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Antigens Cell-Independent Or T Cell-Dependent Induced Early In Long-Lived Bone Marrow Plasma Cells Are Induced Early in Response to T Cell-Independent or T Cell-Dependent Antigens This information is current as of October 2, 2021. Alexandra Bortnick, Irene Chernova, William J. Quinn III, Monica Mugnier, Michael P. Cancro and David Allman J Immunol 2012; 188:5389-5396; Prepublished online 23 April 2012; doi: 10.4049/jimmunol.1102808 Downloaded from http://www.jimmunol.org/content/188/11/5389 Supplementary http://www.jimmunol.org/content/suppl/2012/04/24/jimmunol.110280 Material 8.DC1 http://www.jimmunol.org/ References This article cites 48 articles, 23 of which you can access for free at: http://www.jimmunol.org/content/188/11/5389.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on October 2, 2021 • 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 © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Long-Lived Bone Marrow Plasma Cells Are Induced Early in Response to T Cell-Independent or T Cell-Dependent Antigens Alexandra Bortnick,* Irene Chernova,* William J. Quinn, III,* Monica Mugnier,† Michael P. Cancro,* and David Allman* The signals required to generate long-lived plasma cells remain unresolved. One widely cited model posits that long-lived plasma cells derive from germinal centers (GCs) in response to T cell-dependent (TD) Ags. Thus, T cell-independent (TI) Ags, which fail to sustain GCs, are considered ineffective at generating long-lived plasma cells. However, we show that long-lived hapten-specific plasma cells are readily induced without formation of GCs. Long-lived plasma cells developed in T cell-deficient mice after a single immunization with haptenated LPS, a widely used TI Ag. Long-lived plasma cells also formed in response to TD Ag when the GC response was experimentally prevented. These observations establish that long-lived plasma cells are induced in both TI and TD Downloaded from responses, and can arise independently of B cell maturation in GCs. The Journal of Immunology, 2012, 188: 5389–5396. ntibodies play pivotal roles in host defense and can cause and therefore more protective, Abs (12). This viewpoint is sup- disease when specific for self-antigens. Plasma cells, the ported by data showing that the bulk of BM plasma cells induced main source of Abs, are thought to consist of two pools: by TD Ag secrete high-affinity class-switched Abs (13). However, A http://www.jimmunol.org/ short-lived cells that secrete low-affinity IgM Abs and form extra- the notion that long-lived plasma cells must derive from GCs follicular foci in the spleen or lymph node; and long-lived cells appears incompatible with recent data showing that low-affinity that secrete high-affinity, isotype-switched Abs found mainly in IgM Abs can mediate long-term protection against certain mi- the bone marrow (BM) (1). Whereas short-lived plasma cells die crobial pathogens (14). within 3–5 d (2), long-lived plasma cells are thought to persist for Classically, Ags that do not engage Th cells are thought to months or years in mice and perhaps decades in people (3–6). generate transient IgM responses that reflect the activity of short- Sustained serum Ab titers due to long-lived plasma cells are es- lived plasma cells (2, 15–17). These T cell-independent (TI) Ags sential for protective immunity against many pathogens (3, 7–9). may also generate short-lived GCs that fail to engender SHM Therefore, defining the events underlying the generation of long- and affinity maturation (18, 19). However, several recent studies by guest on October 2, 2021 lived plasma cells is essential for understanding how Ab-mediated challenge the long-standing paradigm that TI Ab responses are immunity is established and maintained. always short-lived. For instance, immunization of T cell-deficient Why some plasma cells achieve longevity whereas others are mice with the spirochete Borrelia hermsii induces long-term IgM- short-lived is not known. One current and widely cited model posits dependent protection (20, 21). IgM Abs induced by the intracel- that long-lived plasma cells emanate chiefly from germinal centers lular bacteria Franciscella tularensis and Ehrlichia muris also (GCs) in response to T cell-dependent (TD) Ags (4, 10). GCs are mediate long-term protection; however, these responses may re- microanatomical structures enriched with Ag-stimulated B cells flect the continuous generation of short-lived Ab-secreting cells undergoing class switch recombination, somatic hypermutation (22, 23). More recently, E. muris and the encapsulated bacterium (SHM), and affinity-based selection (11). Indeed, it was proposed Streptococcus pneumoniae were shown to elicit a long-standing recently that long-lived plasma cells are generated preferentially pool of Ag-specific BM plasma cells in T cell-sufficient mice (24– within the GC to favor the continuous secretion of high-affinity, 26). Although the latter work provides evidence that typical TD Ags are not unique in their ability to induce long-term Ab re- sponses, these studies did not address whether long-lived plasma *Department of Pathology and Laboratory Medicine, University of Pennsylvania cells can be generated in the absence of T cells. Therefore, School of Medicine, Philadelphia, PA 19104; and †Laboratory of Lymphocyte Biol- ogy, The Rockefeller University, New York, NY 10065 whether T cell-derived signals are strictly required to generate Received for publication September 28, 2011. Accepted for publication March 22, long-lived plasma cells remains unclear. 2012. Our work addresses the capacity of TI and TD Ags to induce This work was supported by National Institutes of Health Grants T32 AI070099 (to long-lived plasma cells during the earliest phases of plasma cell A.B.) and R21 AI090700 (to D.A.) and Department of Defense Grant W81WWXWH- differentiation. We show that haptenated LPS, a classic type 1 TI 10-1-0185 (to M.P.C.). Ag, readily induces a long-standing pool of BM plasma cells in Address correspondence and reprint requests to Dr. David Allman, University of mice that lack T cells. These Ab-secreting cells are detected for Pennsylvania, 36th & Hamilton Walk, 230 John Morgan Building, Philadelphia, PA 19104-6082. E-mail address: [email protected] .100 d after a single immunization, exhibit a t1/2 of 45–55 d, and The online version of this article contains supplemental material. arise despite an inability to detect Ag-induced GC B cells. These Abbreviations used in this article: BCL6, B cell lymphoma gene-6; BM, bone mar- data challenge the long-standing notion that type 1 TI Ags fail to row; CGG, chicken g-globulin; GC, germinal center; IR, ionizing radiation; NP, (4- induce the formation of long-lived plasma cells, and suggest that hydroxy-3-nitrophenyl)acetyl; SHM, somatic hypermutation; TD, T cell-dependent; long-lived plasma cells need not arise from GCs. Similarly, we TI, T cell-independent. show that long-lived plasma cells also form in response to a Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 standard TD Ag without undergoing maturation and selection in www.jimmunol.org/cgi/doi/10.4049/jimmunol.1102808 5390 LONG-LIVED PLASMA CELLS GCs, as plasma cells secreting low-affinity IgM Abs persisted for Statistical analysis $100 d in mice in which we prevented GC formation early in Significant differences in plasma cell frequencies between two experimen- these responses. These findings indicate that maturation in GCs is tal groups were evaluated with the unpaired two-tailed t test, using Excel not requisite for achieving longevity in the plasma cell lineage and software. also suggest that competence to enter long-lived plasma cell pools is achieved early in TI and TD Ab responses. Results Persistence of LPS-induced TI plasma cells Materials and Methods 2 2 2 2 We immunized C57BL/6 (B6) or T cell-deficient B6.TcRb / d / Mice adults with the hapten (4-hydroxy-3-nitrophenyl)acetyl (NP) con- 2 2 2 2 C57BL/6 (B6), B6.TcRb / d / , and MD4 Ig transgenic (anti-HEL) jugated to LPS or CGG. We studied the Ab response to NP in B6 females (age 8–10 wk) were obtained from Jackson Laboratories. 2 2 background mice for two reasons. First, the kinetics of both AID / mice were provided by Dr. Nina Papavasiliou (The Rockefeller University). All animal procedures were approved by the University of plasma cell differentiation and GC-dependent somatic hypermu- Pennsylvania Office of Regulatory Affairs. tation and selection in response to NP are well established (29, 30). Second, NP-responsive B-lineage cells are readily identified Chimeras by flow cytometry with NP-conjugated fluorescent proteins, and Hosts were exposed to whole-body radiation (900 R) 5 d post immunization, such cells can be resolved in conventional inbred mice without 6 and then given 1 3 10 BM cells i.v. from MD4 IgH+L transgenic mice in using Ig transgenes to increase frequencies of Ag-responsive which all B cells are specific for hen egg lysozyme (27). BM cells were depleted of CD3ε+ cells using a MACs LD column before i.v.
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