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Pascal Schneider - One of the best experts on this subject based on the ideXlab platform.

  • Inhibition of NK Reactivity Against Solid Tumors by Platelet-Derived RANKL
    'MDPI AG', 2019
    Co-Authors: Kim L. Clar, Pascal Schneider, Clemens Hinterleitner, Helmut R. Salih, Stefanie Maurer
    Abstract:

    NK cells play an important role in tumor immunosurveillance. Their reactivity is governed by various activating and inhibitory surface Receptors, which include several members of the TNF/TNF Receptor Family. For more than 50 years, it has been recognized that tumor immunosurveillance and in particular NK cell antitumor reactivity is largely influenced by platelets, but the underlying mechanisms remain to be fully elucidated. Here we report that upon activation, which reportedly occurs following interaction with cancer cells, platelets upregulate the TNF Family member RANKL. Comparative analysis of the expression of RANK among different NK cell subsets and RANKL on platelets in cancer patients and healthy volunteers revealed a distinct malignant phenotype, and platelet-derived RANKL was found to inhibit the activity of normal NK cells against cancer cells. Notably, NK cell antitumor reactivity could be partially restored by application of denosumab, a RANKL-neutralizing antibody approved for treatment of benign and malignant osteolysis. Together, our data not only unravel a novel mechanism of tumor immune evasion mediated by platelets, but they also provide a functional explanation for the clinical observation that denosumab, beyond protecting from bone loss, may prolong disease-free survival in patients with solid tumors

  • Interactions of tumor necrosis factor (TNF) and TNF Receptor Family members in the mouse and human.
    The Journal of biological chemistry, 2006
    Co-Authors: Claudia Bossen, Karine Ingold, Sylvie Hertig, Jean Luc Bodmer, Christine Ambrose, Aubry Tardivel, Olivier Gaide, Jurg Tschopp, Pascal Schneider
    Abstract:

    Ligands of the tumor necrosis factor superFamily (TNFSF) (4-1BBL, APRIL, BAFF, CD27L, CD30L, CD40L, EDA1, EDA2, FasL, GITRL, LIGHT, lymphotoxin alpha, lymphotoxin alphabeta, OX40L, RANKL, TL1A, TNF, TWEAK, and TRAIL) bind members of the TNF Receptor superFamily (TNFRSF). A comprehensive survey of ligand-Receptor interactions was performed using a flow cytometry-based assay. All ligands engaged between one and five Receptors, whereas most Receptors only bound one to three ligands. The Receptors DR6, RELT, TROY, NGFR, and mouse TNFRH3 did not interact with any of the known TNFSF ligands, suggesting that they either bind other types of ligands, function in a ligand-independent manner, or bind ligands that remain to be identified. The study revealed that ligand-Receptor pairs are either cross-reactive between human and mouse (e.g. Tweak/Fn14, RANK/RANKL), strictly species-specific (GITR/GITRL), or partially species-specific (e.g. OX40/OX40L, CD40/CD40L). Interestingly, the Receptor binding patterns of lymphotoxin alpha and alphabeta are redundant in the human but not in the mouse system. Ligand oligomerization allowed detection of weak interactions, such as that of human TNF with mouse TNFR2. In addition, mouse APRIL exists as two different splice variants differing by a single amino acid. Although human APRIL does not interact with BAFF-R, the shorter variant of mouse APRIL exhibits weak but detectable binding to mouse BAFF-R.

  • a soluble form of b cell maturation antigen a Receptor for the tumor necrosis factor Family member april inhibits tumor cell growth
    Journal of Experimental Medicine, 2000
    Co-Authors: Paul D Rennert, Sylvie Hertig, Pascal Schneider, Teresa G Cachero, Jeffrey Thompson, Luciana Trabach, Nils Holler, Fang Qian, Colleen Mullen, Kathy Strauch
    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 upregulated in many tumors including colon and prostate carcinomas. Here we identify B cell maturation antigen (BCMA) and transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI), two predicted members of the TNF Receptor Family, as Receptors 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 proliferation 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.

  • baff binds to the tumor necrosis factor Receptor like molecule b cell maturation antigen and is important for maintaining the peripheral b cell population
    Journal of Experimental Medicine, 2000
    Co-Authors: Jeffrey S Thompson, Pascal Schneider, Teresa G Cachero, Susan L Kalled, Li Chun Wang, Eric A Lefevre, Fabienne Mackay, Sarah A Bixler, Mohammad Zafari, Zhongying Liu
    Abstract:

    The tumor necrosis factor (TNF) Family member B cell activating factor (BAFF) binds B cells and enhances B cell Receptor–triggered proliferation. We find that B cell maturation antigen (BCMA), a predicted member of the TNF Receptor Family expressed primarily in mature B cells, is a Receptor for BAFF. Although BCMA was previously localized to the Golgi apparatus, BCMA was found to be expressed on the surface of transfected cells and tonsillar B cells. A soluble form of BCMA, which inhibited the binding of BAFF to a B cell line, induced a dramatic decrease in the number of peripheral B cells when administered in vivo. Moreover, culturing splenic cells in the presence of BAFF increased survival of a percentage of the B cells. These results are consistent with a role for BAFF in maintaining homeostasis of the B cell population.

  • tramp a novel apoptosis mediating Receptor with sequence homology to tumor necrosis factor Receptor 1 and fas apo 1 cd95
    Immunity, 1997
    Co-Authors: Jean Luc Bodmer, Pascal Schneider, Kim Burns, Kay Hofmann, Veronique Steiner, Margot Thome, Thierry Bornand, Michael Hahne, Michael Schroter, Karin Becker
    Abstract:

    A novel member of the tumor necrosis factor (TNF) Receptor Family, designated TRAMP, has been identified. The structural organization of the 393 amino acid long human TRAMP is most homologous to TNF Receptor 1. TRAMP is abundantly expressed on thymocytes and lymphocytes. Its extracellular domain is composed of four cysteine-rich domains, and the cytoplasmic region contains a death domain known to signal apoptosis. Overexpression of TRAMP leads to two major responses, NF-kappaB activation and apoptosis. TRAMP-induced cell death is inhibited by an inhibitor of ICE-like proteases, but not by Bcl-2. In addition, TRAMP does not appear to interact with any of the known apoptosis-inducing ligands of the TNF Family.

Herbert Schwarz - One of the best experts on this subject based on the ideXlab platform.

  • expression of cd137 on hodgkin and reed sternberg cells inhibits t cell activation by eliminating cd137 ligand expression
    Cancer Research, 2013
    Co-Authors: Wan Lu Pang, Liang Kai Koh, Mei Chung Moh, Siew Meng Chong, Antonio Castella, Suhail Alsalam, Teng Ee Tan, Shu Uin Gan, Cheong Kin Cheng, Herbert Schwarz
    Abstract:

    Hodgkin lymphoma is caused by a minority population of malignant Hodgkin and Reed-Sternberg (HRS) cells that recruit an abundance of inflammatory cells. The long-term survival of HRS cells among the vast majority of immune cells indicates that they have developed potent immune escape mechanisms. We report that the TNF Receptor Family member CD137 (TNFRSF9) is expressed on HRS cells, while normal B cells, from which HRS cells are most often derived, do not express CD137. In 48 of 53 cases of classical Hodgkin lymphoma, CD137 was detected on HRS cells. Ectopically expressed CD137 transferred by trogocytosis from HRS cells to neighboring HRS and antigen-presenting cells, which constitutively express the CD137 ligand (CD137L and TNFSF9), became associated with CD137L and the CD137-CD137L complex was internalized. Disappearance of CD137L from the surface of HRS and antigen-presenting cells led to reduced costimulation of T cells through CD137, reducing IFN-γ release and proliferation. Our results reveal a new regulatory mechanism for CD137L expression that mediates immune escape by HRS cells, and they identify CD137 as a candidate target for immunotherapy of Hodgkin lymphoma.

  • cd137 ligand activated microglia induces oligodendrocyte apoptosis via reactive oxygen species
    Journal of Neuroinflammation, 2012
    Co-Authors: Yee Andy Yeo, Julia María Martínez Gómez, Stephan Gasser, Ludovic J Croxford, Engang Ling, Herbert Schwarz
    Abstract:

    CD137 (4-1BB, TNFRSF9), a member of the tumor necrosis factor (TNF) Receptor Family, is a potent T cell co-stimulatory molecule. CD137 ligand (CD137L) is expressed by antigen presenting cells (APC) as a transmembrane protein and transmits activating signals into APC. In this study we investigated the effects of CD137L signaling in microglia, the resident APC in the central nervous system. In vitro, the murine microglia cell lines BV-2 and N9, as well as primary murine microglia responded with activation as evidenced by adherence and secretion of proinflammatory cytokines, MMP-9, and soluble intercellular adhesion molecule (ICAM). CD137L signaling is also important for microglia activation in vivo, since CD137L-deficient mice exhibited profoundly less microglia activation during experimental autoimmune encephalomyelitis (EAE) which is a well-established murine model for neuroinflammation and human multiple sclerosis (MS). Also CD137 is expressed in the CNS of mice during EAE. Activated microglia has been reported to mediate the destruction of axonal myelin sheaths and cause the death of oligodendrocytes, the main pathogenic mechanisms in EAE and MS. Corresponding to the lower microglia activation there were also fewer apoptotic oligodendrocytes in the CNS of CD137L-deficient mice. In vitro co-culture confirmed that CD137L-activated microglia induces apoptosis in oligodendrocytes, and identified reactive oxygen species as the mechanism of apoptosis induction. These data demonstrate activating effects of CD137L signaling to microglia, and show for the first time that the CD137 Receptor/ligand system may be a mediator of neuroinflammatory and neurodegenerative disease, by activating microglia which in turn kill oligodendrocytes.

  • signal transduction mechanisms of cd137 ligand in human monocytes
    Cellular Signalling, 2007
    Co-Authors: Liane Sollner, D Shaqireen, Herbert Schwarz
    Abstract:

    Bidirectional signalling, i.e. simultaneous signalling through a Receptor as well as its cell surface-bound ligand has been identified for several members of the TNF and TNF Receptor Family members. Reverse signalling through the ligands offers the advantage of an immediate feed-back and a more precise fine tuning of biological responses. Little is known about the molecular nature of reverse signalling through the ligands. CD137 ligand, member of the TNF Family is expressed on monocytes and induces activation, migration, prolongation of survival and proliferation of monocytes. Here we show that reverse signalling by CD137 ligand is mediated by protein tyrosine kinases, p38 mitogen activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1,2, MAP/ERK kinase (MEK), Phosphoinositide-3-kinase (PI3-K) and protein kinase A (PKA) but not by protein kinase C (PKC). This study also shows that reverse signalling relies on the same signal transduction molecules as signalling through classical Receptors and is in its nature not different from it.

  • cd137 is expressed on blood vessel walls at sites of inflammation and enhances monocyte migratory activity
    The FASEB Journal, 2007
    Co-Authors: Daniela Drenkard, Teng Ee Tan, Joachim Langstein, Florian M Becke, Thilo Spruss, Leoni A Kunzschughart, Yaw Chyn Lim, Herbert Schwarz
    Abstract:

    The cytokine Receptor CD137 is a member of the TNF Receptor Family and a potent T cell costimulatory molecule. Its ligand is expressed on antigen presenting cells as a transmembrane protein and it ...

  • significance of reverse signal transduction for the biology of the cd137 Receptor ligand system
    2006
    Co-Authors: Herbert Schwarz
    Abstract:

    CD137 is a member of the TNF Receptor Family and it has originally been identified as a potent T cell costimulatory molecule. Recently, it has become evident that CD137 signals can also inhibit T cell activity under certain conditions. The CD137 Receptor/ligand system has the ability to signal bidirectionally. CD137 ligand is also expressed as a cell membrane protein and it can also transduce signals into the cells it is expressed on, referred to as reverse signaling. The signals through CD137 ligand are activating or costimulatory for antigen presenting cells (APC). Together with CD137, which can deliver costimulatory signals to T cells, the CD137 Receptor/ligand pair can therefore form a potent proinflammatory system enhancing immune reactions by stimulating APC as well as T cells. CD137 ligand signals, however, negatively regulate T cell proliferation and survival, and it is possible that this activity of CD137 ligand participates in the termination of immune responses. The bidirectional signaling capacity allows the CD137 Receptor/ligand system to mediate extensive crosstalk between immune cells and between immune and non-immune cells. CD137 (4-1BB, induced by lymphocyte activation, ILA) is a member of the tumor necrosis factor (TNF) Receptor Family (Kwon and Weissman, 1989; Schwarz et al., 1993). CD137 has originally been identified as a potent T cell costimulatory molecule and a promising target for immunotherapy of cancer (Melero et al., 1997). Recent evidence also demonstrates a role for CD137 signaling in T cells for inhibiting immune responses and autoimmune disease (Foell et al., 2003; 2004). The other chapters of this book and several recent reviews provide a comprehensive overview over the various activities of CD137 signaling on immune functions and their potential therapeutic applications (Al-Shamkhani, 2004; Croft, 2003; Kwon et al., 2000; Sica and Chen, 2000). Interaction of CD137 with CD137 ligand, however, not only initiates a signal into the CD137-expressing cell but also into the CD137 ligand-expressing

Giovina Ruberti - One of the best experts on this subject based on the ideXlab platform.

  • an n terminal domain shared by fas apo 1 cd95 soluble variants prevents cell death in vitro
    Journal of Immunology, 1996
    Co-Authors: Giuliana Papoff, Isabella Cascino, Adriana Eramo, G Starace, D H Lynch, Giovina Ruberti
    Abstract:

    Fas/Apo-1 molecule, also designated as CD95, is a member of the TNF Receptor Family. Fas cross-linking by its natural ligand or by agonistic mAbs results in rapid induction of apoptosis in susceptible cells. in addition to the Fas full-length mRNA, human activated PBMC and tumor cell lines express several mRNA Fas variants that derive from alternative splicing of the primary transcript. All five variants identified, two of which are newly described here, code for soluble proteins that, with the exception of FasTMDel, are truncated in the extracytoplasmic region and possess short C-terminal amino acid sequences corresponding to a different reading frame. We have identified Abs that recognize all splicing variants and established a sandwich ELISA by which the soluble Fas molecules could be detected in culture supernatants of transfected cell lines and in PBMC following T cell activation. Next, we have studied in detail the functional role of these variants by apoptosis inhibition studies. We found that all soluble proteins block the apoptosis induced by either an agonistic Ab or, more importantly, by the natural Fas ligand in Fas-positive sensitive cell lines. interestingly, this functional property can be assigned to the first 49 amino acids of the mature protein that is the only region shared by the five soluble Fas molecules.

  • fas apo 1 cd95 Receptor lacking the intracytoplasmic signaling domain protects tumor cells from fas mediated apoptosis
    Journal of Immunology, 1996
    Co-Authors: Isabella Cascino, Giuliana Papoff, R De Maria, Roberto Testi, Giovina Ruberti
    Abstract:

    FAS/Apo-1 (CD95) is an apoptosis-signaling cell surface Receptor belonging to the TNF Receptor Family. Tumor cells resistant to Fas-mediated apoptosis have been described, but to date, the mechanisms responsible for this resistance are not well understood. We found that a series of apoptosis-resistant clones from human HUT78 lymphoma cells express a splicing variant coding for a truncated Fas molecule that lacks the intracellular death-signaling domain. The mutation responsible for the FasExo8Del expression was identified as a deletion-insertion in the intron 7/exon 8 region of the Fas gene. Moreover this mutation affects the phenotype in a dominant negative fashion, i.e., even in the presence of the normal Receptor.

Jean Luc Bodmer - One of the best experts on this subject based on the ideXlab platform.

  • Interactions of tumor necrosis factor (TNF) and TNF Receptor Family members in the mouse and human.
    The Journal of biological chemistry, 2006
    Co-Authors: Claudia Bossen, Karine Ingold, Sylvie Hertig, Jean Luc Bodmer, Christine Ambrose, Aubry Tardivel, Olivier Gaide, Jurg Tschopp, Pascal Schneider
    Abstract:

    Ligands of the tumor necrosis factor superFamily (TNFSF) (4-1BBL, APRIL, BAFF, CD27L, CD30L, CD40L, EDA1, EDA2, FasL, GITRL, LIGHT, lymphotoxin alpha, lymphotoxin alphabeta, OX40L, RANKL, TL1A, TNF, TWEAK, and TRAIL) bind members of the TNF Receptor superFamily (TNFRSF). A comprehensive survey of ligand-Receptor interactions was performed using a flow cytometry-based assay. All ligands engaged between one and five Receptors, whereas most Receptors only bound one to three ligands. The Receptors DR6, RELT, TROY, NGFR, and mouse TNFRH3 did not interact with any of the known TNFSF ligands, suggesting that they either bind other types of ligands, function in a ligand-independent manner, or bind ligands that remain to be identified. The study revealed that ligand-Receptor pairs are either cross-reactive between human and mouse (e.g. Tweak/Fn14, RANK/RANKL), strictly species-specific (GITR/GITRL), or partially species-specific (e.g. OX40/OX40L, CD40/CD40L). Interestingly, the Receptor binding patterns of lymphotoxin alpha and alphabeta are redundant in the human but not in the mouse system. Ligand oligomerization allowed detection of weak interactions, such as that of human TNF with mouse TNFR2. In addition, mouse APRIL exists as two different splice variants differing by a single amino acid. Although human APRIL does not interact with BAFF-R, the shorter variant of mouse APRIL exhibits weak but detectable binding to mouse BAFF-R.

  • tramp a novel apoptosis mediating Receptor with sequence homology to tumor necrosis factor Receptor 1 and fas apo 1 cd95
    Immunity, 1997
    Co-Authors: Jean Luc Bodmer, Pascal Schneider, Kim Burns, Kay Hofmann, Veronique Steiner, Margot Thome, Thierry Bornand, Michael Hahne, Michael Schroter, Karin Becker
    Abstract:

    A novel member of the tumor necrosis factor (TNF) Receptor Family, designated TRAMP, has been identified. The structural organization of the 393 amino acid long human TRAMP is most homologous to TNF Receptor 1. TRAMP is abundantly expressed on thymocytes and lymphocytes. Its extracellular domain is composed of four cysteine-rich domains, and the cytoplasmic region contains a death domain known to signal apoptosis. Overexpression of TRAMP leads to two major responses, NF-kappaB activation and apoptosis. TRAMP-induced cell death is inhibited by an inhibitor of ICE-like proteases, but not by Bcl-2. In addition, TRAMP does not appear to interact with any of the known apoptosis-inducing ligands of the TNF Family.

Gail A. Bishop - One of the best experts on this subject based on the ideXlab platform.

  • tumor necrosis factor Receptor associated factor 2 traf2 deficient b lymphocytes reveal novel roles for traf2 in cd40 signaling
    Journal of Biological Chemistry, 2003
    Co-Authors: Bruce S Hostager, Sokol Haxhinasto, Gail A. Bishop, Sarah L Rowland
    Abstract:

    CD40 function is initiated by tumor necrosis factor (TNF) Receptor-associated factor (TRAF) adapter proteins, which play important roles in signaling by numerous Receptors. Characterizing roles of individual TRAFs has been hampered by limitations of available experimental models and the poor viability of most TRAF-deficient mice. Here, B cell lines made deficient in TRAF2 using a novel homologous recombination system reveal new roles for TRAF2. We demonstrate that TRAF2 participates in synergy between CD40 and B cell antigen Receptor signals, and in CD40-mediated, TNF-dependent IgM production. We also find that TRAF2 participates in the degradation of TRAF3 associated with CD40 signaling, a role that may limit inhibitory actions of TRAF3. Finally, we show that TRAF2 and TRAF6 have overlapping functions in CD40-mediated NF-κB activation and CD80 up-regulation. These findings demonstrate previously unappreciated roles for TRAF2 in signaling by TNF Receptor Family members, using an approach that facilitates the analysis of genes critical to the viability of whole organisms.

  • recruitment of cd40 and tumor necrosis factor Receptor associated factors 2 and 3 to membrane microdomains during cd40 signaling
    Journal of Biological Chemistry, 2000
    Co-Authors: Bruce S Hostager, Ian M Catlett, Gail A. Bishop
    Abstract:

    Signals delivered to antigen-presenting cells through CD40 are critical for the activation of immune responses. Intracellular tumor necrosis factor (TNF) Receptor-associated factors (TRAFs) are key elements of the signal transduction pathways of many TNF Receptor Family members, including CD40. We show for the first time that engagement of CD40 in intact B cells induces the rapid translocation of TRAF2 from the cytoplasm to the plasma membrane. We found that CD40 engagement also results in its recruitment, together with TRAF2 and TRAF3, to membrane microdomains, regions of the plasma membrane enriched in signaling molecules such as the Src Family kinases. Using a membrane-permeable chelator of zinc or a mutant TRAF2 molecule, we show that the putative zinc-binding domains of TRAFs contribute to their recruitment to microdomains and to the downstream activation of c-Jun N-terminal kinase. We suggest that the zinc RING and zinc finger domains of TRAFs are required for communication between CD40 and microdomain-associated signaling molecules and may serve a similar role in the signal transduction pathways of other TNF Receptor Family members.