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3 Cleavage Products of Notch 2/Site and Myelopoiesis by Dysregulating ADAM10 Overexpression Shifts Lympho- and Myelopoiesis by Dysregulating Site 2/Site 3 Cleavage Products of Notch This information is current as David R. Gibb, Sheinei J. Saleem, Dae-Joong Kang, Mark of October 4, 2021. A. Subler and Daniel H. Conrad J Immunol 2011; 186:4244-4252; Prepublished online 2 March 2011; doi: 10.4049/jimmunol.1003318 http://www.jimmunol.org/content/186/7/4244 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2011/03/02/jimmunol.100331 Material 8.DC1 http://www.jimmunol.org/ References This article cites 45 articles, 16 of which you can access for free at: http://www.jimmunol.org/content/186/7/4244.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 October 4, 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 © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology ADAM10 Overexpression Shifts Lympho- and Myelopoiesis by Dysregulating Site 2/Site 3 Cleavage Products of Notch David R. Gibb,*,1 Sheinei J. Saleem,*,1 Dae-Joong Kang,* Mark A. Subler,† and Daniel H. Conrad* Although the physiological consequences of Notch signaling in hematopoiesis have been extensively studied, the differential effects of individual notch cleavage products remain to be elucidated. Given that ADAM10 is a critical regulator of Notch and that its deletion is embryonically lethal, we generated mice that overexpress ADAM10 (ADAM10 transgenic [A10Tg]) at early stages of lympho- and myeloid development. Transgene expression resulted in abrogated B cell development, delayed T cell development in the thymus, and unexpected systemic expansion of CD11b+Gr-1+ cells, also known as myeloid-derived suppressor cells. Mixed bone marrow reconstitution assays demonstrated that transgene expression altered hematopoiesis via a cell-intrinsic mechanism. Consistent with previously reported observations, we hypothesized that ADAM10 overexpression dysregulated Notch by uncou- Downloaded from pling the highly regulated proteolysis of Notch receptors. This was confirmed using an in vitro model of hematopoiesis via culturing A10Tg hematopoietic Lineage2Sca-1+c-Kit+ cells with OP-9 stromal cells in the presence or absence of Delta-like 1, a primary ligand for Notch. Blockade of the site 2 (S2) and site 3 (S3) cleavage of the Notch receptor demonstrated differential effects on hematopoiesis. OP9-DL1 cultures containing the ADAM10 inhibitor (S2 cleavage site) enhanced and rescued B cell development from wild-type and A10Tg Lineage2Sca-1+c-Kit+ cells, respectively. In contrast, blockade of g-secretase at the S3 cleavage site induced accumulation of the S2 product and consequently prevented B cell development and resulted in myeloid cell http://www.jimmunol.org/ accumulation. Collectively, these findings indicate that the differential cleavage of Notch into S2 and S3 products regulated by ADAM10 is critical to hematopoietic cell-fate determination. The Journal of Immunology, 2011, 186: 4244–4252. isintegrin and metalloproteinases (ADAMs) regulate cell substrates contributes to the pathogenesis of multiple disease states, signaling pathways by cleaving the extracellular domains including allergy, cancer, and inflammation (1, 2). Accordingly, D of membrane-bound receptors and ligands. Consequently, there is growing interest in ADAM10 as a pharmacological target these proteins serve as initiators for signaling pathways that require for these conditions. However, determination of the physiologic regulated intramembrane proteolysis (RIP) of receptor:ligand consequences of ADAM10-mediated cleavage events has been complexes. In vitro-based assays have revealed that ADAM10 is an limited by lethality of ADAM10-null murine embryos (3). by guest on October 4, 2021 important mediator of ectodomain shedding and RIP of numerous Production of ADAM10-deficient embryos and conditional substrates, such as the low-affinity IgE receptor CD23 and the knockout mice has demonstrated a critical role for ADAM10 in Notch ligand Delta-like 1 (DL1). Proteolytic processing of these developmental pathways, including thymocyte and marginal zone B cell development (4, 5). Each report concluded that impaired de- *Department of Microbiology and Immunology, Virginia Commonwealth University, velopment in the absence of ADAM10 was the result of diminished Massey Cancer Center, School of Medicine, Richmond, VA 23298; and †Depart- Notch signaling, which depends on RIP for signal activation. ment of Human and Molecular Genetics, Virginia Commonwealth University, Massey Many studies have demonstrated the importance of Notch sig- Cancer Center, School of Medicine, Richmond, VA 23298 naling in lymphocyte development. The Notch signaling pathway is 1D.R.G. and S.J.S. contributed equally to this work. highly conserved, consisting of four families of receptors (Notch1– Received for publication October 7, 2010. Accepted for publication February 1, 2011. 4) that interact with ligands (Jagged and Delta) expressed by This work was supported by National Institute of Allergy and Infectious Diseases/ neighboring cells (6–8). Following ribosomal synthesis, the Notch National Institutes of Health (Grants R01AI18697 and U19AI077435) (to D.H.C.), receptor undergoes a furin-mediated maturation at site 1 in the the American Heart Association (Grant 0815066E) (to D.R.G.), and National Insti- tutes of Health-National Cancer Institute Center Support Grant P30 CA016059 for Golgi apparatus prior to trafficking to the cell surface. At the the Virginia Commonwealth University Transgenic and Flow Cytometry Facility. surface, Notch is expressed as an integral membrane protein, Address correspondence and reprint requests to Dr. Daniel H. Conrad, Department of consisting of both extracellular (NEXT) and intracellular domains Microbiology and Immunology, Virginia Commonwealth University, Massey Cancer (NICD). Once engaged with its ligand, the extracellular domain Center, School of Medicine, P.O. Box 980678, Richmond, VA 23298. E-mail address: [email protected] undergoes an ADAM10-mediated cleavage at site 2 (S2). This The online version of this article contains supplemental material. event generates a substrate for g-secretase complex to perform Abbreviations used in this article: A10Tg, ADAM10 transgenic; CLP, common lym- a final cleavage of Notch at site 3 (S3), releasing the transcrip- phoid progenitor; CMP, common myeloid progenitor; DL1, Delta-like 1; ETP, early tionally active NICD (Fig. 6) (9). Several studies have reported the thymocyte progenitor; GMP, granulocyte-macrophage progenitor; GSI, g-secretase inhibitor; HSC, hematopoietic stem cell; LSK, Lineage2Sca-1+c-Kit+; LT-HSC, accumulation of intact receptor and the S2 product as a result of long-term hematopoietic stem cell; MDSC, myeloid-derived suppressor cell; MEP, ADAM10 and g-secretase blockade, respectively (10, 11). Al- megakaryocyte-erythroid progenitor; MPP, multipotent progenitor population; though inhibition of both enzymes prevents NICD activation, the NEXT, Notch extracellular domain; NICD, Notch intracellular domain; PLN, periph- eral lymph node; PS, presenilin; RIP, regulated intramembrane proteolysis; S2, site 2; consequences of accumulation of these different cleaved products S3, site 3; ST-HSC, short-term hematopoietic stem cell; T-ALL, T cell acute lym- on hematopoiesis remains to be determined. phocytic leukemia; WT, wild-type. Notch is critical for T cell lineage commitment and maturation as Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 well as marginal zone B cell development (6, 12). Notch1 signaling www.jimmunol.org/cgi/doi/10.4049/jimmunol.1003318 The Journal of Immunology 4245 in common lymphoid progenitors (CLPs) is required for early Virginia Commonwealth University Institutional Animal Care and Use thymocyte development (13), and enforced signaling enhances Committee. T cell development (12). In humans, mutations in the negative Flow cytometry and cell sorting regulatory region of the Notch1 receptor allow ligand-independent cleavage, resulting in excessive Notch1 signaling and the forma- Cell isolation and labeling was conducted as described previously (5). In addition, peritoneal fluid cells were obtained by flushing the peritoneal tion of T cell acute lymphocytic leukemia (T-ALL) (9). Several cavity with PBS (5 ml). BM cells were isolated by flushing excised tibias groups report the use of g-secretase inhibitors (GSIs) as a means and femurs with complete RPMI 1640 medium. Single-cell suspensions of of suppressing the expansion of T-ALL cells and thus as a poten- peripheral lymph node (PLN) cells, thymocytes, and splenocytes were tial method for treating T-ALL and other Notch-dependent lym- created by disrupting inguinal, brachial, axillary lymph nodes, thymus, and spleens, respectively, with glass slides. Cells were labeled following
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