The Experts below are selected from a list of 74661 Experts worldwide ranked by ideXlab platform

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

  • Regulatory T Cells Inhibit T Cell Activity by Downregulating CD137 Ligand via CD137 Trogocytosis.
    2021
    Co-Authors: Khang Luu, Mugdha Vijay Patwardhan, Qun Zeng, Stina L. Wickström, Andreas Lundqvist, Herbert Schwarz
    Abstract:

    CD137 is a costimulatory molecule expressed on activated T cells. CD137 Ligand (CD137L) is expressed by antigen presenting cells (APC), which use the CD137-CD137L system to enhance immune responses. It was, therefore, surprising to discover CD137 expression on regulatory T cells (Treg). The function of CD137 in Treg are controversial. While some studies report that CD137 signalling converts Treg to effector T cells (Teff), other studies find that CD137-expressing Treg display a stronger inhibitory activity than CD137- Treg. Here, we describe that CD137 on Treg binds to CD137L on APC, upon which one of the two molecules is transferred via trogocytosis to the other cell, where CD137-CD137L forms a complex that is internalized and deprives APC of the immune-stimulatory CD137L. Truncated forms of CD137 that lack the cytoplasmic domain of CD137 are also able to downregulate CD137L, demonstrating that CD137 signalling is not required. Comparable data have been obtained with human and murine cells, indicating that this mechanism is evolutionarily conserved. These data describe trogocytosis of CD137 and CD137L as a new mechanism employed by Treg to control immune responses by downregulating the immunostimulatory CD137L on APC.

  • identification of CD137 expressing b cells in multiple sclerosis which secrete il 6 upon engagement by CD137 Ligand
    2020
    Co-Authors: Hiu Yi Wong, Shu Uin Gan, Ankshita Prasad, John Jia En Chua, Herbert Schwarz
    Abstract:

    The potent costimulatory effect of CD137 has been implicated in several murine autoimmune disease models. CD137 costimulates and polarizes antigen-specific T cells towards a potent Th1/Tc1 response, and is essential for the development of experimental autoimmune encephalomyelitis (EAE), a murine model of Multiple Sclerosis (MS). This study aimed to investigate a role of CD137 in MS. Immunohistochemical and immunofluorescence staining of MS brain tissues was used to identify expression of CD137. CD137+ cells were identified in MS brain samples, with active lesions having the highest frequency of CD137+ cells. CD137 expression was found on several leukocyte subsets, including T cells, B cells and endothelial cells. In particular, CD137+ B cells were found in meningeal infiltrates. In vitro experiments showed that CD137 engagement on activated B cells increased early TNF and persistent IL-6 secretion with increased cell proliferation. These CD137+ B cells could interact with CD137L-expressing cells, secrete pro-inflammatory cytokines and accumulate in the meningeal infiltrate. This study demonstrates CD137 expression by activated B cells, enhancement of the inflammatory activity of B cells upon CD137 engagement, and provides evidence for a pathogenic role of CD137+ B cells in MS.

  • CD137 Ligand-CD137 Interaction is Required For Inflammasome-Associated Brain Injury Following Ischemic Stroke
    2020
    Co-Authors: David Y. Fann, Herbert Schwarz, Emily Pauline Nickles, Luting Poh, Vismitha Rajeev, Sharmelee Selvaraji, Thiruma V. Arumugam
    Abstract:

    The CD137L-CD137 axis is a potent co-stimulatory immune checkpoint regulator that forms a bidirectional signaling pathway between the CD137 Ligand (CD137L) and CD137 receptor to regulate immunological activities. This study investigated the potential involvement of the CD137L-CD137 axis on inflammasome-associated brain injury and neurological deficits in a mouse model of focal ischemic stroke. Cerebral ischemia was induced in male C57BL/6J wild-type (WT), CD137L-deficient (CD137L KO) and CD137-deficient (CD137 KO) mice by middle cerebral artery occlusion (MCAO; 60 min), followed by reperfusion (6 h and 24 h). Brain infarct volume and neurological deficit scores were significantly lower in both CD137L KO and CD137 KO mice compared to WT controls. Moreover, CD137L-deficient brains had significantly lower levels of the pyroptotic protein, NT-Gasdermin D, while CD137-deficient brains had significantly lower levels of the pro-apoptotic proteins, cleaved caspase-3, pyroptotic protein, NT-Gasdermin D, and of the secondary pyroptotic protein NT-Gasdermin E, following ischemic stroke. This protection by CD137L and CD137 deletion was associated with a significant decrease in inflammasome signaling. In conclusion, our data provide evidence for the first time that the CD137L-CD137 axis contributes to brain injury and neurological deficits by activating the inflammasome signaling pathway following ischemic stroke.

  • CD137 CD137 Ligand signalling regulates the immune balance a potential target for novel immunotherapy of autoimmune diseases
    2020
    Co-Authors: Hiu Yi Wong, Herbert Schwarz
    Abstract:

    CD137 (TNFRSF9, 4-1BB) is a potent co-stimulatory molecule of the tumour necrosis factor receptor superfamily (TNFRSF) that is expressed by activated T cells. CD137/CD137 Ligand (CD137L) signalling primarily induces a potent cell-mediated immune response, while signalling of cell surface-expressed CD137L into antigen presenting cells enhances their activation, differentiation and migratory capacity. Studies have shown that bidirectional CD137/CD137L signalling plays an important role in the pathogenesis of autoimmune diseases. This review discusses the mechanisms how CD137/CD137L signalling contributes to immune deviation of helper T cell pathways in various murine models, and the potential of developing immunotherapies targeting CD137/CD137L signalling for the treatment of autoimmune diseases.

  • deletion of CD137 Ligand exacerbates renal and cutaneous but alleviates cerebral manifestations in lupus
    2019
    Co-Authors: Anselm Mak, Qianqiao Tang, Hiu Yi Wong, Bhushan Dharmadhikari, Nien Yee Kow, Thomas Paulraj Thamboo, Lik Wei Wong, Sreedharan Sajikumar, Herbert Schwarz
    Abstract:

    The CD137-CD137 Ligand (CD137L) costimulatory system is a critical immune checkpoint with pathophysiological implications in autoimmunity. In this study, we investigated the role of CD137L-mediated costimulation on renal, cutaneous and cerebral manifestations in lupus and the underlying immunological mechanism. Lupus-prone C57BL/6lpr-/- (B6.lpr) mice were crossed to C57BL/6.CD137L-/- mice to obtain CD137L-deficient B6.lpr [double knock out (DKO)] mice. We investigated the extent of survival, glomerulonephritis, skin lesions, cerebral demyelination, immune deviation and long-term synaptic plasticity among the two mouse groups. Cytokine levels, frequency of splenic leukocyte subsets and phenotypes were compared between DKO, B6.lpr and B6.WT mice. A 22 month observation of 226 DKO and 137 B6.lpr mice demonstrated significantly more frequent proliferative glomerulonephritis, larger skin lesions and shorter survival in DKO than in B6.lpr mice. Conversely, microglial activation and cerebral demyelination were less pronounced while long-term synaptic plasticity, was superior in DKO mice. Splenic Th17 cells were significantly higher in DKO than in B6.lpr and B6.WT mice while Th1 and Th2 cell frequencies were comparable between DKO and B6.lpr mice. IL-10 and IL-17 expression by T cells was not affected but there were fewer IL-10-producing myeloid (CD11b+) cells, and also lower serum IL-10 levels in DKO than in B6.lpr mice. The absence of CD137L causes an immune deviation toward Th17, fewer IL-10-producing CD11b+ cells and reduced serum IL-10 levels which potentially explain the more severe lupus in DKO mice while leading to reduced microglia activation, lesser cerebral damage and less severe neurological deficits.

Helmut R Salih - One of the best experts on this subject based on the ideXlab platform.

  • CD137 Ligand mediates opposite effects in human and mouse nk cells and impairs nk cell reactivity against human acute myeloid leukemia cells
    2010
    Co-Authors: Tina Baessler, Jean Enno Charton, Benjamin J Schmiedel, Frank Grunebach, Matthias Krusch, Alexander Wacker, Hansgeorg Rammensee, Helmut R Salih
    Abstract:

    Natural killer (NK) cells play an important role in the immunosurveillance of leukemia. Their reactivity is governed by a balance of activating and inhibitory receptors including various members of the tumor necrosis factor receptor (TNFR) family. Here we report that human NK cells acquire expression of the TNFR family member CD137 upon activation, and NK cells of acute myeloid leukemia (AML) patients display an activated phenotype with substantial CD137 expression. CD137 Ligand (CD137L) was detectable on leukemic cells in 35% of 65 investigated AML patients, but not on healthy CD34(+) cells, and expression was associated with monocytic differentiation. Bidirectional signaling following CD137-CD137L interaction induced the release of the immunomodulatory cytokines interleukin-10 and TNF by AML cells and directly diminished granule mobilization, cytotoxicity, and interferon-gamma production of human NK cells, which was restored by blocking CD137. Cocultures of NK cells with CD137L transfectants confirmed that human CD137 inhibits NK-cell reactivity, while activating signals were transduced by its counterpart on NK cells in mice. Our data underline the necessity to study the function of seemingly analog immunoregulatory molecules in mice compared with men and demonstrate that CD137-CD137L interaction enables immune evasion of AML cells by impairing NK-cell tumor surveillance in humans.

  • the role of CD137 and its Ligand in chronic lymphocytic leukemia cll
    2008
    Co-Authors: Tina Baessler, Benjamin J Schmiedel, Matthias Krusch, Lothar Kanz, Corina Buechele, Helmut R Salih
    Abstract:

    Abstract Tumor immunosurveillance is dependent on the reciprocal interaction between tumor cells and anti-tumor immunity mediated e.g. by NK cells. This has led to the concept of tumor immunoediting, which incorporates the multitude of mechanisms underlying this dual tumor- and immune-sculpting interaction. Various members of the TNF/TNFR family modulate differentiation, proliferation, activation, and death of both tumor and immune effector cells. Very recently the TNFR family member CD137 has been shown to be induced on NK cells by Fc receptor triggering indicating that not only the Fab region but also the Fc part of a given antibody may be responsible for effects attributed to CD137 modulation (Lin et al., Blood 2008, 112: 699). Thus we here studied the role of human CD137 and its cognate counterpart, the CD137 Ligand (CD137L) in the interaction of CLL with NK cells. High levels of CD137L expression were detected on B-CLL cells in all investigated patients (n=40). Incubation of CLL cells in the presence of an immobilized CD137-Ig fusionprotein significantly induced the release of the immunoregulatory cytokine TNF demonstrating that CLL-expressed CD137L was capable to transduce bidirectional signals. Furthermore, we found that NK cells of CLL patients displayed substantial CD137 expression. While being absent on resting NK cells, CD137 expression was upregulated on the CD56dimCD16+ but not the CD56brightCD16− NK cell subset of healthy donors upon activation e.g. with IL-2 or IL-15. In addition, CD137 was also induced on NK cells after incubation in supernatants of PBMC of CLL patients. Surprisingly, disruption of CD137-CD137L interaction in cocultures of allogenic NK cells with patient CLL cells by blocking CD137 antibody caused a significant increase in NK cell cytotoxicity. The observed inhibitory effect of CD137L on NK cell reactivity was confirmed in cytotoxicity assays using CD137L-transfectants with mock-transfectants as control. Furthermore, blocking CD137-CD137L interaction also substantially enhanced Rituximab-induced antibody dependent cellular cytotoxicity in an allogenic setting. Importantly, CD137 blockade also substantially enhanced CD107a expression as a surrogate marker for granule mobilization on autologous NK cells within PBMC of B-CLL patients, and this effect was observed both in the absence and more pronounced in the presence of Rituximab. Thus, expression of functional CD137L by CLL cells impairs anti-tumor immunity by diminishing both direct and antibody-dependent cellular cytotoxicity of allogenic and autologous NK cells. Modulation of the CD137-CD137L system might therefore be a suitable therapeutic approach in strategies like antibody therapy which rely on a sufficient NK cell anti-tumor response.

  • role of CD137 4 1bb and its Ligand in the nk cell mediated immune surveillance of acute myeloid leukemia
    2007
    Co-Authors: Tina Baessler, Helga Schmetzer, Benjamin J Schmiedel, Matthias Krusch, Katrin M Baltz, Lothar Kanz, Helmut R Salih
    Abstract:

    NK cells play an important role in the reciprocal interaction of tumor cells with the immune system and participate in the surveillance and eradication of hematological malignancies including acute myeloid leukemia (AML). NK cell reactivity is governed by a balance of activating and inhibitory receptors including various members of the TNF receptor (TNFR) superfamily. The TNFR superfamily member CD137/4-1BB has been shown to stimulate proliferation and IFN-γ production, but not cytotoxicity of NK cells in mice. Surprisingly, yet nothing is known regarding the consequences of CD137-CD137 Ligand (CD137L) interaction for NK cell reactivity in humans. In this study we demonstrate that CD56dimCD16+ but not CD56brightCD16− NK cells express CD137 upon stimulation with the activating cytokines IL-2 and IL-15 with peak expression between 48 and 60h. Furthermore, we found that 5 of 7 investigated AML cell lines and 16 of 51 (33%) primary AML cells of patients expressed substantial CD137L levels, while no CD137L expression was detected on CD34+ cells of healthy donors (n=5). CD137L expression was not restricted to a specific French-American-British (FAB) subtype, but was significantly (p

  • serum levels of CD137 Ligand and cd178 are prognostic factors for progression of myelodysplastic syndrome
    2004
    Co-Authors: Helmut R Salih, Volkmar Nuessler, Peter A Kiener, Claudio Denzlinger, Gary C Starling, Helga Schmetzer
    Abstract:

    Excess apoptosis leading to ineffective hematopoiesis is a common feature of myelodysplastic syndrome (MDS). CD178 (Fas Ligand/APO-1 Ligand) and CD137 Ligand (CD137L), 2 molecules involved in the regulation of apoptosis, have previously been found in sera of patients with malignancies and have been hypothesized to participate in the pathogenesis of various diseases. We analyzed sera of patients with MDS and found that while time to progression of MDS correlated with the IPSS score there was no correlation of CD137L or CD178 serum levels with this score or with karyotype, bone marrow blast count or cytopenia. However, when cut-off-values for significant differentiation between cases with higher/lower levels of these molecules were determined we found that high levels of soluble CD137L (sCD137L) and low serum levels of soluble CD178 (sCD178) correlate with statistical significance to rapid progression of disease as estimated by log-rank-test. Conversely, low levels of sCD137L and high levels of sCD178 correlate significantly with prolongation of time to progression of disease. Our results indicate that serum levels of sCD137L and sCD178 represent valuable novel indicators for prognosis and disease progression and may be a useful parameter for treatment decisions in patients with MDS.

  • Soluble CD137 (4-1BB) Ligand Is Released Following Leukocyte Activation and Is Found in Sera of Patients with Hematological Malignancies
    2001
    Co-Authors: Helmut R Salih, G. C. Starling, Helga Schmetzer, Christine Burke, Volkmar Nuessler, R. Pelka-fleischer, Robert Dunn, Peter A Kiener
    Abstract:

    Expression of CD137 Ligand (4-1BBL), a member of the TNF family of proteins, has been reported on several types of APCs, various carcinoma cells, and can be induced on activated T cells. In this study, we report that the soluble Ligand was released constitutively at low levels from leukocytes and at higher levels following cellular activation. Release from cells was blocked by addition of a metalloproteinase inhibitor which concomitantly caused the accumulation of 4-1BBL on the cell surface. In addition, we show that a soluble form of 4-1BBL was present at high levels in the sera of some patients with various hematological diseases, but only at low levels in healthy donors. Soluble 4-1BBL was active in that it competed with recombinant 4-1BBL for binding to the 4-1BB receptor and was able to costimulate IL-2 and IFN-γ release from peripheral T cells. These results indicate that the release of soluble 4-1BBL from the cell surface is mediated by one or more sheddases and likely regulates 4-1BB-4-1BBL interactions between cells in vivo. Cleavage of 4-1BBL to an active soluble form would alter both proximal and distal cellular responses, including cell survival and costimulatory or inflammatory responses, that are mediated through the 4-1BB pathway. This, in turn, would likely alter disease progression or outcome.

Hyeonwoo Lee - One of the best experts on this subject based on the ideXlab platform.

  • the murine CD137 CD137 Ligand signalosome a signal platform generating signal complexity
    2020
    Co-Authors: Beom K Choi, Hyeonwoo Lee
    Abstract:

    CD137, a member of the TNFR family, is a costimulatory receptor, and CD137L, a member of the TNF family, is its Ligand. Studies using CD137- and CD137L-deficient mice and antibodies against CD137 and CD137L have revealed the diverse and paradoxical effects of these two proteins in various cancers, autoimmunity, infections, and inflammation. Both their cellular diversity and their spatiotemporal expression patterns indicate that they mediate complex immune responses. This intricacy is further enhanced by the bidirectional signal transduction events that occur when these two proteins interact in various types of immune cells. Here, we review the biology of murine CD137/CD137L, particularly, the complexity of their proximal signaling pathways, and speculate on their roles in immune responses.

  • anti CD137 suppresses tumor growth by blocking reverse signaling by CD137 Ligand
    2017
    Co-Authors: Sang W Kang, Byoung S Kwon, Hyeonwoo Lee, Sangchul Lee, So H Park, Juyang Kim, Hyeon H Kim, Sukil Seo, Hong R Cho, Byungsuk Kwon
    Abstract:

    CD137 (4-1BB) is a T-cell costimulatory molecule, and agonstic CD137 antibodies are currently being evaluated in the clinic as cancer immunotherapy. Recently, it was found that CD137 −/− mice or mice injected with agonistic anti-CD137 antibodies exhibit heightened antitumor responses, contrary to expectations based on other knowledge of CD137 function. Here, we report findings related to reverse signaling by CD137 Ligand (CD137L) in antigen-presenting dendritic cells (DC) in tumors that address these paradoxical results. Specifically, CD137L suppressed intratumoral differentiation of IL12-producing CD103 + DC and type 1 tumor-associated macrophages (TAM). Differentiation of these cell types is important because they are required to generate IFNγ-producing CD8 + cytotoxic T lymphocytes (Tc1). Notably, CD137L blockade increased levels of IL12 and IFNγ, which promoted intratumoral differentiation of IFNγ-producing Tc1, IL12-producing CD103 + DC, and type 1 TAM within tumors. Our results offer an explanation for the paradoxical effects of CD137 blockade, based on differential immunomodulatory effects of CD137 signaling and reverse signaling in T cells and DC, respectively. Further, they show how CD137L blockade can seed a forward-feedback loop for activation of CD103 + DC/type 1 TAM and Tc1 that can create a self-perpetuating cycle of highly effective immunosurveillance. Cancer Res; 77(21); 5989–6000. ©2017 AACR .

  • tmem126a a CD137 Ligand binding protein couples with the tlr4 signal transduction pathway in macrophages
    2015
    Co-Authors: Euncheol Kim, Byungsuk Kwon, Jihoi Moon, Sang W Kang, Hyeonwoo Lee
    Abstract:

    We showed previously that a novel protein, transmembrane protein 126A (TMEM126A), binds to CD137 Ligand (CD137L, 4-1BBL) and couples with its reverse signals in macrophages. Here, we present data showing that TMEM126A relays TLR4 signaling. Thus, up-regulation of CD54 (ICAM-1), MHC II, CD86 and CD40 expression in response to TLR4 activation was diminished in TMEM126A-deficient macrophages. Moreover in TMEM126A-deficient RAW264.7 cells, LPS/TLR4-induced late-phase JNK/SAPK and IRF-3 phosphorylation was abolished. These findings indicate that TMEM126A contributes to the TLR4 signal up-regulating the expression of genes whose products are involved in antigen presentation.

  • cross linking of CD137 Ligand modulates immune responses of thioglycollate elicited mouse peritoneal macrophages
    2011
    Co-Authors: Junsang Bae, Hyeongsup Kim, Jaehong Park, Sanghyuk Park, Hyeonwoo Lee
    Abstract:

    The aim of this study was to investigate effects of CD137 Ligand (CD137L)-mediated reverse signaling on cellular responses in thioglycollate-elicited mouse peritoneal macrophages. Five-week-old male C57B6 mice were injected intraperitoneally with thioglycollate for 3 days to isolate peritoneal macrophages. We counted total cell numbers with a Cell Lab Quanta SC. CD137L expression was examined with a flow cytometer. We also measured expression of inflammatory cytokines by flow cytometry and/or real time-PCR. Cross-linking of CD137L with recombinant CD137-Fc protein (rCD137-Fc) increased total numbers of thioglycollate-elicited mouse peritoneal macrophages (hIgG-Fc- vs. rCD137-Fc-treated group, p < 0.05). However, ligation reduced the increase in IL-1β and IL-6 levels. Real-time PCR analysis showed that treatment of cells with rCD137-Fc also reduced transcript levels of IL-1β, IL-6, iNOS and COX2 (hIgG-Fc- vs. rCD137-Fc-treated group, p < 0.05), as well as expression of CD137L. Reverse signals initiated by CD137L negatively modulate certain immune functions of thioglycollate-elicited peritoneal macrophages.

  • CD137 Ligand mediated reverse signals increase cell viability and cytokine expression in murine myeloid cells involvement of mtor p70s6 kinase and akt
    2009
    Co-Authors: Dongku Kim, Sangchul Lee, Hyeonwoo Lee
    Abstract:

    Cross-linking of CD137 Ligand (CD137L), a member of the TNF family, with recombinant CD137-Fc (rCD137-Fc) protein enhanced adherence of bone marrow-derived macrophages, and increased the expression of ICAM-1, IL-1beta, IL-6, M-CSF and phosphotyrosine proteins. In RAW264.7 cells, a murine myeloid cell line, rCD137-Fc not only increased adherence but also cell multiplication, in a manner comparable to LPS or M-CSF. In addition, it up-regulated expression of IL-1beta, IL-1 receptor antagonist, IL-6, COX2, tenascin C, neuropeptide Y and M-CSF mRNA. Neutralization of M-CSF by incubating the RAW264.7 cells with anti-M-CSF mAb did not prevent the CD137L signal-induced viability. Viability was blocked by PP2, an Src tyrosine kinase inhibitor, rapamycin, an mTOR inhibitor and LY294002, a PI3K inhibitor, but not by Wortmannin, another PI3K inhibitor. Cross-linking of CD137L increased phosphorylation of Akt and p70S6 kinase. The latter was blocked by PP2, rapamycin or LY294002, but not by Wortmannin, whereas phosphorylation of Akt was blocked by LY294002 or Wortmannin. These findings demonstrate that reverse signals evoked by CD137L regulate immune functions in macrophages.

Yasodha Natkunam - One of the best experts on this subject based on the ideXlab platform.

  • use of CD137 Ligand expression in the detection of small b cell lymphomas involving the bone marrow
    2014
    Co-Authors: Shuchun Zhao, Ying Xing, Yasodha Natkunam
    Abstract:

    Staging for small B-cell lymphomas is important for prognostic and therapeutic decision making; however, the detection of lymphoid infiltrates in the bone marrow is often hampered by the lack of specific diagnostic markers. We recently described the hematopoietic tissue distribution patterns of CD137 and CD137 Ligand (CD137L), which have shown promise as immunotherapeutic targets. CD137 expression was primarily confined to cells in the microenvironment, whereas CD137L was expressed in neoplastic cells in most B-cell lymphomas. Here we evaluate the use of CD137L in the detection of small B-cell lymphomas involving the bone marrow. To test the potential efficacy of CD137L in detecting bone marrow lymphoid infiltrates, 166 small B-cell lymphomas were evaluated by immunohistochemistry and double-immunofluorescence labeling on formalin-fixed, paraffin-embedded bone marrow core biopsies. CD137L was highly expressed in bone marrows involved by small B-cell lymphomas and included hairy cell leukemia, mantle cell lymphoma, follicular lymphoma, B-lymphoblastic leukemia, and chronic lymphocytic leukemia. In addition, a small subset of marginal zone lymphoma and most of lymphoplasmacytic lymphoma showed staining. Normal bone marrow cells including myeloid, erythroid and megakaryocytic precursors, and reactive lymphoid aggregates lacked staining. Our findings show that immunohistochemistry for CD137L is capable of reliably distinguishing small B-cell lymphomas from reactive lymphoid aggregates. These data also suggest that CD137L is useful in providing staging information for clinical diagnosis and is likely to furnish a potential target for minimal residual disease assessment as well as immunotherapy in patients with stage 4 disease.

  • CD137 Ligand is expressed in primary and secondary lymphoid follicles and in b cell lymphomas diagnostic and therapeutic implications
    2013
    Co-Authors: Shuchun Zhao, Haiyu Zhang, Ying Xing, Yasodha Natkunam
    Abstract:

    CD137 Ligand (4-1BB Ligand, TNFSF9, CD137L) is a member of the tumor necrosis factor family whose binding to its receptor, CD137 (4-1BB, TNFRSF9), mediates costimulatory and prosurvival signals necessary for T-cell activation and regulation of humoral immune responses. Recent studies have shown that anti-CD137 immunotherapy has promise as a treatment for solid tumors and lymphoid malignancies in preclinical models. Here, we define the tissue expression profile of CD137L, which has not been previously explored. We characterized the expression of CD137L in normal and neoplastic human hematopoietic and nonhematopoietic tissue and found that CD137L is preferentially expressed in B cells of the primary follicles, mantle zones of the secondary follicles, germinal centers, and in normal endothelial cells. Double immunofluorescence labeling in tissue sections and flow cytometry analysis further showed that CD137L is a potential new marker of memory B cells. Evaluation of over 700 human hematopoietic tumors revealed that the majority of B-cell lymphomas expressed CD137L, which include mantle cell lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. In contrast, CD137L expression was lacking in Hodgkin lymphoma and T-cell lymphoma. Our findings suggest that CD137L is a novel diagnostic marker of subtypes of non-Hodgkin B-cell lymphomas and raise the possibility that its expression on tumor cells may be directly targeted for immunomodulatory therapy for lymphoid and other malignancies.

Byungsuk Kwon - One of the best experts on this subject based on the ideXlab platform.

  • anti CD137 suppresses tumor growth by blocking reverse signaling by CD137 Ligand
    2017
    Co-Authors: Sang W Kang, Byoung S Kwon, Hyeonwoo Lee, Sangchul Lee, So H Park, Juyang Kim, Hyeon H Kim, Sukil Seo, Hong R Cho, Byungsuk Kwon
    Abstract:

    CD137 (4-1BB) is a T-cell costimulatory molecule, and agonstic CD137 antibodies are currently being evaluated in the clinic as cancer immunotherapy. Recently, it was found that CD137 −/− mice or mice injected with agonistic anti-CD137 antibodies exhibit heightened antitumor responses, contrary to expectations based on other knowledge of CD137 function. Here, we report findings related to reverse signaling by CD137 Ligand (CD137L) in antigen-presenting dendritic cells (DC) in tumors that address these paradoxical results. Specifically, CD137L suppressed intratumoral differentiation of IL12-producing CD103 + DC and type 1 tumor-associated macrophages (TAM). Differentiation of these cell types is important because they are required to generate IFNγ-producing CD8 + cytotoxic T lymphocytes (Tc1). Notably, CD137L blockade increased levels of IL12 and IFNγ, which promoted intratumoral differentiation of IFNγ-producing Tc1, IL12-producing CD103 + DC, and type 1 TAM within tumors. Our results offer an explanation for the paradoxical effects of CD137 blockade, based on differential immunomodulatory effects of CD137 signaling and reverse signaling in T cells and DC, respectively. Further, they show how CD137L blockade can seed a forward-feedback loop for activation of CD103 + DC/type 1 TAM and Tc1 that can create a self-perpetuating cycle of highly effective immunosurveillance. Cancer Res; 77(21); 5989–6000. ©2017 AACR .

  • is CD137 Ligand CD137l signaling a fine tuner of immune responses
    2015
    Co-Authors: Byungsuk Kwon
    Abstract:

    Now, it has been being accepted that reverse signaling through CD137 Ligand (CD137L) plays an important role in vivo during hematopoiesis and in immune regulation. However, due to technical difficulty in dissecting both directional signaling events simultaneously in vivo, most biological activities caused by CD137-CD137L interactions are considered as results from signaling events of the CD137 receptor. To make the story more complex, CD137(-/-) and CD137L(-/-) mice have increased or decreased immune responses in a context-dependent manner. In this Mini review, I will try to provide a plausible explanation for how CD137L signaling is controlled during immune responses.

  • tmem126a a CD137 Ligand binding protein couples with the tlr4 signal transduction pathway in macrophages
    2015
    Co-Authors: Euncheol Kim, Byungsuk Kwon, Jihoi Moon, Sang W Kang, Hyeonwoo Lee
    Abstract:

    We showed previously that a novel protein, transmembrane protein 126A (TMEM126A), binds to CD137 Ligand (CD137L, 4-1BBL) and couples with its reverse signals in macrophages. Here, we present data showing that TMEM126A relays TLR4 signaling. Thus, up-regulation of CD54 (ICAM-1), MHC II, CD86 and CD40 expression in response to TLR4 activation was diminished in TMEM126A-deficient macrophages. Moreover in TMEM126A-deficient RAW264.7 cells, LPS/TLR4-induced late-phase JNK/SAPK and IRF-3 phosphorylation was abolished. These findings indicate that TMEM126A contributes to the TLR4 signal up-regulating the expression of genes whose products are involved in antigen presentation.

  • recombinant tat CD137 Ligand cytoplasmic domain fusion protein induces the production of il 6 and tnf α in peritoneal macrophages
    2011
    Co-Authors: Jung Dae Kim, Eun A Lee, Nguyen N Quang, Hong Rae Cho, Byungsuk Kwon
    Abstract:

    Background: The Ligand for CD137 (CD137L; also called 4-1BBL) is mainly expressed on activated APCs such as dendritic cells, B cells and macrophages. Even though CD137L functions as a trigger of the CD137 signaling pathway for T cell activation and expansion, engagement of CD137L can deliver a signal leading to the production of proinflammatory cytokines in macrophages. Methods: We generated cell-permeable TAT-CD137L cytoplasmic domain fusion protein (TAT-CD137Lct) and examined its ability to initiate the CD137L reverse signaling pathway. Results: Treatment of TAT-CD137Lct induced the production of high levels of IL-6 and TNF-α mRNAs and proteins in peritoneal macrophages. TAT-CD137Lct increased phosphorylation of Erk, p38 MAPK and Jnk, and activated transcription factors C/EBP and CREB. However, TAT-CD137Lct did not visibly affect the degradation of the inhibitor of NF-kB (IkBα). We further demonstrated that JNK activation was required for TAT-CD137Lct-induced production of TNF-α, while activation of Erk and p38 MAPK were involved in IL-6 and TNF-α production. Conclusion: Our results suggest that TATCD137Lct is an effective activator for the CD137L reverse signaling pathway. [Immune Network 2011;11(4):216-222]

  • CD137 CD137 Ligand interactions in inflammation
    2009
    Co-Authors: Byungsuk Kwon
    Abstract:

    The main stream of CD137 studies has been directed to the function of CD137 in CD8(+) T-cell immunity, including its anti-tumor activity, and paradoxically the immunosuppressive activity of CD137, which proves to be of a great therapeutic potential for animal models of a variety of autoimmune and inflammatory diseases. Recent studies, however, add complexes to the biology of CD137. Accumulating is evidence supporting that there exists a bidirectional signal transduction pathway for the CD137 receptor and its Ligand (CD137L). CD137/CD137L interactions are involved in the network of hematopoietic and nonhematopoietic cells in addition to the well characterized antigen-presenting cell-T cell interactions. Signaling through CD137L plays a critical role in the differentiation of myeloid cells and their cellular activities, suggesting that CD137L signals trigger and sustain inflammation. The overall consequence might be that the amplified inflammation by CD137L enhances the T-cell activity together with CD137 signals by upregulating costimulatory molecules, MHC molecules, cell adhesion molecules, cytokines, and chemokines. Solving this outstanding issue is urgent and will have an important clinical implication.