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Peripheral Tolerance Checkpoints Peripheral Tolerance Checkpoints Imposed by Ubiquitous Antigen Expression Limit Antigen-Specific B Cell Responses under Strongly Immunogenic Conditions This information is current as of September 30, 2021. Jeremy F. Brooks, Peter R. Murphy, James E. M. Barber, James W. Wells and Raymond J. Steptoe J Immunol published online 24 July 2020 http://www.jimmunol.org/content/early/2020/07/23/jimmun ol.2000377 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2020/07/23/jimmunol.200037 Material 7.DCSupplemental 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 30, 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 © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published July 24, 2020, doi:10.4049/jimmunol.2000377 The Journal of Immunology Peripheral Tolerance Checkpoints Imposed by Ubiquitous Antigen Expression Limit Antigen-Specific B Cell Responses under Strongly Immunogenic Conditions Jeremy F. Brooks, Peter R. Murphy, James E. M. Barber, James W. Wells, and Raymond J. Steptoe A series of layered peripheral checkpoints maintain self-reactive B cells in an unresponsive state. Autoantibody production occurs when these checkpoints are breached; however, when and how this occurs is largely unknown. In particular, how self-reactive B cells are restrained during bystander inflammation in otherwise healthy individuals is poorly understood. A weakness has been the unavailability of methods capable of dissecting physiologically relevant B cell responses without the use of an engineered BCR. Resolving this will provide insights that decipher how this process goes awry during autoimmunity or could be exploited Downloaded from for therapy. In this study, we use a strong adjuvant to provide bystander innate and adaptive signals that promote B cell responsiveness in conjunction with newly developed B cell detection tools to study in detail the ways that peripheral tolerance mechanisms limit the expansion and function of self-reactive B cells activated under these conditions. We show that although self-reactive B cells are recruited into the germinal center, their development does not proceed, possibly because of rapid counterselection. Consequently, differentiation of plasma cells is blunted, and Ab responses are transient and devoid of affinity maturation. We propose this approach, and these tools can be more widely applied to track Ag-specific B cell responses to more http://www.jimmunol.org/ disease-relevant Ags, without the need for BCR transgenic mice, in settings where tolerance pathways are compromised or have been genetically manipulated to drive stronger insights into the biology underlying B cell–mediated autoimmunity. The Journal of Immunology, 2020, 205: 000–000. entral B cell tolerance mediated by clonal deletion and excluded from entry into follicles (4, 5), have a curtailed lifespan receptor editing in the bone marrow (BM) is incomplete, (4), and are deleted from the recirculating repertoire. Cell surface C and self-reactive B cells escape into the peripheral rep- and membrane-bound self-antigens, which are BCR-accessible, ertoire. To counter this, many overlapping and complementary are potent inducers of B cell peripheral tolerance (6, 7), whereas peripheral tolerance mechanisms have evolved to limit the re- soluble proteins are less effective (8). Aside from these B cell– by guest on September 30, 2021 sponsiveness of potentially self-reactive B cells. Peripheral B cell intrinsic mechanisms, the presence or absence of cognate Ag- tolerance normally arises when B cells encounter cognate Ag in a specific T cell help is a major controlling influence on the way that leads to “unproductive” BCR signaling, with chronic Ag productivity of B cell responses. Because strong T cell tolerance recognition being most potent and likely essential for this. Chronic is present for soluble self-proteins (6, 9), B cell responses and Ag stimulation leads to BCR desensitization and anergy (1, 2). autoantibody production to soluble self-proteins may be limited Anergic B cells are unable to effectively solicit T cell help (3), are primarily by loss of T cell help (9). Despite the many mechanisms that control self-reactive B cells, in autoimmune diseases, central and/or peripheral tolerance mech- University of Queensland Diamantina Institute, The University of Queensland, Wool- anisms fail. Transcriptional and molecular analyses have revealed loongabba, Queensland 4102, Australia many pathways that control B cell responsiveness (10), and genetic ORCIDs: 0000-0002-0702-9784 (P.R.M.); 0000-0002-1588-5660 (J.E.M.B.); 0000- 0002-9618-6940 (J.W.W.); 0000-0002-6513-6406 (R.J.S.). studies have defined where control pathways or mechanisms can Received for publication April 9, 2020. Accepted for publication July 6, 2020. fail in autoimmune diseases (reviewed in Ref. 11). Other studies identify “accessory signals” capable of breaking peripheral B cell J.F.B. was supported by a Research Training Program Scholarship and Children’s Hospital Foundation Top-Up award (50209, RPCPHD0072017); J.W.W. was sup- tolerance or bypassing the checkpoints that normally control ported by a Fellowship from Perpetual Trustees and R.J.S. was supported by a B cell responsiveness, including innate signaling (TLRs), T cell University of Queensland Vice Chancellor’s Senior Research Fellowship. collaboration (CD40L), and dendritic cell input (BAFF) (12). Some J.F.B. and R.J.S. designed and performed experiments, analyzed data, and wrote the of these mechanisms are of relevance to autoimmune disease (13) manuscript. P.R.M. and J.E.M.B. performed experiments. J.W.W. provided intellec- tual insights and edited the manuscript. and provide valuable insights into how autoimmune disease is ini- Address correspondence and reprint requests to Dr. Raymond J. Steptoe, Univer- tiated or perpetuated. Importantly, understanding how the respon- sity of Queensland Diamantina Institute, Translational Research Institute, Level 6, siveness of self-reactive B cells is controlled will provide important The University of Queensland, 37 Kent Street, Woolloongabba, QLD 4102, insights into how B cell tolerance can be engineered for therapeutic Australia. E-mail address: [email protected] goals. This would be particularly pertinent for approaches, such as The online version of this article contains supplemental material. gene therapy, in which Ags of interest to which tolerance is desired, Abbreviations used in this article: act.OVA, actin.mOVA; BM, bone marrow; Bmem, memory B cell; CSR, class switch recombination; dLN, draining lymph node; FDC, are expressed chronically or ubiquitously, enabling normal B cell follicular dendritic cell; GC, germinal center; HEL, hen egg lysozyme; OVA/CFA, tolerance mechanisms to be exploited. OVA emulsified in CFA; OVA/IFA, OVA emulsified in IFA; PB, plasmablast; PC, The limited availability of tools to accurately monitor naive plasma cell; Tg, transgenic. endogenous self-reactive B cells in non-BCR–engineered models Copyright Ó 2020 by The American Association of Immunologists, Inc. 0022-1767/20/$37.50 has been a challenge to progress in the understanding of B cell www.jimmunol.org/cgi/doi/10.4049/jimmunol.2000377 2 B CELL TOLERANCE UNDER IMMUNOGENIC CONDITIONS tolerance. Most insights have been gained in models in which the cold PBS/FCS (2.5% v/v). BM was repeatedly passaged through a BCR repertoire is genetically manipulated, typically to increase 21-gauge needle to prepare a single-cell suspension, and erythrocytes were the clonal frequency, or for adoptive transfer, to enable Ag- lysed using ammonium chloride buffer. Ab and tetramer staining was performed as previously described (17), and all staining steps were per- specific B cells to be detected. However, this has the conse- formed on ice. For intracellular tetramer staining, cell suspensions were quence of potentially altering tolerance outcomes (14). We aim to stained for CD138–AF700, CD19–BV785, and FITC-conjugated lineage understand the robustness of peripheral tolerance and B cell mix. In some experiments, cells were also stained with Sca-1 PerCP-Cy5.5 checkpoints in a setting devoid of BCR manipulation and I (BioLegend). Cells were then fixed (Fixation Buffer, 420801; BioLegend) and permeabilized (Fix/Perm Buffer, 55473; BD Biosciences, San Jose, which a self-antigen is expressed ubiquitously at the cell surface. CA) and stained with tetramer (OVA-PE tetramer only) as described for A key goal is to understand whether the knowledge gained using surface tetramer staining (17). BCR transgenic (Tg) settings also stands for a setting in which The absolute cell number was enumerated using Flow-Count Fluoro- there is no genetic manipulation of BCR. We employ newly de- spheres (Beckman Coulter, Brea, CA) as previously described (18). Data veloped tools to dissect
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