DOCSLIB.ORG

T Cells Regulate Peripheral Naive Mature B Cell Survival by Cell–Cell Contact Mediated Through SLAMF6 and SAP

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
T Cells Regulate Peripheral Naive Mature B Cell Survival by Cell–Cell Contact Mediated Through SLAMF6 and SAP T Cells Regulate Peripheral Naive Mature B Cell Survival by Cell −Cell Contact Mediated through SLAMF6 and SAP This information is current as Lihi Radomir, Sivan Cohen, Matthias P. Kramer, Eszter of September 23, 2021. Bakos, Hadas Lewinsky, Avital Barak, Ziv Porat, Richard Bucala, Polina Stepensky, Shirly Becker-Herman and Idit Shachar J Immunol 2017; 199:2745-2757; Prepublished online 13 September 2017; Downloaded from doi: 10.4049/jimmunol.1700557 http://www.jimmunol.org/content/199/8/2745 Supplementary http://www.jimmunol.org/content/suppl/2017/09/13/jimmunol.170055 http://www.jimmunol.org/ Material 7.DCSupplemental References This article cites 46 articles, 16 of which you can access for free at: http://www.jimmunol.org/content/199/8/2745.full#ref-list-1 Why The JI? Submit online. by guest on September 23, 2021 • 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 *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 © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology T Cells Regulate Peripheral Naive Mature B Cell Survival by Cell–Cell Contact Mediated through SLAMF6 and SAP Lihi Radomir,*,1 Sivan Cohen,*,1 Matthias P. Kramer,* Eszter Bakos,* Hadas Lewinsky,* Avital Barak,* Ziv Porat,† Richard Bucala,‡ Polina Stepensky,x Shirly Becker-Herman,* and Idit Shachar* The control of lymphoid homeostasis is the result of a very fine balance between lymphocyte production, proliferation, and apoptosis. In this study, we focused on the role of T cells in the maintenance/survival of the mature naive peripheral B cell population. We show that naive B and T cells interact via the signaling lymphocyte activation molecule (SLAM) family receptor, SLAMF6. This interaction induces cell type–specific signals in both cell types, mediated by the SLAM-associated protein (SAP) family of adaptors. This signaling results in an upregulation of the expression of the cytokine migration inhibitory factor in the T cells and augmented expression of its receptor CD74 on the B cell counterparts, consequently enhancing B cell survival. Downloaded from Furthermore, in X-linked lymphoproliferative disease patients, SAP deficiency reduces CD74 expression, resulting in the pertur- bation of B cell maintenance from the naive stage. Thus, naive T cells regulate B cell survival in a SLAMF6- and SAP-dependent manner. The Journal of Immunology, 2017, 199: 2745–2757. he survival of peripheral naive mature B cells is dependent is modified by the addition of chondroitin sulfate, and this form of on three key cascades: 1) BCR tonic signals (e.g., Iga and CD74 is expressed on the surface of APCs (including monocytes and http://www.jimmunol.org/ T Syk) (1, 2); 2) the B cell activating factor receptor, which B cells) and epithelial cells (7). It was previously shown that mac- binds the B cell activating factor, belonging to the TNF family (the rophage MIF binds to the CD74 extracellular domain, a process that B cell activating factor is also known as BLyS/TALL-1/THANK/ results in the initiation of a signaling pathway in these cells (8). zTNF4) (3); and 3) CD74 (invariant chain) expressed on B cells, CD74 stimulation by MIF induces a signaling cascade leading to and its cognate ligand, macrophage migration inhibitory factor NF-kB activation, as well as transcription of genes that regulate (MIF), which is secreted by almost all cell types. These pathways the entry of the stimulated B cells into the S phase, an increase in have complementary roles in B cell survival (4, 5). DNA synthesis, cell division, and augmented expression of anti- CD74 is a type II integral membrane protein that acts as a chaperone apoptotic proteins (5, 9, 10). The CD74 receptor induces a similar by guest on September 23, 2021 for MHC class II protein expression (6). A small proportion of CD74 survival cascade in oncogenically transformed cells derived from chronic lymphocytic leukemia (CLL) patients (11). To define the molecules whose expression is modulated by CD74 to regulate *Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel; †Department of Biological Services, Weizmann Institute of Science, Rehovot 76100, CLL cell survival, we previously screened for CD74 target genes. Israel; ‡Department of Internal Medicine, Yale University School of Medicine, New One molecule, whose expression was strongly upregulated by x Haven, CT 06520; and Pediatric Hematology-Oncology and Bone Marrow Transplan- CD74 activation, is signaling lymphocyte activation molecule tation Unit, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel 1 (SLAM)F5 (CD84), a member of the SLAM Ig superfamily (12). L.R. and S.C. contributed equally to this work. The SLAM family of receptors includes homophilic and het- ORCIDs: 0000-0002-0289-5261 (M.P.K.); 0000-0003-3059-181X (Z.P.); 0000-0003- 0004-6159 (I.S.). erophilic receptors that modulate the behavior of immune cells (13– 15). These receptors share a common ectodomain organization: a Received for publication April 19, 2017. Accepted for publication August 10, 2017. membrane-proximal Ig-like constant domain, and a membrane- This work was supported in part by the Binational Science Foundation, the Cooper- ation Program in Cancer Research of the Deutsches Krebsforschungszentrum distal Ig variable domain that is responsible for ligand recognition. and Israel’s Ministry of Science, Technology and Space, the Quinquin Foundation, and SLAM receptors interact with SLAM-associated protein (SAP)–related the Rubenstein Charitable Foundation. I.S. is the incumbent of the Dr. Morton and A. Kleiman Professorial Chair. molecules, a group of SRC homology 2 (SH2) domain adaptors. The SAP family is comprised of three members: SAP, Ewing’s L.R., S.C., and M.P.K. designed research, performed research, analyzed data, and wrote the paper; E.B., L.R., H.L., A.B., and Z.P. designed research, performed sarcoma–associated transcript 2 (EAT-2), and, in rodents, EAT-2– research, and analyzed data; R.B. and P.S. provided essential reagents and wrote related transducer (16, 17). SAP controls signal transduction path- the paper; S.B.-H. designed research and analyzed data; and I.S. designed research, analyzed data, and wrote the paper. ways downstream of the SLAM family receptors, and it is a key Address correspondence and reprint requests to Dr. Idit Shachar, Department of regulator of normal immune function in T, NK, and NKT cells (15, Immunology, Weizmann Institute of Science, Herzl Street, Rehovot 76100, Israel. 18). However, B cells do not express SAP (19), and EAT-2 was E-mail address: [email protected] suggested to serve as its functional homolog in these cells (20, 21). The online version of this article contains supplemental material. The SLAM receptors and their adaptor molecules were shown to Abbreviations used in this article: 7-AAD, 7-aminoactinomycin D; CLL, chronic be required for germinal center development and humoral memory lymphocytic leukemia; EAT-2, Ewing’s sarcoma–associated transcript 2; MIF, macro- phage migration inhibitory factor; PB, peripheral blood; SAP, SLAM-associated (22–24). However, their role in naive B cell maintenance has not protein; SH2, SRC homology 2; siRNA, small interfering RNA; SLAM, signaling been assessed in detail. Lymphocyte populations derived from lymphocyte activation molecule; WT, wild-type; XLP, X-linked lymphoproliferative SAP-deficient mice are grossly normal, although occasional mu- disease. tant animals exhibit a higher percentage of T and NK cells, as well Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$35.00 as a lower percentage of B cells in the spleen (25). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1700557 2746 CD4+ T CELLS REGULATE NAIVE B CELL SURVIVAL In the present study, we hypothesized that the SLAM family EAT-2 (ON-TARGET plus SMART pool) and negative control siRNA (ON- might be involved in the regulation of naive B cell survival in the TARGETplus nontargeting pool) (Dharmacon). cross-talk between naive B and naive T cells in an Ag-independent Real-time RT-PCR analysis environment. Our findings demonstrate that interaction of B cells with T cells in a SLAMF6/SAP-mediated manner upregulates RNA extraction and quantitative RT-PCR were performed as previously described (31). Primers are summarized in Table I. CD74 cell surface expression on B cells, inducing their survival in vitro and in vivo. This study highlights a crucial role of SAP Stimulation of murine B cells with CD74 expression on T cells in regulating B cell survival and provides Activation of CD74 was performed as previously described (9). new insights into the requirements for cell collaboration during homeostasis. Blocking SLAMF6 on human B cells Human B cells (1 3 107) were incubated in the presence of 20 mg/ml monoclonal anti–NTB-A Ab (clone NT-7) or mouse IgG1 k isotype control Materials and Methods Abs (BioLegend), as previously described (32). Mice Coculture C57BL/6, CD74-deficient (26), MIF-deficient (27), SLAMF5-deficient (24), SH2D1A (SAP)-deficient (25) SLAMF6-deficient (28), and SLAMF1- Coculture of murine primary B and T cells was performed in 24-well plates with 10% FCS (w/v) Iscove’s medium. Transwell experiments were performed deficient mice (29) were used in this study. All animal procedures were m approved by the Animal Research Committee at the Weizmann Institute of in 24-well plates containing an insert with a 5- m pore polycarbonate Science.
Load more

Recommended publications
  • B-Cell Reconstitution Recapitulates B-Cell Lymphopoiesis Following Haploidentical BM Transplantation and Post-Transplant CY
    Bone Marrow Transplantation (2015) 50, 317–319 © 2015 Macmillan Publishers Limited All rights reserved 0268-3369/15 www.nature.com/bmt LETTER TO THE EDITOR B-cell reconstitution recapitulates B-cell lymphopoiesis following haploidentical BM transplantation and post-transplant CY Bone Marrow Transplantation (2015) 50, 317–319; doi:10.1038/ From week 9, the proportion of transitional B cells progressively bmt.2014.266; published online 24 November 2014 decreased (not shown), whereas that of mature B cells increased (Figure 1d). To further evaluate the differentiation of mature cells, we included markers of naivety (IgM and IgD) and memory (IgG) in The treatment of many hematological diseases benefits from our polychromatic panel. At week 9, when a sufficient proportion myeloablative or non-myeloablative conditioning regimens of cells were available for the analysis, B cells were mostly naive followed by SCT or BMT. HLA-matched donors are preferred but and remained so for 26 weeks after haploBMT (Figure 1d). Despite not always available. Instead, haploidentical donors can be rapidly low, the proportion of memory B cells reached levels similar to identified. Unmanipulated haploidentical BMT (haploBMT) with that of marrow donors (Supplementary Figure 1D). non-myeloablative conditioning and post-transplant Cy has been To further investigate the steps of B-cell maturation, we developed to provide a universal source of BM donors.1 Cy, analyzed CD5, a regulator of B-cell activation, and CD21, a which depletes proliferating/allogeneic cells, prevents GVHD.1 component of the B-cell coreceptor complex, on transitional B Importantly, the infection-related mortality was remarkably low, cells. These surface markers characterize different stages of 5,6 5,6 suggesting effective immune reconstitution.1,2 However, a transitional B-cell development.
    [Show full text]
  • B Cell Subsets in Autoimmune Disease B Cell Subsetsb Cell in Autoimmune Disease
    Thesis for doctoral degree (Ph.D.) 2018 Thesis for doctoral degree (Ph.D.) 2018 (Ph.D.) degree doctoral Thesis for B cell subsets in autoimmune disease B cell subsets in autoimmune disease B cell in autoimmune subsets Katrin Habir Katrin Habir From DEPARTMENT OF MEDICINE Karolinska Institutet, Stockholm, Sweden B CELL SUBSETS IN AUTOIMMUNE DISEASE Katrin Habir Stockholm 2018 All previously published papers were reproduced with permission from the publisher. Published by Karolinska Institutet. Printed by Printed by Eprint AB 2018 © Katrin Habir, 2018 ISBN 978-91-7676-900-3 B CELL SUBSETS IN AUTOIMMUNE DISEASE THESIS FOR DOCTORAL DEGREE (Ph.D.) AKADEMISK AVHANDLING som för avläggande av medicine doktorsexamen vid Karolinska Institutet offentligen försvaras i CMM Lecture Hall, L8:00, Center for Molecular Medicine (CMM), Karolinska Universitetssjukhuset, Solna. Friday February 2nd 2018 at 09.00 by Katrin Habir Principal Supervisor: Opponent: Dr. Stephen Malin Associate Professor Bengt Johansson Lindbom Karolinska Institutet Lunds Universitet Department of Medicine Department of Experimental Medical Science Division of Cardiovascular Medicine Division of Adaptive Immunity Co-supervisors: Examination Board: Professor Gunilla Karlsson Hedestam Professor Birgitta Heyman Karolinska Institutet Uppsala Universitet Department of Microbiology, Tumor and Cell Department of Medical Biochemistry and Biology Microbiology Division of Microbiology-Immunology Professor Dan Grandér Karolinska Institutet Associate Professor Lisa Westerberg Department of Oncology-Pathology Karolinska Institutet Department of Microbiology, Tumor and Cell Biology Associate Professor Angela Silveira Karolinska Institutet Department of Medicine Division of Cardiovascular Medicine “We still do not know one thousandth of one percent of what nature has revealed to us.” Albert Einstein THIS THESIS IS DEDICATED TO MY BELOVED ONES ABSTRACT B lymphocytes are a type of white blood cells, belonging to the adaptive arm of the immune system and involved in creating immunological memory.
    [Show full text]
  • Self-Reactive B Cells in the GALT Are Actively Curtailed to Prevent Gut Inflammation
    Self-reactive B cells in the GALT are actively curtailed to prevent gut inflammation Ashima Shukla, … , John R. Apgar, Robert C. Rickert JCI Insight. 2019;4(16):e130621. https://doi.org/10.1172/jci.insight.130621. Research Article Immunology Inflammation Immune homeostasis in the gut-associated lymphoid tissues (GALT) is critical to prevent the development of inadvertent pathologies. B cells, as the producers of antibodies and cytokines, play an important role in maintaining the GALT homeostasis. However, the mechanism by which B cells specifically direct their responses toward non-self-antigens and become ignorant to self-antigens in the GALT is not known. Therefore, we developed what we believe to be a novel mouse model by expressing duck egg lysozyme (DEL) in gut epithelial cells in presence of HEL-reactive B cells. Notably, we observed a transient activation and rapid deletion of self-reactive B cells in Peyer’s patches and mesenteric lymph nodes upon self-antigen exposure. The survival of self-reactive B cells upon exposure to their self-antigen was partially rescued by blocking receptor editing but could be completely rescued by stronger survival signal, such as ectopic expression of BCL2. Importantly, rescuing the self-reactive B cells promoted production of autoantibodies and gut inflammation. Mechanistically, we identify a specific activation of TGF-β signaling in self-reactive B cells in the gut and a critical role of this pathway in maintaining peripheral tolerance. Collectively, our studies describe functional consequences and the fate of self-reactive B cells in GALT and provide potentially novel mechanistic insights governing self-tolerance of B cells in the gut.
    [Show full text]
  • The Pathogenic Role of Innate Lymphoid Cells in Autoimmune-Related and Inflammatory Skin Diseases
    Cellular & Molecular Immunology www.nature.com/cmi REVIEW ARTICLE The pathogenic role of innate lymphoid cells in autoimmune-related and inflammatory skin diseases Suqing Zhou 1, Qianwen Li1, Haijing Wu1 and Qianjin Lu1 Innate lymphoid cells (ILCs), as an important component of the innate immune system, arise from a common lymphoid progenitor and are located in mucosal barriers and various tissues, including the intestine, skin, lung, and adipose tissue. ILCs are heterogeneous subsets of lymphocytes that have emerging roles in orchestrating immune response and contribute to maintain metabolic homeostasis and regulate tissue inflammation. Currently, more details about the pathways for the development and differentiation of ILCs have largely been elucidated, and cytokine secretion and downstream immune cell responses in disease pathogenesis have been reported. Recent research has identified that several distinct subsets of ILCs at skin barriers are involved in the complex regulatory network in local immunity, potentiating adaptive immunity and the inflammatory response. Of note, additional studies that assess the effects of ILCs are required to better define how ILCs regulate their development and functions and how they interact with other immune cells in autoimmune-related and inflammatory skin disorders. In this review, we will distill recent research progress in ILC biology, abnormal functions and potential pathogenic mechanisms in autoimmune-related skin diseases, including systemic lupus erythematosus (SLE), scleroderma and inflammatory diseases, as well as psoriasis and atopic dermatitis (AD), thereby giving a comprehensive review of the diversity and plasticity of ILCs and their unique functions in disease conditions with the aim to provide new insights into molecular diagnosis and suggest potential value in immunotherapy.
    [Show full text]
  • Transitional B Cells in Early Human B Cell Development – Time to Revisit the Paradigm?
    ORIGINAL RESEARCH published: 02 December 2016 doi: 10.3389/fimmu.2016.00546 Transitional B Cells in Early Human B Cell Development – Time to Revisit the Paradigm? Victoria G. Martin1†, Yu-Chang Bryan Wu2†, Catherine L. Townsend1, Grace H. C. Lu2, Joselli Silva O’Hare3, Alexander Mozeika4, Anthonius C. C. Coolen4, David Kipling5, Franca Fraternali2,4 and Deborah K. Dunn-Walters1,3* 1 Division of Infection, Immunity and Inflammatory Disease, Faculty of Life Sciences & Medicine, King’s College London, London, UK, 2 Randall Division of Cell and Molecular Biophysics, Faculty of Life Sciences & Medicine, King’s College London, Edited by: London, UK, 3 Faculty of Health and Medical Sciences, School of Biosciences and Medicine, University of Surrey, Guildford, Ana María Hernández, Surrey, UK, 4 Faculty of Life Sciences & Medicine, Institute for Mathematical and Molecular Biomedicine, King’s College Center of Molecular Immunology, London, London, UK, 5 Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK Cuba Reviewed by: The B cell repertoire is generated in the adult bone marrow by an ordered series of gene Tam Quach, Feinstein Institute for Medical rearrangement processes that result in massive diversity of immunoglobulin (Ig) genes Research, USA and consequently an equally large number of potential specificities for antigen. As the Harry W. Schroeder, process is essentially random, the cells exhibiting excess reactivity with self-antigens are University of Alabama at Birmingham, USA generated and need to be removed from the repertoire before the cells are fully mature. *Correspondence: Some of the cells are deleted, and some will undergo receptor editing to see if changing Deborah K.
    [Show full text]
  • Cd1d Regulates B Cell Development but Not B Cell Accumulation and IL10 Production in Mice with Pathologic CD5+ B Cell Expansion Victoria L
    Palmer et al. BMC Immunology (2015) 16:66 DOI 10.1186/s12865-015-0130-z RESEARCH ARTICLE Open Access Cd1d regulates B cell development but not B cell accumulation and IL10 production in mice with pathologic CD5+ B cell expansion Victoria L. Palmer, Vincent K. Nganga, Mary E. Rothermund, Greg A. Perry and Patrick C. Swanson* Abstract Background: CD1d is a widely expressed lipid antigen presenting molecule required for CD1d-restricted invariant natural killer T (iNKT) cell development. Elevated CD1d expression is detected in CD5+ IL10-producing B cells, called B10 B cells, and is correlated with poorer prognosis in chronic lymphocytic leukemia (CLL), a CD5+ B cell malignancy with B10-like functional properties. Whether CD1d expression regulates CD5+ B cell accumulation, IL10 competence, and antibody production in naïve mice with pathologic CD5+ B cell expansion remains untested. Results: Using three different transgenic mouse models of benign or leukemic CD5+ Bcellexpansion,wefoundthat CD1d was differentially expressed on CD5+ B cells between the three models, but loss of CD1d expression had no effect on CD5+ B cell abundance or inducible IL10 expression in any of the models. Interestingly, in the CLL-prone Eμ-TCL1 model, loss of CD1d expression suppressed spontaneous IgG (but not IgM) production, whereas in the dnRAG1xEμ-TCL1 (DTG) model of accelerated CLL, loss of CD1d expression was associated with elevated numbers of splenic CD4+ and CD8+ T cells and an inverted CD4+:CD8+ T cell ratio. Unexpectedly, before leukemia onset, all three transgenic CD1d-deficient mouse strains had fewer splenic transitional B cells than their CD1d-proficient counterparts.
    [Show full text]
  • High-Dimensional Flow-Cytometric Analysis of Human B-Cell Populations
    High-dimensional flow-cytometric analysis of human B-cell populations The BD FACSCelesta™ cell analyzer and FlowJo™ software together enable deep analysis of B-cell biology Features B-cell development is a stepwise process initiated in the fetal • High-resolution analysis of over 7 distinct liver and postnatal bone marrow and continued in the peripheral B-cell subsets using a 12-color panel lymphoid organs upon encounter with antigens. The various stages of B-cell differentiation can be identified by evaluating • Evaluation of distinct B-cell populations across different tissue types the expression and levels of distinct cell-surface markers, which are regulated throughout the course of B-cell differentiation. • Robust data analysis using the t-SNE analysis feature of FlowJo™ v10 software Multicolor flow cytometry is a powerful tool that has driven key discoveries in B-cell biology by facilitating the investigation of B-cell markers during cell development, differentiation and pathologies such as immunodeficiency, autoimmune disorders and malignancies. This datasheet describes a 12-color flow cytometry panel for the analysis of the most prominent B-cell subsets in human peripheral blood and bone marrow. The 12-color panel included markers uniquely expressed in certain cell subsets such as CD138 in plasma cells, as well as co-expressed markers (CD38 and CD24) (Figure 1A). The panel was designed to identify immature/transitional subsets (T1, T2 and T3), naive B cells, memory B-cell subsets, plasmablasts and plasma cells. The cells in the naive B-cell subset that uniquely express the ATP-binding cassette B1 (ABCB1) transporter were identified by analysis of cell extrusion of MitoTracker™ Green FM (ThermoFisher), a green-fluorescent mitochondrial stain.
    [Show full text]
  • Transitional B Cells Involved in Autoimmunity and Their Impact On
    Zhou et al. J Transl Med (2020) 18:131 https://doi.org/10.1186/s12967-020-02289-w Journal of Translational Medicine REVIEW Open Access Transitional B cells involved in autoimmunity and their impact on neuroimmunological diseases Yang Zhou1†, Ying Zhang1†, Jinming Han1, Mengge Yang1, Jie Zhu1,2 and Tao Jin1* Abstract Transitional B cells (TrB cells) represent a crucial link between immature B cells in the bone marrow and mature peripheral B cells. Although TrB cells represent one of the regulatory B cell subpopulations in healthy individuals, the frequency of CD24hiCD38hi TrB cells in circulation may be altered in individuals with autoimmune diseases, such as multiple sclerosis, neuromyelitisoptica spectrum disorders, systemic lupus erythematosus, Sjögren’s syndrome, rheumatoid arthritis, systemic sclerosis, and juvenile dermatomyositis. Although TrB cells play regulatory roles under infammatory conditions, consequences of their functional impairment vary across autoimmune diseases. Since the origin, development, and function of TrB cells, especially in humans, remain unclear and controversial, this review aimed to discuss the characteristics of TrB cells at steady state and explore their role in various immune diseases, including autoimmune rheumatic diseases and neuroimmunological diseases. Keywords: Transitional B cells, TrB-associated molecules, Autoimmune rheumatic diseases, Multiple sclerosis, Neuromyelitisoptica spectrum disorders Introduction as immature transitional B cells, where they eventually B cells are centrally involved in the pathogenesis of auto- develop into mature B cells [4, 5]. However, in humans, immunity, exerting diverse efects such as contribut- the maturation of TrB cells may not be restricted to the ing to T cell activation through antibody production spleen [5]. TrB cells account for approximately 4% of all and antigen presentation.
    [Show full text]
  • Characterization of Human T-Bet-Expressing B Lymphocytes and Their Role in the Hiv Immune Response
    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2017 Characterization Of Human T-Bet-Expressing B Lymphocytes And Their Role In The Hiv Immune Response James Knox University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Allergy and Immunology Commons, Cell Biology Commons, Immunology and Infectious Disease Commons, Medical Immunology Commons, and the Microbiology Commons Recommended Citation Knox, James, "Characterization Of Human T-Bet-Expressing B Lymphocytes And Their Role In The Hiv Immune Response" (2017). Publicly Accessible Penn Dissertations. 2742. https://repository.upenn.edu/edissertations/2742 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2742 For more information, please contact [email protected]. Characterization Of Human T-Bet-Expressing B Lymphocytes And Their Role In The Hiv Immune Response Abstract Humoral immunity is critical for the prevention and control of viral infections, yet the specific B cells and mechanisms regulating antiviral responses in humans remain poorly defined. The Th1-associated transcription factor T-bet coordinates intracellular pathogen immune responses, and recent murine studies identified a -bet-exprT essing B cell subset that mediates humoral antiviral immunity, but an analogous cell population has not been identified in humans. In this study, we sought to investigate the role of T-bet-expressing B cells during human viral infections. We identified -betT expression within the memory B cell compartment of healthy individuals and described a relationship between the transcription factor and IgG1 and IgG3, two antiviral antibody isotypes. The T-bet+ B cell population was comprised of two discrete subsets: T-bet low resting memory cells and a highly activated, transcriptionally distinct T-bet high subset displaying an atypical memory phenotype.
    [Show full text]
  • An Overview of B Cells – from Discovery to Therapy Mini Review
    An Overview of B Cells – from Discovery to Therapy Mini Review Immunology In the past two decades, significant advances have been made in B cell biology. These critical immune cells remain an active area of research particularly because disruption of B cell development or function results in a number of autoimmune diseases and malignancies. In addition to producing antibodies, B cells are professional antigen presenting cells that can present antigens to T cells to generate effective immune responses. B cells are however, a heterogeneous population of cells at different stages of maturation along the lineage, each with unique functional properties. This mini-review provides a brief history of the discovery of B cells, as well as describes the characteristics of each B cell lineage and the processes of B cell development, maturation and activation. Finally, we highlight the application of B cell biology in the development of novel therapeutics for the treatment of B cell mediated diseases. Contents 1. A brief history of the discovery of B cells 2. B cell development and maturation 3. B cell activation and the humoral immune response 4. B cells as therapeutic targets 1. A brief history of the discovery of B cells B cells are an integral part of the adaptive immune response. They represent a distinct lineage, with separate and unique functions from T cells. In addition to producing antibodies, they perform critical immune functions such as generating immunological memory, antigen presentation and regulatory cytokine production. Our current understanding of B cell biology was initiated in 1965 with a landmark study by Max Cooper and Robert Good.
    [Show full text]
  • PI3Kδ Hyper-Activation Promotes Development of B Cells That
    ARTICLE DOI: 10.1038/s41467-018-05674-8 OPEN PI3Kδ hyper-activation promotes development of B cells that exacerbate Streptococcus pneumoniae infection in an antibody-independent manner Anne-Katrien Stark 1,2, Anita Chandra1,2,3,4, Krishnendu Chakraborty1,3, Rafeah Alam1, Valentina Carbonaro1, Jonathan Clark5, Srividya Sriskantharajah6, Glyn Bradley7, Alex G. Richter8,9, Edward Banham-Hall1,3,4, Menna R. Clatworthy10, Sergey Nejentsev3, J. Nicole Hamblin6, Edith M. Hessel6, Alison M. Condliffe11 & Klaus Okkenhaug 1,2 1234567890():,; Streptococcus pneumoniae is a major cause of pneumonia and a leading cause of death world- wide. Antibody-mediated immune responses can confer protection against repeated expo- sure to S. pneumoniae, yet vaccines offer only partial protection. Patients with Activated PI3Kδ Syndrome (APDS) are highly susceptible to S. pneumoniae. We generated a conditional knock-in mouse model of this disease and identify a CD19+B220− B cell subset that is induced by PI3Kδ signaling, resides in the lungs, and is correlated with increased suscept- ibility to S. pneumoniae during early phases of infection via an antibody-independent mechanism. We show that an inhaled PI3Kδ inhibitor improves survival rates following S. pneumoniae infection in wild-type mice and in mice with activated PI3Kδ. These results suggest that a subset of B cells in the lung can promote the severity of S. pneumoniae infection, representing a potential therapeutic target. 1 Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge CB21 3AT, UK. 2 Division of Immunology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK. 3 Department of Medicine, University of Cambridge, Cambridge CB2 OQQ, UK.
    [Show full text]
  • Molecular Regulation of Peripheral B Cells and Their Progeny in Immunity
    Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Molecular regulation of peripheral B cells and their progeny in immunity Mark R. Boothby,1,2 Emily Hodges,3 and James W. Thomas1,2 1Department of Pathology–Microbiology–Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA; 2Department of Medicine, Rheumatology Division, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA; 3Department of Biochemistry, Vanderbilt Genetics Institute, Nashville, Tennessee 37232, USA Mature B lymphocytes are crucial components of adap- potentials. A vast trove of findings illuminates the tran- tive immunity, a system essential for the evolutionary fit- scriptional regulation and chromatin modifications (for ness of mammals. Adaptive lymphocyte function requires convenience, referred to here as epigenetic) that program an initially naïve cell to proliferate extensively and its developmental progression from common lymphoid pro- progeny to have the capacity to assume a variety of fates. genitors (CLPs) to the establishment of the naïve popu- These include either terminal differentiation (the long- lations of mature T and B cells (e.g., for review, see lived plasma cell) or metastable transcriptional repro- Busslinger 2004; Champhekar et al. 2015). Similarly, the gramming (germinal center and memory B cells). In this process of diversifying subsets of T cells after their activa- review, we focus principally on the regulation of differen- tion has been studied and reviewed intensively (Glimcher tiation and functional diversification of the “B2” subset. and Murphy 2000; Fang and Zhu 2017; Henning et al. An overview is combined with an account of more recent 2018). Mature B lymphocytes also have the potential to advances, including initial work on mechanisms that distribute their progeny among several distinct fates or eliminate DNA methylation and potential links between intermediate states after they have encountered a ligand intracellular metabolites and chromatin editing.
    [Show full text]