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Cells Expression and Function of CD300 in NK Expression and Function of CD300 in NK Cells Dikla Lankry, Hrvoje Simic, Yair Klieger, Francesca Levi-Schaffer, Stipan Jonjic and Ofer Mandelboim This information is current as of September 27, 2021. J Immunol 2010; 185:2877-2886; Prepublished online 23 July 2010; doi: 10.4049/jimmunol.0903347 http://www.jimmunol.org/content/185/5/2877 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2010/07/23/jimmunol.090334 Material 7.DC1 References This article cites 44 articles, 13 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/185/5/2877.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 27, 2021 • 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 © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Expression and Function of CD300 in NK Cells Dikla Lankry,* Hrvoje Simic,† Yair Klieger,* Francesca Levi-Schaffer,‡ Stipan Jonjic,† and Ofer Mandelboim* The killing activity of NK cells is regulated by signals derived from inhibitory and activating NK cell receptors, including the CD300 family of proteins. CD300a was reported to be expressed on all NK cells and to deliver an inhibitory signal upon binding to a yet unknown ligand/s. The CD300a protein contains four ITIMs and is highly homologous to CD300c. Little is known about the function and distribution of these two receptors and the identity of their ligand/s. In this article, we show that CD300a is indeed an inhibitory receptor expressed by human NK cells, but surprisingly, we show that not all NK clones are inhibited in a CD300a- dependent manner. We demonstrate, using a panel of 13 new anti-CD300a and CD300c Abs that we generated, that CD300a and CD300c are indistinguishable on the surface of NK cells. Using mutational-analysis survey, we show that tyrosine 267 located in the third ITIM motif of the CD300a protein is important for the inhibitory function of CD300a. The Journal of Immunology, 2010, 185: 2877–2886. Downloaded from atural killer cells are bone marrow-derived lymphocytes The KIR gene family is divided, based on functional activity, that make up 5–15% of the PBLs (1, 2). NK cells are into inhibitory and stimulating KIRs (17, 18). Products of in- N able to kill a broad spectrum of pathogens and tumors hibitory KIR genes are characterized by long cytoplasmic tails without prior specific stimulation (3–5), although recent evidence featuring ITIMs that, upon engagement, transmit inhibitory sig- suggests that NK cells possess some adaptive properties. The NK nals. In contrast, stimulating KIRs have short cytoplasmic tails http://www.jimmunol.org/ cytotoxicity is controlled by multiple activating and inhibitory sur- lacking ITIMs but instead they carry a positively charged amino face receptors and intracellular signal-transduction molecules (6– acid in the transmembrane region, which provides a docking site 9). In humans, the major NK-triggering receptors include the for the activating adaptor molecule DAP12 (17, 18). In addition to NKp80, NKG2D, CD16, and the natural cytotoxic receptors, which MHC class I binding receptors, other inhibitory receptors also include NKp46, NKp44, and NKp30 (3, 6, 10–13). exist. However, interestingly, as opposed to the class I inhibitory Inhibition of NK cell activity is mediated mainly by the two receptors, the inhibitory receptors that do not bind MHC class I major families of MHC-specific inhibitory receptors, which include are sometimes expressed on all NK cells (9). the Ig superfamily receptors (killer Ig-related receptor [KIR] and The CD300 proteins are a family of leukocyte membrane reg- leukocyte Ig-like receptor) and the C-type lectin (CD94/NKG2A) ulatory molecules that modulate leukocyte responses. There are by guest on September 27, 2021 receptor superfamily (14–16). The different inhibitory receptors seven members in the family, named CD300a–g (19). The CD300a show diverse specificity and can discriminate between different and CD300c receptors, which are the subject of this work, are cell class I MHC proteins. An important feature of all inhibitory NK surface glycoproteins that are encoded by independent, but closely receptors that interact with MHC class I is that they are expressed linked, genes on human chromosome 17q 22–24. Both molecules in a variegated fashion so that each NK cell expresses multiple are members of the Ig superfamily and each contains a single V- receptors in a complex combinatorial repertoire (16). like Ig domain, a membrane proximal region, a transmembrane region, and a cytoplasmic region. The Ig domains of the CD300a and CD300c molecules show 80% identity at the amino acid level *Lautenberg Center for General and Tumor Immunology, BioMedical Research In- (20–23). The CD300a molecule has a long cytoplasmic tail of 100 stitute, Hadassah Medical School and ‡Department of Pharmacology and Experimen- tal Therapeutics, Faculty of Medicine, School of Pharmacy, Hebrew University, aa. This region contains four tyrosines, three of which are found Jerusalem, Israel; and †Department of Histology and Embryology, Center for Pro- within the ITIM consensus sequences (20, 21). The CD300a cy- teomics, Faculty of Medicine, University of Rijeka, Rijeka, Croatia toplasmic region also contains a di-leucine motif that is associated Received for publication October 15, 2009. Accepted for publication June 24, 2010. with endocytosis and delivery to lysosomes (20, 22). The CD300c This work was supported by Israeli Science Foundation and The Israeli Science Foun- molecule has a proline-rich membrane proximal region, a trans- dation (Morasha) Grants, a Croatia Israel Research Grant, a MOST-DKFZ Research Grant, European Consortium Grant MRTN-CT-2005, the Rosetrees Trust, Israel Cancer membrane region containing a charged glutamic acid residue, and Association Grant 20100003, the Association for International Cancer Research, a Cro- a short cytoplasmic tail of only 18 aa. atia-Israel Joint Research Grant (all to O.M.), and European Union Grant FP7- The CD300a and CD300c receptors demonstrate several unique REGPOT-2008-1 (to S.J.). O.M is a Crown Professor of Molecular Immunology. characteristics. First, like the KIR gene family, they share a high Address correspondence and reprint requests to Dr. Ofer Mandelboim, The Lauten- berg Center for General and Tumor Immunology, Hadassah Medical School, Hebrew degree of homology but might have different functions (23), University, P.O. Box 12272, Jerusalem, Israel or Dr. Stipan Jonjic, Department of perhaps similar to the pairwised receptors (17, 18). Second, most Histology and Embryology Center for Proteomics, Faculty of Medicine, University of of the inhibitory receptors expressed by NK cells have one or two Rijeka, Brace Branchetta 2051 000, Rijeka, Croatia. E-mail addresses: oferm@ekmd. huji.ac.il or [email protected] ITIM motifs at the cytoplasmic tail, with the exception of leu- The online version of this article contains supplemental material. kocyte Ig-like receptor 1 and CD300a, which have four ITIM Abbreviations used in this paper: Bulk NK, bulk NK cultures; HA, hemagglutinin; INH, motifs (20). Thus, it will be interesting to investigate which of inhibited; KIR, killer Ig-related receptor; MIX, mixed population of inhibited and the ITIMs are important for CD300a function. Third, none of the noninhibited clones; NK Fresh, freshly isolated NK cells; non-INH, noninhibited; activating receptors identified contains a charged glutamic acid WT, wild-type. residue in the transmembrane, suggesting that CD300c delivers Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 its activating signals via signaling proteins other than those pre- www.jimmunol.org/cgi/doi/10.4049/jimmunol.0903347 2878 EXPRESSION AND FUNCTION OF CD300 IN NK CELLS viously observed or that CD300c is not an activating receptor. (including the last seven nucleotides of human CD300c extracellular por- Finally, the ligands for both receptors are still unknown. tion) and 39-CC GAA TTC TTA GCG AGG GGC CAG GGT CTG (in- In this study, we investigated the activity of CD300a. We dem- cluding an EcoRI restriction site). The two amplified fragments were mixed, and PCR was performed with the 59 HindIII primer and the 39 onstrate that CD300a is actually functional only on a subset of NK EcoRI primer for the generation of the CD300c z construct. To insert clones and that CD300a and CD300c are indistinguishable on the HA tag, the following primers were used: 59HindIII and 39-AGC the cell surface, and we identified a critical ITIM that is important GTA ATC TGG AAC ATC GTA TGG GTA AGG AAA ATA GCC TGG for CD300a function. GAC AAG (including the HA tag fragment) and 59-TAC CCA TAC GAT GTT CCA GAT TAC GCT CTG AGC CAC CCC ATG ACC GTG (in- cluding the HA tag fragment) and 3EcoRI. The CD300c HA z construct Materials and Methods was cloned into a pcDNA3 expression vector (Invitrogen, Carlsbad, CA) Abs and cells and stably transfected into BW cells. The following mouse anti-human Abs were used: anti-CD300a/c (P192) Ig-fusion proteins (20), anti-CD300a/c (MEM-260, Cedarlane Laboratories, Hornby, Ontario, Canada), anti-MHCI (W6/32), anti-KIR2DL1 (HP3E4), anti-KIR2DL3 The Ig fusion proteins CD300a-Ig, CD300c-Ig, and D1-Ig were generated as (CD158b, Beckman Coulter, Fullerton, CA), anti-CD16 (B73.1.1), anti- described previously (28).
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