningsfonden i Norrland, Grant 223-502-08 from Insamlingsstiftelsen, Umeå University, and Grant VLL 759:0-2008 from Centrala ALF medel.

² Address correspondence and reprint requests to Dr. Lucia Mincheva-Nilsson, Department of Clinical Immunology, Umeå University, S-90185 Umeå, Sweden. E-mail address: lucia.mincheva-nilsson{at}climi.umu.se

³ Abbreviations used in this paper: FasL, Fas ligand; MIC, MHC class I chain-related; STB, syncytiotrophoblast; ULBP, UL-16 binding protein; RAET, retinoic acid early transcript; MVB, multivesicular body; MFI, mean fluorescence intensity.