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RnDSy-lu-2945 The TNF Superfamily TNF Homology Domain Ribbon Structure The TNF Superfamily Ligands Receptors The tumor necrosis factor (TNF) superfamily in humans currently consists of 19 ligands and 29 receptors, with three additional TNF family receptors 4-1BB Ligand having been identified in mice. Most TNF ligands are type II trans- membrane proteins with extracellular domains that can be cleaved by 4-1BB specific metalloproteinases to generate soluble cytokines. Cleaved and APRIL BCMA non-cleaved ligands are active as noncovalent homotrimers except for Lymphotoxin β, which forms heterotrimers with TNF-β/Lymphotoxin a BAFF TACI (LTa) and BAFF, which forms heterotrimers with APRIL. TNF family ligands are characterized by a stalk of varying length connecting the BAFF R transmembrane domain to the core region, which contains the hallmark CD27 structure of TNF family ligands, the TNF homology domain (THD). The CD27 Ligand CD30 THD is an anti-parallel β-pleated sheet sandwich with a “jelly-roll” topology. Conserved residues within the β strands provide specific inter- CD40 subunit contacts, which stabilize the trimeric structure. Sequences in the EDAR loops connecting adjacent β strands are family member-specific and are CD30 Ligand important for conferring receptor specificity. Receptors for TNF family XEDAR ligands are oligomeric, type I or type III transmembrane proteins that contain multiple extracellular cysteine-rich domains (CRDs). Several of CD40 Ligand Fas these receptors contain intracellular death domains (DDs) that recruit EDA-A1 caspase-interacting proteins to initiate apoptosis upon ligand binding. DcR3 Other TNF superfamily receptors that lack DDs bind TNF receptor- EDA-A2 GITR associated factors (TRAFs) and activate multiple intracellular signaling Fas Ligand pathways that can lead to proliferation or differentiation. These receptors HVEM can also initiate apoptosis, but they do so via indirect mechanisms. GITR Ligand TNF superfamily ligands and receptors are important for numerous DR3 LIGHT processes that regulate immune cell functions including apoptosis, B cell homeostasis and activation, natural killer cell activation, T cell co- TL1A/VEGI LTβR stimulation, and other cell type-specific responses such as hair follicle LTα1β2 development and osteoclast development. TNF superfamily members TWEAK R also play a significant role in regulating the pathogenesis of human LTα β 2 1 TWEAK diseases including cancer, osteoporosis, osteoarthritis, chronic OX40 inflammation, and autoimmune diseases.1,2 Nearly all TNF superfamily OX40 Ligand ligand-receptor pathways are being investigated as targets for the TNF RI α development of agonist or antagonist therapeutics.2,3 TNF- R&D Systems offers a wide selection of high quality reagents to TNF-β/LTα TNF RII facilitate the study of TNF superfamily members including recombinant proteins, ELISA kits, and antibodies for blocking/neutralization, TRAIL R1 immunohistochemistry, immunoprecipitation, Western blotting, TRAIL TRAIL R2 and flow cytometry. For a complete, up-to-date listing and more information on these products, please visit our website at TRANCE/RANK Ligand TRAIL R3 www.RnDSystems.com/TNFSF. References 1. Aggarwal, B.B. et al. (2012) Blood 119:651. TRAIL R4 2. Tansey, M.G. & D.E. Szymkowski (2009) Drug Discov. Today 14:1082. Neurotrophins OPG 3. Hymowitz, S.G. & A. Ashkenazi (2005) Nat. Chem. Biol. 1:353. APP ? RANK ? LIGAND/RECEPTOR DOMAIN KEY SELECT FUNCTIONS NGF R TNF homology domain (THD) B cell homeostasis & activation Cysteine-rich domain (CRD) Natural killer cell activation DR6 Death domain (DD) T cell co-stimulation RELT Pro-apoptotic TROY Interactions with decoy receptors Diagrams include human family members only. Additional mouse TNF superfamily members include DcTRAIL R1, Other cell type-specific responses DcTRAIL R2, and TNFRH3. TNF Superfamily Members Mediate B Cell Homeostasis and Activation Several TNF superfamily members play key roles in early B cell maturation, homeostasis, differentiation, and activation. While BAFF R is required for normal B cell maturation, interactions between BAFF- Ligands Receptors BAFF R, BAFF-TACI, APRIL-BCMA, and CD40 Ligand-CD40 promote B cell differentiation and 4-1BB Ligand homeostasis. The interaction between CD40 Ligand and CD40 is necessary for germinal center B cell 4-1BB differentiation, and CD27 and CD30 are memory B cell markers. Interactions between CD27 Ligand, BCMA APRIL CD30 Ligand, or CD40 Ligand and their respective receptors are also involved in B cell co-stimulation TACI by T cells and natural killer cells. Current research suggests roles for BAFF, APRIL, BAFF R, TACI, and BAFF R BCMA in immune deficiency, autoimmune diseases, and lymphoid cell cancers.1-3 Mutations of the BAFF TACI and BAFF R genes are associated with common variable immunodeficiency (CVID).1 Alternatively, BAFF overexpression is often observed in patients with autoimmune diseases such as lupus, CD27 Ligand CD27 rheumatoid arthritis, and multiple sclerosis, where it is thought that high levels of BAFF may lead to 2 the inappropriate survival of low-affinity, self-reactive B cells. In addition, BAFF, APRIL, and their CD30 Ligand CD30 receptors are overexpressed in lymphoid cancers and their role in multiple myeloma is being 3 CD40 investigated. CD40 Ligand References 1. Eibel, H. et al. (2010) Curr. Opin. Allergy Clin. Immunol. 10:526. 3. Quinn, J. et al. (2011) Blood 117:890. 2. Mackay, F. & P. Schneider (2009) Nat. Rev. Immunol. 9:491. Differentiation Differentiation TACI BAFF R Survival BCMA TACI APRIL TACI CD27 BCMA CD30 Memory B Cell Differentiation Plasma Cell TACI Plasma Cell BAFF R CD40 Ligand BCMA Proliferation CD40 TACI BAFF R Survival Germinal Center B Cell B Cell Development and Activation Requires TNF Superfamily Marginal Zone Members. Immature B cells (blue) express BAFF R prior to leaving the B Cell bone marrow. Mature B cells (purple) in the marginal zone and follicles Proliferation express BAFF R and TACI. CD27, CD30, and CD40 expressed on mature, Activation TACI BAFF R Differentiation naïve follicular B cells can mediate the thymus-dependent co-stimulatory TACI signal provided by T helper cells (yellow) that is necessary to activate the Differentiation BAFF R BAFF R CD40 Ligand B cell. Activated B cells maintain expression of TACI, BAFF R, and CD40. CD40 CD40 Ligand promotes activated B cell proliferation and differentiation as MHC II TCR they enter the germinal center. Following differentiation, plasma cells ex- CD27 CD27 Ligand press TACI and BCMA, which promote plasma cell survival. Similarly, TACI, Differentiation CD40 CD40 Ligand Survival CD30 BCMA, BAFF R, CD30, and CD27 are expressed by memory B cells and act to CD30 Ligand Activated B Cell B Cell Precursor Transitional B Cell Naïve B Cell maintain memory B cell homeostasis. Terminal processes are boxed, inter- T Helper Cell mediary processes are shown unboxed. CD40/TNFRSF5 Antibody (ng/mL) 100 101 102 103 150 80 3500 3500 Cell Proliferation (Mean CPM) Proliferation Cell 70 120 3000 3000 60 50 2500 2500 90 2000 2000 40 60 30 1500 1500 Relative Cell Number Cell Relative Relative Cell Number Cell Relative 20 Cell Proliferation (Mean CPM) Proliferation Cell 30 1000 1000 10 500 500 0 0 10-1 100 101 102 100 101 102 103 104 100 101 102 103 104 CD40 Ligand/TNFSF5 g/mL BAFF/TNFSF13B 4-1BB Ligand/TNFSF9 CD40 Ligand-induced Proliferation and Neutralization by an Anti-Human CD40 Detection of BAFF by Flow Cytometry. Mouse splenocytes were stained with a Detection of 4-1BB Ligand by Flow Cytometry. The A20 mouse B cell lymphoma cell Antibody. Proliferation of human B cell enriched peripheral blood mononuclear cells PE-conjugated Rat Anti-Mouse BAFF/TNFSF13B Monoclonal Antibody (Catalog line was stained with a PE-conjugated Rat Anti-Mouse 4-1BB Ligand/TNFSF9 was assessed following treatment with increasing concentrations of Recombinant # IC1357P; filled histogram) or a PE-conjugated Rat IgG2A Isotype Control (Catalog Monoclonal Antibody (Catalog # FAB1246P; filled histogram) or a PE-conjugated Rat Human CD40 Ligand/TNFSF5 (Catalog # 6245-CL; orange line) in the presence of # IC006P; open histogram). IgG2B Isotype Control (Catalog # IC013P; open histogram). 20 ng/mL Recombinant Human IL-4 (Catalog # 204-IL). The stimulatory effect induced by 10 µg/mL Recombinant Human CD40 Ligand/TNFSF5 was neutralized by treating the cells with increasing concentrations of a Mouse Anti-Human CD40/TNFRSF5 Monoclonal Antibody (Catalog # MAB6322; green line). Learn more | rndsystems.com/TNFSFBcells TNF Superfamily Members Regulate Natural Killer Cells LIGANDS RECEPTORS Upon activation, natural killer (NK) cells secrete cytotoxic and inflammatory cytokines that cause Ligands Receptors apoptosis or lysis of targeted cells. While some pathogens can directly activate NK cells, NK cells are 4-1BB Ligand 4-1BB Ligand 4-1BB indirectly activated in response to most pathogens by accessory cells. Several TNF superfamily APRIL 4-1BB CD27 Ligand BCMA members have been implicated in mediating NK cell activation and regulation by accessory cells. CD27 These members include 4-1BB, CD27, CD30, CD40, and GITR and their respective ligands, as well as BAFF TACI CD30 Ligand CD30 HVEM via LIGHT and TNF RII via TNF-a or TNF-β. NK cells also express Fas Ligand and TNF-a on their cell BAFF R CD40 Ligand CD27 surface that, when bound to target cell-expressed Fas or TNF RI, respectively, initiate caspase-mediated CD27 Ligand CD40 apoptosis of the target cell. TNF superfamily-mediated apoptosis and the ability of activated NK
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  • The Unexpected Role of Lymphotoxin Β Receptor Signaling

    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.