The Unexpected Role of Lymphotoxin Β Receptor Signaling

Total Page:16

File Type:pdf, Size:1020Kb

The Unexpected Role of Lymphotoxin Β Receptor Signaling Oncogene (2010) 29, 5006–5018 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 www.nature.com/onc REVIEW The unexpected role of lymphotoxin b receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development MJ Wolf1, GM Seleznik1, N Zeller1,3 and M Heikenwalder1,2 1Department of Pathology, Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland and 2Institute of Virology, Technische Universita¨tMu¨nchen/Helmholtz Zentrum Mu¨nchen, Munich, Germany The cytokines lymphotoxin (LT) a, b and their receptor genesis. Consequently, the inflammatory microenviron- (LTbR) belong to the tumor necrosis factor (TNF) super- ment was added as the seventh hallmark of cancer family, whose founder—TNFa—was initially discovered (Hanahan and Weinberg, 2000; Colotta et al., 2009). due to its tumor necrotizing activity. LTbR signaling This was ultimately the result of more than 100 years of serves pleiotropic functions including the control of research—indeed—the first observation that tumors lymphoid organ development, support of efficient immune often arise at sites of inflammation was initially reported responses against pathogens due to maintenance of intact in the nineteenth century by Virchow (Balkwill and lymphoid structures, induction of tertiary lymphoid organs, Mantovani, 2001). Today, understanding the underlying liver regeneration or control of lipid homeostasis. Signal- mechanisms of why immune cells can be pro- or anti- ing through LTbR comprises the noncanonical/canonical carcinogenic in different types of tumors and which nuclear factor-jB (NF-jB) pathways thus inducing cellular and molecular inflammatory mediators (for chemokine, cytokine or adhesion molecule expression, cell example, macrophages, lymphocytes, chemokines or proliferation and cell survival. Blocking LTbR signaling or cytokines) drive or potentially prevent carcinogenesis Fcc-receptor mediated immunoablation of LT-expressing is subject of intense research (Supplementary material). cells was demonstrated to be beneficial in various infectious Here, we focus on the cytokines lymphotoxin (LT) a or noninfectious inflammatory or autoimmune disorders. and b and their involvement in inflammation-induced Only recently, LTbR signaling was shown to initiate carcinogenesis. inflammation-induced carcinogenesis, to influence primary tumorigenesis and to control reemergence of carcinoma in various cancer models through distinct mechanisms. Indeed, LTbR signaling inhibition has already been used LT, a molecule with a long history as efficient anti-inflammatory, anti-cancer therapy in some experimental models. Here, we review the pleiotropic In the 1960s and early 1970s, two molecules were functions attributed to LT, the effects of its deregulation described based on their ability to promote cell death and extensively discuss the recent literature on LT’s in target cells (for example, L cells; fibroblasts) (Ruddle link to carcinogenesis. and Waksman, 1967; Granger and Williams, 1968). Oncogene (2010) 29, 5006–5018; doi:10.1038/onc.2010.260; In 1967, a ‘cytotoxic factor’ was described causing published online 5 July 2010 toxicity on fibroblasts in presence of specific antigens (Ruddle and Waksman, 1967, 1968). Further, in 1968, Keywords: lymphotoxin b receptor signaling; inflamma- a cytotoxic molecule produced by lymphocytes was tion-induced carcinogenesis; NF-kB signaling; lympho- reported and named LT (Granger and Williams, 1968; toxin a; lymphotoxin b Granger et al., 1969). In 1975, a substance was depicted causing efficient necrosis in various tumor types in vivo throughout a cytotoxic activity and was thus denomi- nated ‘tumor necrosis factor’ (TNF) (Carswell et al., Inflammation-induced carcinogenesis 1975). These molecules subsequently caught attention of several research groups using these cytotoxic, tumor- In the last decade, several studies have corroborated the necrotizing capabilities for their therapeutic potential in tight link between chronic inflammation and carcino- the treatment of human cancer. In 1984, human LT was the first cytokine to be purified from a b-lymphoblastoid cell line (Aggarwal et al., 1984) and thereafter its amino- Correspondence: Dr M Heikenwalder, Department of Pathology, Institute of Neuropathology, University Hospital Zurich, Schmelz- acid sequence and structure were determined (Aggarwal bergstrasse 12, CH-8091 Zurich, Switzerland. et al., 1985a; Nedwin et al., 1985a). Neutralization of E-mail: [email protected] or LT activity by LT-specific antibodies led to the isolation [email protected] of a second cytotoxic factor from a human myeloid cell 3Current address: Department of Neuropathology, University of Freiburg, D-79106 Freiburg, Germany. line, already known as TNFa (Aggarwal et al., 1985b). Received 1 March 2010; revised 21 May 2010; accepted 27 May 2010; Amino-acid sequence determination revealed close published online 5 July 2010 relationship of TNF to LT, resulting in the renaming Unexpected role of LTbR signaling in carcinogenesis MJ Wolf et al 5007 of LT into TNFb. It became evident that these two cellular stress responses, development and maintenance cytokines are prototypic members of a gene super- of lymphoid organs (Figure 1). family, later defined as the TNF superfamily (TNFSF) Activation of the canonical NF-kB pathway mainly (Hehlgans and Pfeffer, 2005). Interestingly, murine and occurs in response to inflammatory cytokines such as human TNFa and b genes are close to each other within TNF, and IL-1, engagement of the T-cell receptor and in the major histocompatibility complex region (mouse, response to bacterial infection (for example, lipopoly- chromosome 17 (Nedospasov et al., 1986a, b); man, saccharide). Interestingly, LTbR activation (through short arm of chromosome 6 (Nedwin et al., 1985b; LIGHT or LTab heterotrimers) can also activate the Muller et al., 1987)). Later a third ligand—homologous canonical NF-kB (Dejardin et al., 2002; Muller and to TNFb—was identified within the major histocompa- Siebenlist, 2003; Haybaeck et al., 2009). tibility complex locus and named LTb (TNFSF3; In addition to the canonical pathway a parallel (Hiserodt et al., 1977; Ware and Granger, 1979; signaling cascade exists called noncanonical pathway Browning et al., 1993; Pokholok et al., 1995), whereas of NF-kB activation. Stimulation of a subset of TNFR subsequently TNFb was termed LTa or TNFSF1B. At family members, such as LTbR and CD40, can activate present, 19 different ligands belong to the TNFSF, the noncanonical NF-kB pathway (Coope et al., 2002; including, for example, TRAIL, RANKL, BAFF, CD40 Pomerantz and Baltimore, 2002). These stimuli appear (Aggarwal, 2003), mediating their cellular response to converge upon NF-kB-inducing kinase (Xiao et al., through 29 receptors, which contain an extracellular 2001), which is required for IKKa phosphorylation cysteine-rich domain (Aggarwal, 2003) and in some (Ling et al., 1998). In this pathway, IKKa is thought to cases (for example, TNFR1, TNFR2, TRAIL R1, exist as a homodimer, independent of NEMO/IKKg TRAIL R2, Fas) a death domain. and IKKb (Senftleben et al., 2001). Activated IKKa phosphorylates p100, thereby inducing its proteasome- dependent processing to p52. The p52/RelB dimer LT, LTbR and their cellular origin then translocates into the nucleus to induce gene expres- sion through NF-kB activation by the LTa1b2,LTbR, Under physiological conditions, LT is expressed by NF-kB-inducing kinase, IKKa pathway. This pathway T-, B-, natural killer (NK)- and lymphoid tissue-inducer is crucial for development and maintenance of spleen cells (Aggarwal et al., 2003). Although LTa mRNA architecture, follicular dendritic cell maturation, lymph expression is inducible in B-cells, LTb mRNA is node, Peyer’s patch and NALT organogenesis as well as constitutively produced (Browning et al., 1993; Worm regulation of B-cell survival (Weih and Caamano, 2003). and Geha, 1994). LTb is exclusively anchored in Studies with mutant mice showed a phenotypic overlap the membrane as a type II transmembrane protein, between LT or LTbR deficiencies and inactivated NF- binding LTa to form membrane-anchored heterotrimers kB signaling (Bonizzi and Karin, 2004; Bonizzi et al., (LTa1b2 and LTa2b1; Browning et al., 1993, 1995). 2004). Some of these findings are currently challenged LTab heterotrimers can also be cleaved from the cell by recently published results in vitro (Britanova et al., surface by matrix metalloproteases eliciting responses 2008). Thus, explanations for the noncanonical pathway on distal cells (Young et al., 2010). In contrast to LTb, specificity await further experiments. À/À À/À À/À LTa can be secreted as a soluble LTa3 homotrimer. LTa ,LTb and LTbR mice display severe LTa and TNF homotrimers bind and signal through the developmental defects in lymph node and Peyer’s TNF receptors TNFR1 or TNFR2. LTa1b2 triggers patch neogenesis, a disorganized lymphoid micro- LTbR, whereas LTa2b1 was reported to bind TNFR1 architecture and lack of mature follicular dendritic cells and TNFR2, but this is a diminutive LT form expressed (Pfeffer et al., 1993; De Togni et al., 1994; Koni et al., by T-cells (o2%) with an undefined biological role 1997; Futterer et al., 1998; Ngo et al., 1999). In addition, (Ware, 2005). LIGHT (TNFSF14) is an alternative LTaÀ/À and LTbRÀ/À mice show inflammatory disorders ligand for the LTbR but also interacts with herpesvirus in nonlymphoid organs (for example, lung, liver, kidney; entry mediator (Schneider
Recommended publications
  • Regulation of CCR7-Dependent Cell Migration Through CCR7 Homodimer Formation
    www.nature.com/scientificreports OPEN Regulation of CCR7-dependent cell migration through CCR7 homodimer formation Received: 6 September 2016 Daichi Kobayashi 1,2,6,7, Masataka Endo2, Hirotaka Ochi2, Hironobu Hojo3, Accepted: 24 July 2017 Masayuki Miyasaka4,5,6 & Haruko Hayasaka2 Published: xx xx xxxx The chemokine receptor CCR7 contributes to various physiological and pathological processes including T cell maturation, T cell migration from the blood into secondary lymphoid tissues, and tumor cell metastasis to lymph nodes. Although a previous study suggested that the efcacy of CCR7 ligand-dependent T cell migration correlates with CCR7 homo- and heterodimer formation, the exact extent of contribution of the CCR7 dimerization remains unclear. Here, by inducing or disrupting CCR7 dimers, we demonstrated a direct contribution of CCR7 homodimerization to CCR7-dependent cell migration and signaling. Induction of stable CCR7 homodimerization resulted in enhanced CCR7- dependent cell migration and CCL19 binding, whereas induction of CXCR4/CCR7 heterodimerization did not. In contrast, dissociation of CCR7 homodimerization by a novel CCR7-derived synthetic peptide attenuated CCR7-dependent cell migration, ligand-dependent CCR7 internalization, ligand-induced actin rearrangement, and Akt and Erk signaling in CCR7-expressing cells. Our study indicates that CCR7 homodimerization critically regulates CCR7 ligand-dependent cell migration and intracellular signaling in multiple cell types. Recruitment of lymphocytes from the blood into secondary lymphoid tissues is a process contributing to con- tinuous immune surveillance. Tis process is tightly regulated by the interaction between lymphoid chemokines expressed in lymphoid tissues and their specifc G-protein-coupled receptors in migrating cells1, 2. CCR7 is one of the major chemokine receptors preferentially expressed in a wide range of immune cells, including naïve T and B cells, central memory T cells, mature dendritic cells3, and plasmacytoid dendritic cells4, 5.
    [Show full text]
  • Following Ligation of CCL19 but Not CCL21 Arrestin 3 Mediates
    Arrestin 3 Mediates Endocytosis of CCR7 following Ligation of CCL19 but Not CCL21 Melissa A. Byers, Psachal A. Calloway, Laurie Shannon, Heather D. Cunningham, Sarah Smith, Fang Li, Brian C. This information is current as Fassold and Charlotte M. Vines of September 25, 2021. J Immunol 2008; 181:4723-4732; ; doi: 10.4049/jimmunol.181.7.4723 http://www.jimmunol.org/content/181/7/4723 Downloaded from References This article cites 82 articles, 45 of which you can access for free at: http://www.jimmunol.org/content/181/7/4723.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 25, 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 © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Arrestin 3 Mediates Endocytosis of CCR7 following Ligation of CCL19 but Not CCL211 Melissa A. Byers,* Psachal A. Calloway,* Laurie Shannon,* Heather D. Cunningham,* Sarah Smith,* Fang Li,† Brian C.
    [Show full text]
  • CXCL13/CXCR5 Interaction Facilitates VCAM-1-Dependent Migration in Human Osteosarcoma
    International Journal of Molecular Sciences Article CXCL13/CXCR5 Interaction Facilitates VCAM-1-Dependent Migration in Human Osteosarcoma 1, 2,3,4, 5 6 7 Ju-Fang Liu y, Chiang-Wen Lee y, Chih-Yang Lin , Chia-Chia Chao , Tsung-Ming Chang , Chien-Kuo Han 8, Yuan-Li Huang 8, Yi-Chin Fong 9,10,* and Chih-Hsin Tang 8,11,12,* 1 School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taipei City 11031, Taiwan; [email protected] 2 Department of Orthopaedic Surgery, Chang Gung Memorial Hospital, Puzi City, Chiayi County 61363, Taiwan; [email protected] 3 Department of Nursing, Division of Basic Medical Sciences, and Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Puzi City, Chiayi County 61363, Taiwan 4 Research Center for Industry of Human Ecology and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Guishan Dist., Taoyuan City 33303, Taiwan 5 School of Medicine, China Medical University, Taichung 40402, Taiwan; [email protected] 6 Department of Respiratory Therapy, Fu Jen Catholic University, New Taipei City 24205, Taiwan; [email protected] 7 School of Medicine, Institute of Physiology, National Yang-Ming University, Taipei City 11221, Taiwan; [email protected] 8 Department of Biotechnology, College of Health Science, Asia University, Taichung 40402, Taiwan; [email protected] (C.-K.H.); [email protected] (Y.-L.H.) 9 Department of Sports Medicine, College of Health Care, China Medical University, Taichung 40402, Taiwan 10 Department of Orthopedic Surgery, China Medical University Beigang Hospital, Yunlin 65152, Taiwan 11 Department of Pharmacology, School of Medicine, China Medical University, Taichung 40402, Taiwan 12 Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan * Correspondence: [email protected] (Y.-C.F.); [email protected] (C.-H.T.); Tel.: +886-4-2205-2121-7726 (C.-H.T.); Fax: +886-4-2233-3641 (C.-H.T.) These authors contributed equally to this work.
    [Show full text]
  • TNF Decoy Receptors Encoded by Poxviruses
    pathogens Review TNF Decoy Receptors Encoded by Poxviruses Francisco Javier Alvarez-de Miranda † , Isabel Alonso-Sánchez † , Antonio Alcamí and Bruno Hernaez * Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Campus de Cantoblanco, Universidad Autónoma de Madrid, Nicolás Cabrera 1, 28049 Madrid, Spain; [email protected] (F.J.A.-d.M.); [email protected] (I.A.-S.); [email protected] (A.A.) * Correspondence: [email protected]; Tel.: +34-911-196-4590 † These authors contributed equally. Abstract: Tumour necrosis factor (TNF) is an inflammatory cytokine produced in response to viral infections that promotes the recruitment and activation of leukocytes to sites of infection. This TNF- based host response is essential to limit virus spreading, thus poxviruses have evolutionarily adopted diverse molecular mechanisms to counteract TNF antiviral action. These include the expression of poxvirus-encoded soluble receptors or proteins able to bind and neutralize TNF and other members of the TNF ligand superfamily, acting as decoy receptors. This article reviews in detail the various TNF decoy receptors identified to date in the genomes from different poxvirus species, with a special focus on their impact on poxvirus pathogenesis and their potential use as therapeutic molecules. Keywords: poxvirus; immune evasion; tumour necrosis factor; tumour necrosis factor receptors; lymphotoxin; inflammation; cytokines; secreted decoy receptors; vaccinia virus; ectromelia virus; cowpox virus Citation: Alvarez-de Miranda, F.J.; Alonso-Sánchez, I.; Alcamí, A.; 1. TNF Biology Hernaez, B. TNF Decoy Receptors TNF is a potent pro-inflammatory cytokine with a broad range of biological effects, Encoded by Poxviruses. Pathogens ranging from the activation of inflammatory gene programs to cell differentiation or 2021, 10, 1065.
    [Show full text]
  • Dimerization of Ltβr by Ltα1β2 Is Necessary and Sufficient for Signal
    Dimerization of LTβRbyLTα1β2 is necessary and sufficient for signal transduction Jawahar Sudhamsua,1, JianPing Yina,1, Eugene Y. Chiangb, Melissa A. Starovasnika, Jane L. Groganb,2, and Sarah G. Hymowitza,2 Departments of aStructural Biology and bImmunology, Genentech, Inc., South San Francisco, CA 94080 Edited by K. Christopher Garcia, Stanford University, Stanford, CA, and approved October 24, 2013 (received for review June 6, 2013) Homotrimeric TNF superfamily ligands signal by inducing trimers survival in a xenogeneic human T-cell–dependent mouse model of of their cognate receptors. As a biologically active heterotrimer, graft-versus-host disease (GVHD) (11). Lymphotoxin(LT)α1β2 is unique in the TNF superfamily. How the TNFRSF members are typically activated by TNFSF-induced three unique potential receptor-binding interfaces in LTα1β2 trig- trimerization or higher order oligomerization, resulting in initiation ger signaling via LTβ Receptor (LTβR) resulting in lymphoid organ- of intracellular signaling processes including the canonical and ogenesis and propagation of inflammatory signals is poorly noncanonical NF-κB pathways (2, 3). Ligand–receptor interactions α β understood. Here we show that LT 1 2 possesses two binding induce higher order assemblies formed between adaptor motifs in sites for LTβR with distinct affinities and that dimerization of LTβR the cytoplasmic regions of the receptors such as death domains or α β fi by LT 1 2 is necessary and suf cient for signal transduction. The TRAF-binding motifs and downstream signaling components such α β β crystal structure of a complex formed by LT 1 2,LT R, and the fab as Fas-associated protein with death domain (FADD), TNFR1- fragment of an antibody that blocks LTβR activation reveals the associated protein with death domain (TRADD), and TNFR-as- lower affinity receptor-binding site.
    [Show full text]
  • LIGHT Is Expressed in Foam Cells and Involved in Destabilization of Atherosclerotic Plaques Through Induction of Matrix Metalloproteinase-9 and IL-8
    LIGHT is Expressed in Foam Cells and Involved in Destabilization of Atherosclerotic Plaques through Induction of Matrix Metalloproteinase-9 and IL-8 Won-Jung Kim and Won-Ha Lee Department of Genetic Engineering, Kyungpook National University, Daegu, Korea ABSTRACT Background: LIGHT (TNFSF14) is a member of tumor necrosis factor superfamily and is the ligand for TR2 (TNFRSF14/HVEM). LIGHT is known to have pro- inflammatory roles in atherosclerosis. Methods: To find out the expression pattern of LIGHT in atherosclerotic plaques, immunohistochemical analysis was performed on human carotid atherosclerotic plaque specimens. LIGHT induced atherogenic events using human monocytic cell line THP-1 were also investigated. Results: Imm- unohistochemical analysis revealed expression of LIGHT and TR2 in foam cell rich regions in the atherosclerotic plaques. Double immunohistochemical analysis further confirmed the expression of LIGHT in foam cells. Stimulation of THP-1 cells, which express TR2, with either recombinant LIGHT or immobilized anti-TR2 monoclonal antibody induced interleukin-8 and matrix metalloproteinase(MMP)-9. Electrophoretic mobility shift assay demonstrated that LIGHT induces nuclear localization of tran- scription factor, nuclear factor (NF)-κB. LIGHT induced activation of MMP-9 is mediated by NF-κB, since treatment of THP-1 cells with the NF-κB inhibitor PDTC (pyrrolidine dithiocarbamate) completely blocked the activation of MMP-9. Conclusion: These data indicate that LIGHT is expressed in foam cells in atherosclerotic plaques and is involved in atherogenesis through activation of pro-atherogenic cytokine IL-8 and destabilization of plaque by inducing matrix degrading enzyme. (Immune Network 2004;4(2):116-122) Key Words: Atherosclerosis, inflammation, matrix metalloproteinase, LIGHT, TNFSF inflammatory cytokines and matrix metallopro- Introduction teinases, and expression of adhesion molecules and Members of tumor necrosis factor superfamily tissue factor (7,8).
    [Show full text]
  • Death of HT29 Adenocarcinoma Cells Induced by TNF Family Receptor Activation Is Caspase-Independent and Displays Features of Both Apoptosis and Necrosis
    Cell Death and Differentiation (2002) 9, 1321 ± 1333 ã 2002 Nature Publishing Group All rights reserved 1350-9047/02 $25.00 www.nature.com/cdd Death of HT29 adenocarcinoma cells induced by TNF family receptor activation is caspase-independent and displays features of both apoptosis and necrosis 1 ,1 CA Wilson and JL Browning* Introduction 1 Department of Exploratory Biology, Biogen, 12 Cambridge Center, Cambridge, Receptors in the TNF family can initiate both canonical MA 02142, USA apoptotic and necrotic death events.1 Prototypical apoptosis * Corresponding author: JL Browning, Department of Exploratory Biology, follows activation of the Fas receptor on T cells leading to Biogen, 12 Cambridge Center, Cambridge, MA 02142, USA; caspase activation and a cascade of events eventually Tel: 617 679-3312; Fax: 617 679-2304; E-mail: [email protected] culminating in the various hallmarks of apoptosis.2,3 Yet even Received 7.12.01; revised 26.1.02; accepted 22.7.02 in this familiar case, Fas/FADD can trigger necrosis in T cells 4,5 Edited by B Osborne in the absence of caspase signaling. In the well-studied L929 fibroblast line, Fas activation triggers apoptosis while TNF initiates a necrotic event that is actually enhanced by Abstract caspase inhibition.1 Similarly, TNF signaling in the presence of caspase inhibitors was reported to lead to the necrosis of The HT29 adenocarcinoma is a common model of epithelial NIH3T3 fibroblasts and the myeloid U937 cell line.6 It has cell differentiation and colorectal cancer and its death is an oft- been dogmatic that apoptosis is only initiated by those TNF analyzed response to TNF family receptor signaling.
    [Show full text]
  • In Sickness and in Health: the Immunological Roles of the Lymphatic System
    International Journal of Molecular Sciences Review In Sickness and in Health: The Immunological Roles of the Lymphatic System Louise A. Johnson MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK; [email protected] Abstract: The lymphatic system plays crucial roles in immunity far beyond those of simply providing conduits for leukocytes and antigens in lymph fluid. Endothelial cells within this vasculature are dis- tinct and highly specialized to perform roles based upon their location. Afferent lymphatic capillaries have unique intercellular junctions for efficient uptake of fluid and macromolecules, while expressing chemotactic and adhesion molecules that permit selective trafficking of specific immune cell subsets. Moreover, in response to events within peripheral tissue such as inflammation or infection, soluble factors from lymphatic endothelial cells exert “remote control” to modulate leukocyte migration across high endothelial venules from the blood to lymph nodes draining the tissue. These immune hubs are highly organized and perfectly arrayed to survey antigens from peripheral tissue while optimizing encounters between antigen-presenting cells and cognate lymphocytes. Furthermore, subsets of lymphatic endothelial cells exhibit differences in gene expression relating to specific func- tions and locality within the lymph node, facilitating both innate and acquired immune responses through antigen presentation, lymph node remodeling and regulation of leukocyte entry and exit. This review details the immune cell subsets in afferent and efferent lymph, and explores the mech- anisms by which endothelial cells of the lymphatic system regulate such trafficking, for immune surveillance and tolerance during steady-state conditions, and in response to infection, acute and Citation: Johnson, L.A.
    [Show full text]
  • Antagonist Antibodies Against Various Forms of BAFF: Trimer, 60-Mer, and Membrane-Bound S
    Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2016/07/19/jpet.116.236075.DC1 1521-0103/359/1/37–44$25.00 http://dx.doi.org/10.1124/jpet.116.236075 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 359:37–44, October 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics Unexpected Potency Differences between B-Cell–Activating Factor (BAFF) Antagonist Antibodies against Various Forms of BAFF: Trimer, 60-Mer, and Membrane-Bound s Amy M. Nicoletti, Cynthia Hess Kenny, Ashraf M. Khalil, Qi Pan, Kerry L. M. Ralph, Julie Ritchie, Sathyadevi Venkataramani, David H. Presky, Scott M. DeWire, and Scott R. Brodeur Immune Modulation and Biotherapeutics Discovery, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut Received June 20, 2016; accepted July 18, 2016 Downloaded from ABSTRACT Therapeutic agents antagonizing B-cell–activating factor/B- human B-cell proliferation assay and in nuclear factor kB reporter lymphocyte stimulator (BAFF/BLyS) are currently in clinical assay systems in Chinese hamster ovary cells expressing BAFF development for autoimmune diseases; belimumab is the first receptors and transmembrane activator and calcium-modulator Food and Drug Administration–approved drug in more than and cyclophilin ligand interactor (TACI). In contrast to the mouse jpet.aspetjournals.org 50 years for the treatment of lupus. As a member of the tumor system, we find that BAFF trimer activates the human TACI necrosis factor superfamily, BAFF promotes B-cell survival and receptor. Further, we profiled the activities of two clinically ad- homeostasis and is overexpressed in patients with systemic vanced BAFF antagonist antibodies, belimumab and tabalumab.
    [Show full text]
  • Defining Natural Antibodies
    PERSPECTIVE published: 26 July 2017 doi: 10.3389/fimmu.2017.00872 Defining Natural Antibodies Nichol E. Holodick1*, Nely Rodríguez-Zhurbenko2 and Ana María Hernández2* 1 Department of Biomedical Sciences, Center for Immunobiology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI, United States, 2 Natural Antibodies Group, Tumor Immunology Division, Center of Molecular Immunology, Havana, Cuba The traditional definition of natural antibodies (NAbs) states that these antibodies are present prior to the body encountering cognate antigen, providing a first line of defense against infection thereby, allowing time for a specific antibody response to be mounted. The literature has a seemingly common definition of NAbs; however, as our knowledge of antibodies and B cells is refined, re-evaluation of the common definition of NAbs may be required. Defining NAbs becomes important as the function of NAb production is used to define B cell subsets (1) and as these important molecules are shown to play numerous roles in the immune system (Figure 1). Herein, we aim to briefly summarize our current knowledge of NAbs in the context of initiating a discussion within the field of how such an important and multifaceted group of molecules should be defined. Edited by: Keywords: natural antibody, antibodies, natural antibody repertoire, B-1 cells, B cell subsets, B cells Harry W. Schroeder, University of Alabama at Birmingham, United States NATURAL ANTIBODY (NAb) PRODUCING CELLS Reviewed by: Andre M. Vale, Both murine and human NAbs have been discussed in detail since the late 1960s (2, 3); however, Federal University of Rio cells producing NAbs were not identified until 1983 in the murine system (4, 5).
    [Show full text]
  • Loss of Lymphotoxin Alpha-Expressing Memory B Cells Correlates with Metastasis of Human Primary Melanoma
    diagnostics Article Loss of Lymphotoxin Alpha-Expressing Memory B Cells Correlates with Metastasis of Human Primary Melanoma Franziska Werner 1 , Christine Wagner 1, Martin Simon 1, Katharina Glatz 2, Kirsten D. Mertz 3,4 , Heinz Läubli 5 , Erika Richtig 6, Johannes Griss 7 and Stephan N. Wagner 1,* 1 Laboratory of Molecular Dermato-Oncology and Tumor Immunology, Department of Dermatology, Medical University of Vienna, 1090 Vienna, Austria; [email protected] (F.W.); [email protected] (C.W.); [email protected] (M.S.) 2 Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, 4031 Basel, Switzerland; [email protected] 3 Institute of Pathology, Cantonal Hospital Baselland, 4410 Liestal, Switzerland; [email protected] 4 University of Basel, 4001 Basel, Switzerland 5 Laboratory for Cancer Immunotherapy, Department of Biomedicine and Medical Oncology, Department of Internal Medicine, University Hospital Basel, 4031 Basel, Switzerland; [email protected] 6 Department of Dermatology, Medical University of Graz, 8036 Graz, Austria; [email protected] 7 Department of Dermatology, Medical University of Vienna, 1090 Vienna, Austria; [email protected] * Correspondence: [email protected] Abstract: Activated antigen-experienced B cells play an unexpected complex role in anti-tumor immunity in human melanoma patients. However, correlative studies between B cell infiltration and Citation: Werner, F.; Wagner, C.; tumor progression are limited by the lack of distinction between functional B cell subtypes. In this Simon, M.; Glatz, K.; Mertz, K.D.; study, we examined a series of 59 primary and metastatic human cutaneous melanoma specimens Läubli, H.; Richtig, E.; Griss, J.; with B cell infiltration.
    [Show full text]
  • Targeting the Lymphotoxin-B Receptor with Agonist Antibodies As a Potential Cancer Therapy
    Research Article Targeting the Lymphotoxin-B Receptor with Agonist Antibodies as a Potential Cancer Therapy Matvey Lukashev,1 Doreen LePage,1 Cheryl Wilson,1 Ve´ronique Bailly,1 Ellen Garber,1 AlexLukashin, 1 Apinya Ngam-ek,1 Weike Zeng,1 Norman Allaire,1 Steve Perrin,1 Xianghong Xu,1 Kendall Szeliga,1 Kathleen Wortham,1 Rebecca Kelly,1 Cindy Bottiglio,1 Jane Ding,1 Linda Griffith,1 Glenna Heaney,1 Erika Silverio,1 William Yang,1 Matt Jarpe,1 Stephen Fawell,1 Mitchell Reff,1 Amie Carmillo,1 Konrad Miatkowski,1 Joseph Amatucci,1 Thomas Crowell,1 Holly Prentice,1 Werner Meier, 1 Shelia M. Violette,1 Fabienne Mackay,1 Dajun Yang,2 Robert Hoffman,3 and Jeffrey L. Browning1 1Departments of Immunobiology, Oncopharmacology, Molecular Engineering, Molecular Profiling, Molecular Discovery, Antibody Humanization, and Cellular Engineering, Biogen Idec, Cambridge, Massachusetts; 2Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan; and 3AntiCancer, Inc., San Diego, California Abstract receptor (TRAILR) 1/2, death receptor (DR) 3, DR6, and possibly ectodermal dysplasia receptor (EDAR). These TNFRs harbor The lymphotoxin-B receptor (LTBR) is a tumor necrosis factor signaling adaptor motifs termed death domains that can initiate receptor family member critical for the development and the extrinsic apoptosis program. In addition, TNFRs of this group maintenance of various lymphoid microenvironments. Herein, can exert antitumor effects via other mechanisms that include we show that agonistic anti-LTBR monoclonal antibody (mAb) tumor sensitization to chemotherapeutic agents, activation of CBE11 inhibited tumor growth in xenograft models and antitumor immunity, and disruption of tumor-associated micro- potentiated tumor responses to chemotherapeutic agents.
    [Show full text]