DOCSLIB.ORG

3901.Full.Pdf

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
3901.Full.Pdf Signaling through CD70 Regulates B Cell Activation and IgG Production Ramon Arens, Martijn A. Nolte, Kiki Tesselaar, Bianca Heemskerk, Kris A. Reedquist, René A. W. van Lier and This information is current as Marinus H. J. van Oers of September 23, 2021. J Immunol 2004; 173:3901-3908; ; doi: 10.4049/jimmunol.173.6.3901 http://www.jimmunol.org/content/173/6/3901 Downloaded from References This article cites 43 articles, 26 of which you can access for free at: http://www.jimmunol.org/content/173/6/3901.full#ref-list-1 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 23, 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 © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Signaling through CD70 Regulates B Cell Activation and IgG Production Ramon Arens,1*† Martijn A. Nolte,1*† Kiki Tesselaar,2† Bianca Heemskerk,3† Kris A. Reedquist,† Rene´A. W. van Lier,† and Marinus H. J. van Oers4* CD70, the cellular ligand of the TNF receptor family member CD27, is expressed transiently on activated T and B cells and constitutively on a subset of B cell chronic lymphocytic leukemia and large B cell lymphomas. In the present study, we used B cells constitutively expressing CD70 to study the functional consequences of signaling through CD70. In vitro, CD70 ligation with anti-CD70 mAbs strongly supported proliferation and cell cycle entry of B cells submitogenically stimulated with either anti-CD40 mAb, LPS, or IL-4. In this process, the cell surface receptors CD25, CD44, CD69, CD95, and GL7 were up-regulated, whereas the expression of CD21, CD62L, surface IgM (sIgM), and sIgD was decreased. Addition of CD70 mAb to low dose LPS-stimulated CD70-positive B cells strongly diminished IgG secretion and enhanced production of IgM. Signaling through CD70 on B cells was Downloaded from dependent on the initiation of both PI3K and MEK pathways. In vivo exposure to either CD70 mAb or the CD70 counterreceptor CD27 down-regulated CD62L and sIgM on CD70-positive B cells. CD70 signaling during T cell-dependent immune responses also decreased IgG-specific Ab titers. Together, the in vitro and in vivo data demonstrate that CD70 has potent reverse signaling properties in B cells, initiating a signaling cascade that regulates expansion and differentiation. The Journal of Immunology, 2004, 173: 3901–3908. http://www.jimmunol.org/ fter encountering Ags, B cells undergo a series of acti- LIGHT (12) have been shown to possess signal transduction ca- vation and maturation events, eventually leading to the pacity. Thus, bidirectional signaling might be a general phenom- A formation of Ab-secreting plasma cells and memory enon in interactions of TNF-TNFR family proteins, thereby abro- cells. In T cell-dependent B cell responses, initial B cell activation gating the discrimination between receptor and ligand. is linked to cell contact-mediated interactions and to stimulation by The TNFR family member CD27 is expressed in both mice and cytokines. In delivering contact-dependent signals, members of the humans on the majority of T cells and thymocytes and on subsets TNF-TNFR family guide survival, proliferation, and the formation of NK cells, and hemopoietic stem cells (13–15). In humans, ex- of memory cells and plasma cells (1). pression of CD27 was found on Ag-experienced B cells (16). Its Fine-tuning of the signals from the TNF and TNFR family ligand CD70 is transiently expressed on the surface of activated B, by guest on September 23, 2021 members is largely achieved by tight regulation of their expres- T, and dendritic cells (17, 18). Functional studies have shown that sion. Most of the effects of TNFR-TNF interactions have been CD27 ligation promotes TCR-driven T cell expansion and effector attributed to intracellular signaling events evoked by members of cell formation (19–22). In addition to these costimulatory effects the TNFR family that can couple to two principal classes of cy- on T cells, several in vitro studies have indicated that CD27 liga- toplasmic adaptor proteins: TNF receptor-associated factors and tion on B cells augments differentiation of B cells into Ab-secret- death domain-containing molecules (2). However, functional ex- ing plasma cells (23–25). periments have also provided evidence for signaling through TNF In contrast to the tightly regulated physiological expression of family members (also called reverse signaling). In particular, TNF CD70, constitutive expression of human CD70 is found on several (3), CD153 (CD30L) (4), CD154 (CD40L) (5, 6), CD197 (CD95L) malignancies, including leukemias and lymphomas (26–28), car- (7), CD137 (4-1BBL) (8), CD134 (OX40L) (9), TNF-related ac- cinomas (29, 30), and brain tumors (31). Previously, we showed tivation-induced cytokine (TRANCE)5 (10), TRAIL (11), and that in vitro cross-linking of CD70 on CD70-expressing malignant B cells augmented proliferation, raising the possibility that CD70 functions as an activation receptor on malignant B cells (28). To *Department of Hematology and †Laboratory for Experimental Immunology, Aca- demic Medical Center, University of Amsterdam, Amsterdam, The Netherlands directly examine the consequences of CD70 signaling on B cell Received for publication January 7, 2004. Accepted for publication July 16, 2004. responses in vitro and in vivo, we used B cells constitutively ex- pressing CD70. Our results demonstrate that CD70 ligation results The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance in B cell proliferation and differentiation, especially in conjunction with 18 U.S.C. Section 1734 solely to indicate this fact. with TLR4, CD40, and IL-4R occupation. 1 R.A. and M.A.N. contributed equally to this work. 2 Current address: Department of Pediatrics, Leiden University Medical Center, Lei- Materials and Methods den, The Netherlands. Animals 3 Current address: Department of Clinical Viro-Immunology, Sanquin Research at CLB, Amsterdam, The Netherlands. C57BL/6, CD70 transgenic (Tg), CD27Ϫ/Ϫ (21), CD27Ϫ/Ϫϫ CD70 Tg ␥Ϫ/Ϫ ␥Ϫ/Ϫϫ 4 Address correspondence and reprint requests to Dr. Marinus H. J. van Oers, Aca- mice (22), IFN- (32), and IFN- CD70 Tg (22) on a B6 back- demic Medical Center, Department of Hematology, F4-224, University of Amster- ground were bred and maintained in the facilities of The Netherlands Can- dam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. E-mail address: cer Institute (Amsterdam, The Netherlands). B cell-specific CD70 Tg mice [email protected] were generated by expression of the murine CD70 gene under control of 5 Abbreviations used in this paper: TRANCE, TNF-related activation-induced cyto- the human CD19 promoter, as previously described (22). The analysis of kine; HPE, high performance ELISA; KLH, keyhole limpet hemocyanin; PKB, pro- the frequency and absolute numbers of mature follicular, marginal zone, tein kinase B; sIg, soluble Ig; Tg, transgenic; TNP, trinitrophenol; WT, wild type. and transitional type 1 and type 2 B cells resulted in similar findings among Copyright © 2004 by The American Association of Immunologists, Inc. 0022-1767/04/$02.00 3902 CD70 SIGNALING IN B CELLS wild-type (WT), C27Ϫ/Ϫ, and CD27Ϫ/Ϫϫ CD70 Tg mice (data not shown). Determination of Ig titers by ELISA All mice used were 6–12 wk old. All animal experiments were performed according to institutional and national guidelines. Maxisorb 96-well plates (Nunc, Roskilde, Denmark) were coated with 1 ␮g/ml TNP-BSA in 0.1 M sodium carbonate buffer (pH 9.7) for 16 h at Immunization and adoptive transfers 4°C. After blocking for 1 h with 2% milk in PBS at room temperature, sera were added at an initial dilution of 1/100 with high performance ELISA ␮ Mice were immunized by i.p. injection with 100 g of trinitrophenol (HPE) buffer (CLB, Amsterdam, The Netherlands) and 1/3 sequential di- (TNP)-keyhole limpet hemocyanin (KLH) emulsified in alum (Biosearch lutions, and incubated for3hatroom temperature. Plates were subse- Technologies, Novato, CA). Sera were collected at days 0, 7, and 14. quently washed six times and incubated with 0.1 ␮g/ml biotinylated rat Anti-TNP-specific Ig levels were determined by ELISA, as described anti-mouse Ig (Southern Biotechnology Associates) of the indicated iso- below. In vivo CD70 cross-linking was accomplished by i.p. injection with type in HPE buffer for1hatroom temperature. After washing, plates were 0.5 mg of anti-mouse CD70 mAb (clone 6D8) (18). For adoptive transfer, incubated with streptavidin-conjugated HRP streptavidin for 45 min, ϫ 6 purified splenic B cells (20 10 ) were resuspended in PBS and washed, and developed with tetramethylbenzidine substrate. The reaction injected i.v. was stopped with2MH2SO4, and OD was measured at 450 nm and endpoint titers were expressed as log . B cell purification 3 For measurement of Ig concentrations in 7-day-old cultures, plates were Single-cell suspensions of splenocytes were obtained by mincing through coated with 1 ␮g/ml unlabeled rat anti-mouse Ig of the indicated isotype, cell strainers, and erythrocytes were lysed with ammonium chloride solu- and collected supernatants were 1/10 diluted in HPE buffer.
Load more

Recommended publications
  • (CS-ⅣA-Be), a Novel IL-6R Antagonist, Inhibits IL-6/STAT3
    Author Manuscript Published OnlineFirst on February 29, 2016; DOI: 10.1158/1535-7163.MCT-15-0551 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Chikusetsusaponin Ⅳa butyl ester (CS-Ⅳa-Be), a novel IL-6R antagonist, inhibits IL-6/STAT3 signaling pathway and induces cancer cell apoptosis Jie Yang 1, 2, Shihui Qian 2, Xueting Cai 1, 2, Wuguang Lu 1, 2, Chunping Hu 1, 2, * Xiaoyan Sun1, 2, Yang Yang1, 2, Qiang Yu 3, S. Paul Gao 4, Peng Cao 1, 2 1. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China 2. Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China 3. Shanghai Institute of Materia Medical, Chinese Academy of Sciences, Shanghai, 201203, China 4. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY10065, USA Running title: CS-Ⅳa-Be, a novel IL-6R antagonist, inhibits IL-6/STAT3 Keywords: Chikusetsusaponin Ⅳ a butyl ester (CS- Ⅳ a-Be), STAT3, IL-6R, antagonist, cancer Grant support: P. Cao received Jiangsu Province Funds for Distinguished Young Scientists (BK20140049) grant, J. Yang received National Natural Science Foundation of China (No. 81403151) grant, and X.Y. Sun received National Natural Science Foundation of China (No. 81202576) grant. Corresponding author: Peng Cao Institute: Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu, China Mailing address: 100#, Shizi Street, Hongshan Road, Nanjing, Jiangsu, China Tel: +86-25-85608666 Fax: +86-25-85608666 Email address: [email protected] The first co-authors: Jie Yang and Shihui Qian The authors disclose no potential conflicts of interest.
    [Show full text]
  • BCMA-Targeted Immunotherapy for Multiple Myeloma Bo Yu1, Tianbo Jiang2 and Delong Liu2*
    Yu et al. Journal of Hematology & Oncology (2020) 13:125 https://doi.org/10.1186/s13045-020-00962-7 REVIEW Open Access BCMA-targeted immunotherapy for multiple myeloma Bo Yu1, Tianbo Jiang2 and Delong Liu2* Abstract B cell maturation antigen (BCMA) is a novel treatment target for multiple myeloma (MM) due to its highly selective expression in malignant plasma cells (PCs). Multiple BCMA-targeted therapeutics, including antibody-drug conjugates (ADC), chimeric antigen receptor (CAR)-T cells, and bispecific T cell engagers (BiTE), have achieved remarkable clinical response in patients with relapsed and refractory MM. Belantamab mafodotin-blmf (GSK2857916), a BCMA-targeted ADC, has just been approved for highly refractory MM. In this article, we summarized the molecular and physiological properties of BCMA as well as BCMA-targeted immunotherapeutic agents in different stages of clinical development. Keywords: B cell maturation antigen, BCMA, Belantamab mafodotin, CAR-T, Antibody-drug conjugate, Bispecific T cell engager Introduction B cell maturation antigen (BCMA) Recent advances in novel therapeutics such as prote- BCMA is encoded by a 2.92-kb TNFRSF17 gene located asome inhibitors (PI) and immunomodulatory drugs on the short arm of chromosome 16 (16p13.13) and (IMiD) have significantly improved the treatment out- composed of 3 exons separated by 2 introns (Fig. 1). comes in patients with multiple myeloma (MM) [1–8]. BCMA is a 184 amino acid and 20.2-kDa type III trans- However, most MM patients eventually relapse due to membrane glycoprotein, with the extracellular N the development of drug resistance [9]. In addition, terminus containing a conserved motif of 6 cysteines many of the current popular target antigens, such as [18–21].
    [Show full text]
  • Snapshot: Cytokines III Cristina M
    SnapShot: Cytokines III Cristina M. Tato and Daniel J. Cua Schering-Plough Biopharma (Formerly DNAX Research), Palo Alto, CA 94304, USA Cytokine Receptor Source Targets Major Function Disease Association TNFα Murine: Macrophages, Neutrophils, Inflammatory; ↓ = disregulated fever; increased TNFR,p55; TNFR,p75 monocytes, T cells, macrophages, promotes activation susceptibility to bacterial infection; others monocytes, and production of enhanced resistance to LPS-induced septic Human: endothelial cells acute-phase proteins shock TNFR,p60; TNFR,p80 ↑ = exacerbation of arthritis and colitis LTα Murine: T cells, B cells Many cell types Promotes activation ↓ = defective response to bacterial TNFR,p55; TNFR,p75 and cytotoxicity; pathogens; absence of peripheral lymph development of lymph nodes and Peyer’s patches Human: nodes and Peyer’s TNFR,p60; TNFR,p80 patches LTβ LTβR T cells, B cells Myeloid cells, other Peripheral lymph ↓ = increased susceptibility to bacterial cell types node development; infection; absence of lymph nodes and proinflammatory Peyer’s patches ↑ = ectopic lymph node formation LIGHTa LTβR, DcR3, HVEM Activated T cells, B cells, NK cells, Costimulatory; ↓ = defective CD8 T cell costimulation monocytes, DCs DCs, other tissue promotes CTL activity TWEAK Fn14 Monocytes, Tissue progenitors, Proinflammatory; macrophages, epithelial, promotes cell growth endothelial endothelial for tissue repair and remodeling APRIL TACI, BAFF-R, BCMA Macrophages, DCs B cell subsets Promotes T cell- ↓ = impaired class switching to IgA independent
    [Show full text]
  • Tumor Invasion in Draining Lymph Nodes Is Associated with Treg Accumulation in Breast Cancer Patients
    ARTICLE https://doi.org/10.1038/s41467-020-17046-2 OPEN Tumor invasion in draining lymph nodes is associated with Treg accumulation in breast cancer patients Nicolas Gonzalo Núñez 1,7,9, Jimena Tosello Boari 1,9, Rodrigo Nalio Ramos 1, Wilfrid Richer1, Nicolas Cagnard2, Cyrill Dimitri Anderfuhren 3, Leticia Laura Niborski1, Jeremy Bigot1, Didier Meseure4,5, Philippe De La Rochere1, Maud Milder4,5, Sophie Viel1, Delphine Loirat1,5,6, Louis Pérol1, Anne Vincent-Salomon4,5, Xavier Sastre-Garau4,8, Becher Burkhard 3, Christine Sedlik 1,5, ✉ Olivier Lantz 1,4,5, Sebastian Amigorena1,5 & Eliane Piaggio 1,5 1234567890():,; Tumor-draining lymph node (TDLN) invasion by metastatic cells in breast cancer correlates with poor prognosis and is associated with local immunosuppression, which can be partly mediated by regulatory T cells (Tregs). Here, we study Tregs from matched tumor-invaded and non-invaded TDLNs, and breast tumors. We observe that Treg frequencies increase with nodal invasion, and that Tregs express higher levels of co-inhibitory/stimulatory receptors than effector cells. Also, while Tregs show conserved suppressive function in TDLN and tumor, conventional T cells (Tconvs) in TDLNs proliferate and produce Th1-inflammatory cytokines, but are dysfunctional in the tumor. We describe a common transcriptomic sig- nature shared by Tregs from tumors and nodes, including CD80, which is significantly associated with poor patient survival. TCR RNA-sequencing analysis indicates trafficking between TDLNs and tumors and ongoing Tconv/Treg conversion. Overall, TDLN Tregs are functional and express a distinct pattern of druggable co-receptors, highlighting their potential as targets for cancer immunotherapy.
    [Show full text]
  • Direct Estimation of Differential Networks
    Biometrika (2013), xx, x, pp. 1–16 C 2013 Biometrika Trust Advance Access publication on dd mm year Printed in Great Britain Direct estimation of differential networks BY SIHAI DAVE ZHAO Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA [email protected] 5 T. TONY CAI Department of Statistics, The Wharton School, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [email protected] HONGZHE LI 10 Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA [email protected] SUMMARY It is often of interest to understand how the structure of a genetic network differs between 15 two conditions. In this paper, each condition-specific network is modeled using the precision matrix of a multivariate normal random vector, and a method is proposed to directly estimate the difference of the precision matrices. In contrast to other approaches, such as separate or joint estimation of the individual matrices, direct estimation does not require those matrices to be sparse, and thus can allow the individual networks to contain hub nodes. Under the assumption 20 that the true differential network is sparse, the direct estimator is shown to be consistent in support recovery and estimation. It is also shown to outperform existing methods in simulations, and its properties are illustrated on gene expression data from late-stage ovarian cancer patients. Some key words: Differential network; Graphical model; High dimensionality; Precision matrix 1. INTRODUCTION 25 A complete understanding of the molecular basis of disease will require characterization of the network of interdependencies between genetic components.
    [Show full text]
  • A Soluble Form of B Cell Maturation Antigen, a Receptor for the Tumor Necrosis Factor Family Member APRIL, Inhibits Tumor Cell Growth
    Brief Definitive Report A Soluble Form of B Cell Maturation Antigen, a Receptor for the Tumor Necrosis Factor Family Member APRIL, Inhibits Tumor Cell Growth By Paul Rennert,‡ Pascal Schneider,* Teresa G. Cachero,‡ Jeffrey Thompson,‡ Luciana Trabach,‡ Sylvie Hertig,* Nils Holler,* Fang Qian,‡ Colleen Mullen,‡ Kathy Strauch,‡ Jeffrey L. Browning,‡ Christine Ambrose,‡ and Jürg Tschopp* From the *Institute of Biochemistry, BIL Biomedical Research Center, University of Lausanne, CH-1066 Epalinges, Switzerland; and the ‡Departments of Molecular Genetics, Immunology, Inflammation, Cell Biology, and Protein Engineering, Biogen, Incorporated, Cambridge, Massachusetts 02142 Abstract A proliferation-inducing ligand (APRIL) is a ligand of the tumor necrosis factor (TNF) family that stimulates tumor cell growth in vitro and in vivo. Expression of APRIL is highly upregu- lated in many tumors including colon and prostate carcinomas. Here we identify B cell matura- tion antigen (BCMA) and transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI), two predicted members of the TNF receptor family, as re- ceptors for APRIL. APRIL binds BCMA with higher affinity than TACI. A soluble form of BCMA, which inhibits the proliferative activity of APRIL in vitro, decreases tumor cell prolif- eration in nude mice. Growth of HT29 colon carcinoma cells is blocked when mice are treated once per week with the soluble receptor. These results suggest an important role for APRIL in tumorigenesis and point towards a novel anticancer strategy. Key words: tumor necrosis factor • tumorigenesis • cell survival • apoptosis • cancer therapy Introduction TNF-related ligands can induce pleiotropic biological re- tumorigenesis. APRIL is a close sequence homologue of B sponses.
    [Show full text]
  • Characterisation of Chicken OX40 and OX40L
    Characterisation of chicken OX40 and OX40L von Stephanie Hanna Katharina Scherer Inaugural-Dissertation zur Erlangung der Doktorw¨urde der Tier¨arztlichenFakult¨at der Ludwig-Maximilians-Universit¨atM¨unchen Characterisation of chicken OX40 and OX40L von Stephanie Hanna Katharina Scherer aus Baunach bei Bamberg M¨unchen2018 Aus dem Veterin¨arwissenschaftlichenDepartment der Tier¨arztlichenFakult¨at der Ludwig-Maximilians-Universit¨atM¨unchen Lehrstuhl f¨urPhysiologie Arbeit angefertigt unter der Leitung von Univ.-Prof. Dr. Thomas G¨obel Gedruckt mit Genehmigung der Tier¨arztlichenFakult¨at der Ludwig-Maximilians-Universit¨atM¨unchen Dekan: Univ.-Prof. Dr. Reinhard K. Straubinger, Ph.D. Berichterstatter: Univ.-Prof. Dr. Thomas G¨obel Korreferenten: Priv.-Doz. Dr. Nadja Herbach Univ.-Prof. Dr. Bernhard Aigner Prof. Dr. Herbert Kaltner Univ.-Prof. Dr. R¨udiger Wanke Tag der Promotion: 27. Juli 2018 Meinen Eltern und Großeltern Contents List of Figures 11 Abbreviations 13 1 Introduction 17 2 Fundamentals 19 2.1 T cell activation . 19 2.1.1 The activation of T cells requires the presence of several signals 19 2.1.2 Costimulatory signals transmitted via members of the im- munoglobulin superfamily . 22 2.1.3 Costimulatory signals transmitted via members of the cy- tokine receptor family . 23 2.1.4 Costimulatory signals transmitted via members of the tumour necrosis factor receptor superfamily . 24 2.2 The tumour necrosis factor receptor superfamily . 26 2.2.1 The structure of tumour necrosis factor receptors . 26 2.2.2 Functional classification of TNFRSF members . 28 2.3 The tumour necrosis factor superfamily . 29 2.3.1 The structure of tumour necrosis factor ligands .
    [Show full text]
  • ©Ferrata Storti Foundation
    Malignant Lymphomas research paper Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas apoptosis in Burkitt’s lymphomas with loss of multiple pro-apoptotic proteins AZHAR HUSSAIN, JEAN-PIERRE DOUCET, MARINA I. GUTIÉRREZ, MANZOOR AHMAD, KHALED AL-HUSSEIN, DANIELA CAPELLO, GIANLUCA GAIDANO, KISHOR BHATIA Background and Objectives. Normal B-cells in the ger- nduction of cell death can result from signaling via minal center (GC) may be exposed to both tumor necro- external death receptors such as CD95/Fas and tumor sis factor-related apoptosis inducing ligand (TRAIL) and Inecrosis factor-related apoptosis-inducing ligand Fas-L. Whether abrogation of TRAIL apoptosis is a feature (TRAIL) receptors1-4 or it can result from exposure to in the genesis of B cell lymphomas of GC-phenotype is not chemicals, irradiation and serum starvation.5-7 Signal- known. We assessed the integrity of the TRAIL pathway in ing through external receptors activates the extrinsic Fas-resistant and Fas-sensitive Burkitt’s lymphomas (BLs). pathway8 headed by the apical caspases, caspase-8 and Design and Methods. Expression of TRAIL receptors caspase-10. On the other hand, death resulting from was determined by flow cytometry and Western blots. The chemotherapeutic agents appears to require exclusive- extent of apoptosis following exposure to TRAIL was mea- ly the intrinsic pathway9 involving the mitochondrial sured by annexin-V/propidium iodide dual staining. The release of death activators – cytochrome c and integrity of the Fas and TRAIL apoptotic pathways was Smac/Diablo, which in turn activate the caspase cas- determined by Western blotting to assess cleavage of cade led by caspase-9 via the apoptosome.10,11 While downstream caspases.
    [Show full text]
  • Targeting TRAIL-Rs in KRAS-Driven Cancer Silvia Von Karstedt 1,2,3 and Henning Walczak2,4,5
    von Karstedt and Walczak Cell Death Discovery (2020) 6:14 https://doi.org/10.1038/s41420-020-0249-4 Cell Death Discovery PERSPECTIVE Open Access An unexpected turn of fortune: targeting TRAIL-Rs in KRAS-driven cancer Silvia von Karstedt 1,2,3 and Henning Walczak2,4,5 Abstract Twenty-one percent of all human cancers bear constitutively activating mutations in the proto-oncogene KRAS. This incidence is substantially higher in some of the most inherently therapy-resistant cancers including 30% of non-small cell lung cancers (NSCLC), 50% of colorectal cancers, and 95% of pancreatic ductal adenocarcinomas (PDAC). Importantly, survival of patients with KRAS-mutated PDAC and NSCLC has not significantly improved since the 1970s highlighting an urgent need to re-examine how oncogenic KRAS influences cell death signaling outputs. Interestingly, cancers expressing oncogenic KRAS manage to escape antitumor immunity via upregulation of programmed cell death 1 ligand 1 (PD-L1). Recently, the development of next-generation KRASG12C-selective inhibitors has shown therapeutic efficacy by triggering antitumor immunity. Yet, clinical trials testing immune checkpoint blockade in KRAS- mutated cancers have yielded disappointing results suggesting other, additional means endow these tumors with the capacity to escape immune recognition. Intriguingly, oncogenic KRAS reprograms regulated cell death pathways triggered by death receptors of the tumor necrosis factor (TNF) receptor superfamily. Perverting the course of their intended function, KRAS-mutated cancers use endogenous TNF-related apoptosis-inducing ligand (TRAIL) and its receptor(s) to promote tumor growth and metastases. Yet, endogenous TRAIL–TRAIL-receptor signaling can be therapeutically targeted and, excitingly, this may not only counteract oncogenic KRAS-driven cancer cell migration, invasion, and metastasis, but also the immunosuppressive reprogramming of the tumor microenvironment it causes.
    [Show full text]
  • Differential Signaling Via Tumor Necrosis Factor-Associated Factors (Trafs) by CD27 and CD40 in Mouse B Cells
    Differential Signaling via Tumor Necrosis Factor-Associated Factors (TRAFs) by CD27 and CD40 in Mouse B Cells So-Youn Woo1*, Hae-Kyung Park1 and Gail A. Bishop2,3,4 Department of Microbiology1, College of Medicine, Ewha Womans University, Seoul 158-710, Korea, Department of Microbiology2, and Department of Internal Medicine3, The University of Iowa, Veterans Affairs Medical Center4, Iowa City, IA 52242 ABSTRACT Background: CD27 is recently known as a memory B cell marker and is mainly ex- pressed in activated T cells, some B cell population and NK cells. CD27 is a member of tumor necrosis factor receptor family. Like CD40 molecule, CD27 has (P/S/T/A) X(Q/E)E motif for interacting with TNF receptor-associated factors (TRAFs), and TRAF2 and TRAF5 bindings to CD27 in 293T cells were reported. Methods: To investigate the CD27 signaling effect in B cells, human CD40 extracellular domain containing mouse CD27 cytoplamic domain construct (hCD40-mCD27) was transfected into mouse B cell line CH12.LX and M12.4.1. Results: Through the stimulation of hCD40-mCD27 molecule via anti-human CD40 antibody or CD154 ligation, expression of CD11a, CD23, CD54, CD70 and CD80 were increased and secretion of IgM was induced, which were comparable to the effect of CD40 stimulation. TRAF2 and TRAF3 were recruited into lipid-enriched membrane raft and were bound to CD27 in M12.4.1 cells. CD27 stimulation, however, did not increase TRAF2 or TRAF3 degradation. Conclusion: In contrast to CD40 signaling pathway, TRAF2 and TRAF3 degradation was not observed after CD27 stimulation and it might contribute to prolonged B cell activation through CD27 signaling.
    [Show full text]
  • Mechanism CD40-Dependent Cytolytic − Novel CD154
    Vaccination Produces CD4 T Cells with a Novel CD154−CD40-Dependent Cytolytic Mechanism This information is current as Rhea N. Coler, Thomas Hudson, Sean Hughes, Po-wei D. of October 1, 2021. Huang, Elyse A. Beebe and Mark T. Orr J Immunol published online 21 August 2015 http://www.jimmunol.org/content/early/2015/08/20/jimmun ol.1501118 Downloaded from Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision http://www.jimmunol.org/ • 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: by guest on October 1, 2021 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 © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published August 21, 2015, doi:10.4049/jimmunol.1501118 The Journal of Immunology Vaccination Produces CD4 T Cells with a Novel CD154–CD40-Dependent Cytolytic Mechanism Rhea N. Coler,*,†,‡ Thomas Hudson,* Sean Hughes,* Po-wei D. Huang,* Elyse A. Beebe,* and Mark T. Orr*,† The discovery of new vaccines against infectious diseases and cancer requires the development of novel adjuvants with well-defined activities.
    [Show full text]
  • Reviewed by HLDA1
    Human CD Marker Chart Reviewed by HLDA1 T Cell Key Markers CD3 CD4 CD Alternative Name Ligands & Associated Molecules T Cell B Cell Dendritic Cell NK Cell Stem Cell/Precursor Macrophage/Monocyte Granulocyte Platelet Erythrocyte Endothelial Cell Epithelial Cell CD Alternative Name Ligands & Associated Molecules T Cell B Cell Dendritic Cell NK Cell Stem Cell/Precursor Macrophage/Monocyte Granulocyte Platelet Erythrocyte Endothelial Cell Epithelial Cell CD Alternative Name Ligands & Associated Molecules T Cell B Cell Dendritic Cell NK Cell Stem Cell/Precursor Macrophage/Monocyte Granulocyte Platelet Erythrocyte Endothelial Cell Epithelial Cell CD Alternative Name Ligands & Associated Molecules T Cell B Cell Dendritic Cell NK Cell Stem Cell/Precursor Macrophage/Monocyte Granulocyte Platelet Erythrocyte Endothelial Cell Epithelial Cell CD8 CD1a R4, T6, Leu6, HTA1 b-2-Microglobulin, CD74 + + + – + – – – CD74 DHLAG, HLADG, Ia-g, li, invariant chain HLA-DR, CD44 + + + + + + CD158g KIR2DS5 + + CD248 TEM1, Endosialin, CD164L1, MGC119478, MGC119479 Collagen I/IV Fibronectin + ST6GAL1, MGC48859, SIAT1, ST6GALL, ST6N, ST6 b-Galactosamide a-2,6-sialyl- CD1b R1, T6m Leu6 b-2-Microglobulin + + + – + – – – CD75 CD22 CD158h KIR2DS1, p50.1 HLA-C + + CD249 APA, gp160, EAP, ENPEP + + tranferase, Sialo-masked lactosamine, Carbohydrate of a2,6 sialyltransferase + – – + – – + – – CD1c M241, R7, T6, Leu6, BDCA1 b-2-Microglobulin + + + – + – – – CD75S a2,6 Sialylated lactosamine CD22 (proposed) + + – – + + – + + + CD158i KIR2DS4, p50.3 HLA-C + – + CD252 TNFSF4,
    [Show full text]