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Receptor Nkp46 Cells by the NK Β Murine Pancreatic Recognition And Recognition and Killing of Human and Murine Pancreatic β Cells by the NK Receptor NKp46 This information is current as Chamutal Gur, Jonatan Enk, Sameer A. Kassem, Yaron of September 27, 2021. Suissa, Judith Magenheim, Miri Stolovich-Rain, Tomer Nir, Hagit Achdout, Benjamin Glaser, James Shapiro, Yaakov Naparstek, Angel Porgador, Yuval Dor and Ofer Mandelboim J Immunol 2011; 187:3096-3103; Prepublished online 17 Downloaded from August 2011; doi: 10.4049/jimmunol.1101269 http://www.jimmunol.org/content/187/6/3096 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2011/08/18/jimmunol.110126 Material 9.DC1 References This article cites 29 articles, 9 of which you can access for free at: http://www.jimmunol.org/content/187/6/3096.full#ref-list-1 Why The JI? Submit online. by guest on September 27, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Recognition and Killing of Human and Murine Pancreatic b Cells by the NK Receptor NKp46 Chamutal Gur,*,†,1 Jonatan Enk,*,1 Sameer A. Kassem,†,‡ Yaron Suissa,x Judith Magenheim,x Miri Stolovich-Rain,x Tomer Nir,x Hagit Achdout,*,2 Benjamin Glaser,†,‡ James Shapiro,{ Yaakov Naparstek,† Angel Porgador,‖,# Yuval Dor,x and Ofer Mandelboim* Type 1 diabetes is an incurable disease that is currently treated by insulin injections or in rare cases by islet transplantation. We have recently shown that NKp46, a major killer receptor expressed by NK cells, recognizes an unknown ligand expressed by b cells and that in the absence of NKp46, or when its activity is blocked, diabetes development is inhibited. In this study, we investigate whether NKp46 is involved in the killing of human b cells that are intended to be used for transplantation, and we also thoroughly characterize the interaction between NKp46 and its human and mouse b cell ligands. We show that human b cells express an unknown ligand for NKp46 and are killed in an NKp46-dependent manner. We further demonstrate that the expression of the Downloaded from NKp46 ligand is detected on human b cells already at the embryonic stage and that it appears on murine b cells only following birth. Because the NKp46 ligand is detected on healthy b cells, we wondered why type 1 diabetes does not develop in all individuals and show that NK cells are absent from the vicinity of islets of healthy mice and are detected in situ in proximity with b cells in NOD mice. We also investigate the molecular mechanisms controlling NKp46 interactions with its b cell ligand and demonstrate that the recognition is confined to the membrane proximal domain and stalk region of NKp46 and that two glycosylated residues of NKp46, Thr125 and Asn216, are critical for this recognition. The Journal of Immunology, 2011, 187: http://www.jimmunol.org/ 3096–3103. ype 1 diabetes (T1D) is currently an incurable disease that within a short period of time (2, 3). The reasons for this rejection is mainly treated by daily injections of insulin. In rare are largely unknown. T situations, when metabolic instability and severe hypo- Early reports suggest that in addition to T cells, NK cells are glycemia persist, human islet transplantation is considered as involved in the pathogenesis of T1D (4–6). The NK cell cyto- possible treatment (1) (2). However, such treatment is still not very toxicity is complex and regulated by both inhibitory receptors, effective, and in almost all cases, .90% of the islets are rejected which recognize mainly MHC class I proteins, and activating re- by guest on September 27, 2021 ceptors (7–10). The most prominent NK inhibitory receptors are those that recognize the HLA-C proteins, as all of the HLA-C proteins can be divided into two groups, C1 and C2, that are *The Lautenberg Center for General and Tumor Immunology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem recognized by killer Ig-like receptor (KIR) 2DL2 and KIR2DL1, 91120, Israel; †Department of Medicine, Hadassah-Hebrew University Hospital, Jer- respectively (11). Another prominent inhibitory receptor is leu- usalem 91120, Israel; ‡Department of Endocrinology and Metabolism, Hadassah- x kocyte Ig-like receptor-1 (LIR1), which recognizes a broad range Hebrew University Hospital, Jerusalem 91120, Israel; Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew of MHC class I proteins (11, 12). The NK activating receptors University-Hadassah Medical School, Jerusalem 91120, Israel; {Healthcare Solutions recognize pathogen-derived, stress-induced, tumor-derived, and (Alberta Innovates-Health Solutions), University of Alberta, Edmonton, Alberta T6G ‖ even self-ligands (13–16). Prominent among the killer receptors is 2C8, Canada; Shraga Segal Department of Microbiology and Immunology, Ben- Gurion University of the Negev, Beer-Sheva 84105, Israel; and #National Institute NKp46 (NCR1 in mice), as it is expressed exclusively by NK and for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva NK-like cells (8, 17, 18). The only ligands identified so far for 84105, Israel NKp46 are viral hemagglutinins (HA) (19, 20), and the recogni- 1 C.G. and J.E. contributed equally to this work. tion of viral HA by NKp46 is mediated mainly via a2,6-linked 2 Current address: Department of Infectious Diseases, Israel Institute for Biological sialic acid residues carried by NKp46 and largely relies on the Research, Ness-Ziona, Israel. highly conserved sugar-carrying residue of NKp46, Thr225 (19). Received for publication May 6, 2011. Accepted for publication July 11, 2011. Recently, we showed that NKp46 recognizes an unknown ligand This work was supported by grants from the Israeli Science Foundation and the expressed by pancreatic b cells (21). We showed in murine models Israeli Science Foundation (Morasha), a Croatia Israel Research grant, a Ministry of Science, Culture and Sport-German Cancer Research Center Research grant, the Ro- that NK cells kill pancreatic b cells in an NKp46-dependent setrees trust, the Israel Cancer Association (20100003), an Israeli Cancer Research manner and demonstrated that T1D development could be pre- Fund professorship grant, and by the Association for International Cancer Research (all to O.M.). O.M. is a Crown professor of Molecular Immunology. vented by blocking NKp46 activity using active immunizations (21). Address correspondence and reprint requests to Prof. Ofer Mandelboim, The Lauten- berg Center for General and Tumor Immunology, Hebrew University-Hadassah Med- In this study, we extensively and thoroughly analyze the inter- ical School, Institute for Medical Research Israel-Canada, Jerusalem 91120, Israel. actions between NKp46 and its unknown ligand expressed by both E-mail address: [email protected] human and murine b cells. We demonstrate that human b cells, The online version of this article contains supplemental material. which are intended to be used for transplantation, express the Abbreviations used in this article: CEA, carcinoembryonic Ag; HA, hemagglutinin; unknown ligand of NKp46 and are killed in an NKp46-dependent KIR, killer Ig-like receptor; LIR1, leukocyte Ig-like receptor-1; T1D, type 1 diabetes. manner. We also describe the molecular mechanisms controlling Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 the NKp46 interaction with its mouse and human b cell ligands www.jimmunol.org/cgi/doi/10.4049/jimmunol.1101269 The Journal of Immunology 3097 and identify the binding site on NKp46 that is involved in these Ig, with its membrane proximal domain, which also contains the interactions. stalk region and is named NKp46D2-Ig, and with its membrane distal domain, named NKp46D1-Ig. A schematic representation of Materials and Methods NKp46 is presented in Supplemental Fig. 1. As can be seen in Fig. Mice, sera, and fusion proteins 1, isolated human b cells that express insulin (detected by staining All experiments were performed in a specific pathogen-free unit of the with polyclonal anti-insulin Abs; Fig. 1A) also express a putative Hadassah Medical School (Ein-Kerem, Jerusalem) in accordance with the ligand for NKp46, and the NKp46 binding is confined to the guidelines of the ethical committee. The double-transgenic Insulin-rtTA; b membrane proximal domain D2 (Fig. 1B). TET-DTA mice and the conditional ablation of pancreatic cells were b generated as previously described (22). All fusion proteins used in this We also investigated whether the isolated human cells are study—the NCR1-Ig, NKp46-Ig, NKp46D2-Ig, NKp46D1-Ig, KIR2DL1- recognized by the KIR2DL1-Ig, KIR2DL2-Ig, and LIR1-Ig in- Ig, KIR2DL2-Ig, LIR1-Ig, NKp46-T225V-Ig, NKp46-T125V-Ig, and hibitory receptor fusion proteins. Surprisingly, whereas LIR1-Ig NKp46-N216V-Ig—were generated in COS-7 cells and purified by affinity binding was detected, little or no staining was observed with either chromatography using a protein G column, as previously described (20). Human islets intended to be used for transplantations were derived from the KIR2DL-1-Ig or the KIR2DL2-Ig (Fig. 1B). Because similar healthy donors. The anti-NKp46 and control anti-carcinoembryonic Ag results were observed with b cells obtained from four separate (CEA) sera were generated as previously described (21).
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