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Cytolytic Activity Cells Acquire Functional Receptors and Human Embryonic Stem Cell-Derived NK

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Cytolytic Activity Cells Acquire Functional Receptors and Human Embryonic Stem Cell-Derived NK Human Embryonic Stem Cell-Derived NK Cells Acquire Functional Receptors and Cytolytic Activity This information is current as Petter S. Woll, Colin H. Martin, Jeffrey S. Miller and Dan S. of September 23, 2021. Kaufman J Immunol 2005; 175:5095-5103; ; doi: 10.4049/jimmunol.175.8.5095 http://www.jimmunol.org/content/175/8/5095 Downloaded from References This article cites 57 articles, 29 of which you can access for free at: http://www.jimmunol.org/content/175/8/5095.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • 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 by guest on September 23, 2021 *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 © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Human Embryonic Stem Cell-Derived NK Cells Acquire Functional Receptors and Cytolytic Activity1 Petter S. Woll,* Colin H. Martin,* Jeffrey S. Miller,† and Dan S. Kaufman2* Human embryonic stem cells (hESCs) provide a unique resource to analyze early stages of human hematopoiesis. However, little is known about the ability to use hESCs to evaluate lymphocyte development. In the present study, we use a two-step culture method to demonstrate efficient generation of functional NK cells from hESCs. The CD56؉CD45؉ hESC-derived lymphocytes express inhibitory and activating receptors typical of mature NK cells, including killer cell Ig-like receptors, natural cytotoxicity receptors, and CD16. Limiting dilution analysis suggests that these cells can be produced from hESC-derived hemopoietic pro- genitors at a clonal frequency similar to CD34؉ cells isolated from cord blood. The hESC-derived NK cells acquire the ability to lyse human tumor cells by both direct cell-mediated cytotoxicity and Ab-dependent cellular cytotoxicity. Additionally, activated hESC-derived NK cells up-regulate cytokine production. hESC-derived lymphoid progenitors provide a novel means to charac- Downloaded from terize specific cellular and molecular mechanisms that lead to development of specific human lymphocyte populations. These cells may also provide a source for innovative cellular immune therapies. The Journal of Immunology, 2005, 175: 5095–5103. emopoietic cells can be derived from human embryonic ESC-derived NK cells express CD94/NKG2 receptors in an or- stem cells (hESCs)3 allowed to differentiate either by derly and nonstochastic manner; however, they do not express the stromal cell coculture or formation of embryoid bodies Ly49 receptors, which are analogous to the KIRs found in humans H http://www.jimmunol.org/ (1–4). Analyses of transcription factor and cell surface Ag expres- (15). In contrast, mature NK cells isolated from adult mice express sion suggest that hematopoiesis from hESCs follows developmen- both CD94/NKG2 receptors and Ly49 (16). For human hemopoi- tal kinetics similar to what is observed during normal human on- etic cells derived from more mature sources, acquisition of KIR togeny (1–3, 5). To date, most studies have characterized myeloid, expression in vitro appears to be dependent on the stromal cell line erythroid, and megakaryocytic cells derived from hESCs (1–5). used to support NK differentiation. NK cells cocultured on MS-5 Although the process of lymphopoiesis has been well studied start- stromal cells require IL-21 for KIR expression, whereas NK cells ing from hemopoietic stem cell populations isolated from mouse or cocultured on AFT024 cells do not share this requirement (17, 18). human bone marrow or human umbilical cord blood (UCB) (6–9), In these studies, we report that hESCs can efficiently give rise to considerably less is known about the ability of hESCs to differ- NK cells that express both KIRs and CD94/NKG2a, similar to by guest on September 23, 2021 entiate into the lymphoid lineage. what is observed for mature NK cells found in vivo. More impor- NK cells form a central component in the immune defense tantly, the hESC-derived NK cells exhibit appropriate functional against pathogens and various tumors (10). Putative NK cells and characteristics as displayed by ability to lyse cells by two separate B cells have been identified in cultures of differentiated hESCs (3, mechanisms: direct cell-mediated cytotoxicity and Ab-dependent 11). However, these NK cells were characterized solely on basis of cell-mediated cytoxicity (ADCC). These hESC-derived NK cells CD56 expression, without functional analysis. In addition to CD56 also can be induced to produce cytokines, another hallmark of NK expression, mature NK cells typically express inhibitory and acti- cells. vating receptors, and the balance of signals derived from these receptors regulate NK cell activity. Killer cell Ig-like receptors Materials and Methods (KIRs) and CD94/NKG2 heterodimers are two major classes of Cell culture receptors that interact with MHC class I molecules on target cells as their ligands to specify NK cell activity (12–14). Analysis of The hESC line H9 (obtained from Wicell) was maintained as undifferen- NK cells derived from mouse ESCs has been instructive. Mouse tiated cells as described previously (1, 19). Briefly, undifferentiated hESCs were cocultured with mouse embryonic fibroblasts in DMEM:Ham’s F-12 (Invitrogen Life Technologies) supplemented with 15% knockout serum replacer (Invitrogen Life Technologies), 1% MEM-nonessential amino ac- *Stem Cell Institute and Department of Medicine and †Department of Medicine and Cancer Center, University of Minnesota, Minneapolis, MN 55455 ids (Invitrogen Life Technologies), 1 mM L-glutamine (Mediatech), 0.1 mM 2-ME (Sigma-Aldrich), and 4 ng/ml basic fibroblast growth factor Received for publication May 26, 2005. Accepted for publication August 4, 2005. (Invitrogen Life Technologies). The mouse bone marrow stromal cell line The costs of publication of this article were defrayed in part by the payment of page S17 (kindly provided by Dr. K. Dorshkind, University of California, Los charges. This article must therefore be hereby marked advertisement in accordance Angeles, CA) was grown in DMEM (Invitrogen Life Technologies) con- with 18 U.S.C. Section 1734 solely to indicate this fact. taining 10% FBS, 1% penicillin-streptomycin (P/S) (Invitrogen Life Tech- 1 This work supported in part National Institutes of Health Grant HL-72000 (to nologies), 1% MEM-nonessential amino acids, and 0.1 mM 2-ME. Before D.S.K.) and an American Society of Hematology Scholars Award (to D.S.K.). coculture with hESCs, S17 cells were incubated with conditioned medium ␮ 2 Address correspondence and reprint requests to Dr. Dan S. Kaufman, University of containing 10 g/ml mitomycin C (Bedford Laboratories) before attach- Minnesota, Stem Cell Institute, 420 Delaware Street Southeast, MMC 716, Minne- ment onto gelatin (Sigma-Aldrich)-coated 6-well plates (Nalge Nunc In- apolis, MN 55455. E-mail address: [email protected] ternational). The mouse fetal liver cell line AFT024 (kindly provided by Drs. K. Moore and I. Lemischka, Princeton University, Princeton, NJ) (20) 3 Abbreviations used in this paper: hESC, human embryonic stem cell; ADCC, Ab- dependent cell-mediated cytotoxicity; CFC, colony-forming cell; ESC, embryonic was grown at 33°C in DMEM containing 20% FBS, 1% P/S, and 0.05 mM stem cell; Flt3L, Flt3 ligand; KIR, killer cell Ig-like receptor; NCR, natural cytotox- 2-ME. AFT024 cells were irradiated with 2000 rad before coculture with icity receptor; P/S, penicillin and streptomycin; Q-RT-PCR, quantitative RT-PCR; hESC-derived hemopoietic progenitor cells. UCB was obtained from units SCF, stem cell factor; UCB, umbilical cord blood. that were unacceptable for storage in cord blood banks. The use of all Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 5096 NK CELLS DERIVED FROM hESCs human tissue was approved by the Committee on the Use of Human Sub- otherwise. ADCC was analyzed by preincubating Raji cells with 4, 1, 0.25, jects in Research at the University of Minnesota. and 0.062 ␮g/ml anti-CD20 Ab (IgG1␬ isotype, rituximab; Genentech) for 30 min. As a negative control, Raji cells preincubated with 4 ␮g/ml IgG1␬ Hemopoietic differentiation of hESCs isotype control Ab (BD Pharmingen) was used. For evaluation of ability to up-regulate IFN-␥ cytokine production, H9 hESCs were cocultured with mouse bone marrow stromal cell line S17, hESC-derived NK cells were incubated in humidified atmosphere at 37°C resulting in H9/S17 cells, as described previously (1, 21). Differentiation and 5% CO with RPMI 1640 medium supplemented with 10% FBS alone medium composed of RPMI 1640 (Mediatech) supplemented with 15% 2 as negative control, 50 ng/ml PMA (Sigma-Aldrich), and 500 ng/ml cal- FBS (HyClone), 2 mM L-glutamine, 0.1 mM 2-ME, 1% MEM-nonessential cium ionophore III (Sigma-Aldrich), as a positive control, or 10 ␮g/ml amino acids, and 1% P/S was changed every 2–3 days. After 14–17 days IL-12 and 100 ␮g/ml IL-18 (R&D Systems). After overnight stimulation, of differentiation, the differentiated hESCs were harvested and made into a cells were incubated with 10 ␮g/ml brefeldin A (Sigma-Aldrich) for 5 h. single-cell suspension using collagenase type IV (Invitrogen Life Technol- Cell surface Ags were first stained for CD56-PE and CD45-allophycocya- ogies), followed by trypsin/EDTA (0.05%; Mediatech) supplemented with nin, in addition to isotype controls, cells were then fixed and permeabilized 2% chick serum (Sigma-Aldrich).
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