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Cell-Independent Plasma Cell Production Involvement of Twisted Involvement of Twisted Gastrulation in T Cell-Independent Plasma Cell Production Sotiris Tsalavos, Katerina Segklia, Ourania Passa, Anna Petryk, Michael B. O'Connor and Daniel Graf This information is current as of September 26, 2021. J Immunol 2011; 186:6860-6870; Prepublished online 13 May 2011; doi: 10.4049/jimmunol.1001833 http://www.jimmunol.org/content/186/12/6860 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2011/05/13/jimmunol.100183 Material 3.DC1 References This article cites 53 articles, 20 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/186/12/6860.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 26, 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 Involvement of Twisted Gastrulation in T Cell-Independent Plasma Cell Production Sotiris Tsalavos,* Katerina Segklia,* Ourania Passa,* Anna Petryk,†,‡ Michael B. O’Connor,‡ and Daniel Grafx Bone morphogenetic protein (BMP) signaling is increasingly implicated in immune cell differentiation and function; however, direct in vivo evidence for such a role is still missing. In this article, we report that Twisted gastrulation (TWSG1), an extracellular reg- ulator of BMP signaling, is expressed in activated B cells and regulates T-independent B cell responses in the mouse. Twsg1-deficient B cells mount stronger T-independent type 2 responses reflected as increased IgM levels and numbers of Ag-specific IgM-secreting cells. BCR stimulation of Twsg1-deficient B cells results in hyperproliferation, hyperresponsiveness, and decreased apoptosis, whereas TLR stimulation results in hyperproliferation and increased IgG3 production. These changes are reflected on the molecular level by increased transcription of Bcl-6, Pax5, and the BMP-responsive gene Id-2. The TWSG1 effects on B cells Downloaded from appear to be cell intrinsic, suggesting that Twsg1 expression in B cells serves to interpret BMP signals on a per-cell basis. In summary, our observations on the role of TWSG1 in B cell function is opening new paths toward the exploration of the role of BMP signaling in immunological processes. The Journal of Immunology, 2011, 186: 6860–6870. roduction of Abs by B cells is one of the key elements of amounts of IgM within 3–4 d after antigenic stimulation (7). an immune response toward the elimination of invading In vitro, a variety of stimuli induce B cells to differentiate to Ig- http://www.jimmunol.org/ P extracellular pathogens. Depending on the nature of the producing plasma cells such as LPS that via engagement of TLR4 Ag, Ab production can be divided into T cell dependent (TD) and (8) induce plasma cells that switch to IgG2b and IgG3 (9). T cell independent (TI). In TD responses, B cell activation through Bone morphogenetic proteins (BMPs) are members of the TGF- the BCR requires a costimulatory signal through CD40, which is b superfamily of secreted signaling molecules. BMPs were orig- provided by CD40L on activated T cells (T cell help) (1). B cell inally named for their ability to induce ectopic bone formation stimulation through repetitive Ags like polysaccharides on bac- (10) but are actually widely involved in development, homeosta- terial cell walls do not require T cell help and are therefore termed sis, and repair of many tissues (11–13), including the hemato- TI responses (2). TI type I (TI-1) and TI type II immune responses poietic system (14–17). Several BMPs are expressed in adult he- (TI-2) can be distinguished on the basis of the Ag. In vivo, LPS (3) matopoietic and lymphoid cell lines, implying BMP signaling in by guest on September 26, 2021 induces TI-1 responses, whereas Ficoll (4) drives TI-2 responses. the regulation of immune function (16). With respect to B cells, Ab production against TI Ags is rapid. TI Ags have been shown to BMP2 can induce growth arrest in the mouse B cell hybridoma localize to the splenic marginal zone (5, 6), thus triggering mainly line HS-72 (18, 19), and BMP6 has been implied in fine-tuning marginal zone B cells (MZB) and B1 cells that produce large the balance between proliferation, apoptosis, and differentiation of developing human B cells (20, 21). After binding of BMPs to their cognate receptors (BMP type I and II receptor heterodimer), *Institute of Immunology, Biomedical Sciences Research Center Alexander Fleming, Smad-dependent and -independent signaling cascades are being 16672 Vari, Greece; †Department of Pediatrics, University of Minnesota, Minneap- olis, MN 55455; ‡Department of Genetics, Cell Biology and Development, Univer- activated (22). In Smad-dependent signaling, Smad1/5/8 are sity of Minnesota, Minneapolis, MN 55455; and xInstitute of Oral Biology, Faculty of phosphorylated and translocated to the nucleus to exert their Medicine, University of Zurich, 8032 Zurich, Switzerland cellular effects. Known target genes of Smad-dependent signaling Received for publication June 2, 2010. Accepted for publication April 7, 2011. are the inhibitor of differentiation (Id) gene family (23, 24). Id This work was supported by the Association for International Cancer Research and proteins are important regulators of lymphocyte development (25, the European Union 6th Framework Program, Network of Excellence MUGEN 26). With respect to adult B cells, Id3 knockout mice show im- (LSHG-CT-2005-005203). paired B cell proliferation and immune responses (18), whereas S.T. planned, performed research, analyzed data, and wrote the manuscript; K.S. and O.P. performed research and analyzed data; A.P. and M.B.O. contributed vital new Id2 regulates MZB differentiation (27), suppresses IgE class reagents; and D.G. designed the project, performed experiments, analyzed data, and switch recombination, and associates with Pax5, thus regulating wrote the manuscript. AID activity (28). These requirements for Id activity indicate the Address correspondence and reprint requests to Dr. Daniel Graf, Institute of Oral potential involvement of BMP signaling in the regulation of im- Biology, Faculty of Medicine, University of Zurich, Plattenstrasse 11, 8032 Zurich, Switzerland. E-mail address: [email protected] mune functions. However, direct in vivo evidence for BMP func- The online version of this article contains supplemental material. tion on lymphocytes is still missing, likely a reflection of the early and complicated phenotypes observed in most BMP knockout Abbreviations used in this article: ASC, Ab-secreting cells; A.U., arbitrary unit; BM, bone marrow; BMP, bone morphogenetic protein; cKO, conditional knockout; FDG, mice (29). fluorescein di-b-D-galactopyranoside; GC, germinal center; Id, inhibitor of differen- BMP signaling is highly regulated in the extracellular space tiation; MHC-II, MHC class II; MLN, mesenteric lymph node; MZB, marginal zone B cell; rBmp2, recombinant BMP2; rChordin, recombinant Chordin; rTwsg1, where BMPs interact with other secreted proteins, mostly antag- recombinant Twsg1; T1, transitional stage 1; TD, T cell dependent; TI, T cell in- onists such as Gremlin, Chordin, Noggin, and Twisted gastrulation dependent; TI-1, TI type I immune response; TI-2, TI type II immune response; (TWSG1). TWSG1 synergistically interacts with chordin or TWSG1, Twisted gastrulation; wt, wild-type. chordin-like molecules to regulate BMP activity (30). Depending Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 on the context, TWSG1 can modulate BMP activity in a positive www.jimmunol.org/cgi/doi/10.4049/jimmunol.1001833 The Journal of Immunology 6861 or negative manner (31–34). Several in vitro studies point toward Immunizations an important role of TWSG1 in the regulation of the immune Eight- to 12-wk-old mice were injected i.p. with 25 mg of the hapten DNP system. TWSG1 expressed by developing thymocytes in a TCR- coupled to LPS (DNP-LPS) in PBS for the TI-1 and with 25 mg DNP3- dependent manner synergizes with Chordin to block BMP2/4 that Ficoll in PBS for the TI-2 (both from Biosearch Technologies). Sera were negatively regulate thymocyte proliferation and differentiation collected at 7 and 14 d. (17). TWSG1 expressed in mature T cells in a Tob-dependent ELISA and ELISPOT manner has been shown to inhibit proliferation and cytokine production of alloreactive CD4+ T cells (35). The in vivo require- For Ig baseline, relative levels from serum and peritoneal cavity Nunc plates were coated with 2 mg/ml goat anti-mouse Ig(H+L). Igs were detected ments for Twsg1 are background dependent. Whereas it has been using HRP-labeled goat anti-mouse IgM, IgG, IgG1, IgG2a, IgG2b, IgG3, reported that Twsg1-deficient mice are viable but show impaired IgA (all from Southern Biotechnology). The same procedure was also lymphocyte development in some mice (36), Twsg1 null mutants carried out for the detection of IgM, IgG2b, and IgG3 in the in vitro on the C57Bl6 background die in utero and display craniofacial cultures. Specific anti-DNP Igs were detected from collected sera by coating the plates with 1 mg/ml DNP-BSA (Calbiochem). Sera obtained malformations of variable severity (37) (D. Graf and O. Passa, from mice and culture supernatants were serially diluted and added in each unpublished observations).
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