The Experts below are selected from a list of 777 Experts worldwide ranked by ideXlab platform
Byoung S. Kwon - One of the best experts on this subject based on the ideXlab platform.
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Role of endogenous 4-1BB in the development of systemic lupus
2020Co-Authors: Dass S. Vinay, Jae H. Choi, Beom K. Choi, Byoung S. KwonAbstract:Summary Systemic lupus erythematosus (SLE) is characterized by the production of autoantibodies directed against nuclear antigens including nucleosomes and DNA. To determine the role of T-cell costimulatory molecule 4-1BB in the regulation of SLE, MRL-Fas lpr (lpr) mice deficient in 4-1BB (lpr/41BB ‐/‐‐ ) were generated and their disease phenotype was compared to that of control lpr mice. The main finding of this study is that the lpr/41BB ‐/‐‐ mice had more pronounced skin lesions which appeared earlier, increased lymphadenopathy, increased renal damage, and higher mortality than 4-1BB-intact control lpr mice. The increased severity of lesions in lpr/4-1BB ‐/‐‐ mice was closely associated with increases in CD4 + T, CD3 + B220 + double-negative T cells, serum immunoglobulin, anti-dsDNA autoantibodies, and tissue immunoglobulin deposits. These data suggest that the 4-1BB)4-1BB Ligand signalling pathway plays an important role in SLE and that deletion of 4-1BB confers susceptibility to lpr mice, leading to accelerated induction of disease and early mortality.
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factor receptor superfamily, with the high-affinity IgE receptor Costimulation of mast cells by 4-1BB, a member of the tumor necrosis
2020Co-Authors: Yuko Kawakami, Byoung S. Kwon, Michael Croft, Robert S. Mittler, Hong Hong, Carl F. Ware, Toshiaki Hajime Nishimoto, Mari Maeda-yamamotoAbstract:Abstract Mast cells are the major effector cell type for immediate hypersensitivity and other forms of allergic reactions. Expression of 4-1BB, a member of the tumor necrosis factor receptor superfamily, is induced at mRNA and protein levels upon stimulation through the high-affinity receptor for IgE (FceRI). In this study, we present evidence that agonistic anti-4-1BB antibodies can enhance FceRI-induced cytokine production and secretion. Consistent with this, 4-1BB-deficient mast cells exhibit reduced degranulation and cytokine production upon FceRI stimulation. Analysis of 4-1BB Ligand (4-1BBL)-deficient cells supported this notion. As a potential mechanism for these defects, we identified a defect in Ca 2+ flux induced by FceRI stimulation. The defective Ca 2+ flux could be accounted for by the reduced activity of Lyn/Btk/phospholipase C-γ2 pathway and constitutive interactions between 4-1BB and Lyn. Therefore, FceRI-inducible 4-1BB plays a costimulatory function together with FceRI stimulation.From bloodjournal.hematologylibrary.org by guest on June 12, 2013. For personal use only.
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4-1BB (CD137), an inducible costimulatory receptor, as a specific target for cancer therapy.
Journal of Biochemistry and Molecular Biology, 2014Co-Authors: Dass S. Vinay, Byoung S. KwonAbstract:Although considerable progress has been made in understanding how tumors evade immune surveillance, measures to counter the same have not kept pace with the advances made in designing effective strategies. 4-1BB (CD137; TNFRS9), an activation-induced costimulatory molecule, is an important regulator of immune responses. Targeting 4-1BB or its natural Ligand 4-1BB Ligand (4-1BBL) has important implications in many clinical conditions, including cancer. In-depth analysis revealed that 4-1BB-mediated anti-cancer effects are based on its ability to induce activation of cytotoxic T lymphocytes (CTL), and among others, high amounts of IFN-γ. In this review, we will discuss the various aspects of 4-1BB-mediated anti-tumor responses, the basis of such responses, and future directions. [BMB Reports 2014; 47(3): 122-129]
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The Structure of the Trimer of Human 4-1BB Ligand Is Unique among Members of the Tumor Necrosis Factor Superfamily
Journal of Biological Chemistry, 2009Co-Authors: Jung-sue Byun, Su-mi Shin, Amanda J. Rice, Thomas Walz, Byoung S. KwonAbstract:Binding of the 4-1BB Ligand (4-1BBL) to its receptor, 4-1BB, provides the T lymphocyte with co-stimulatory signals for survival, proliferation, and differentiation. Importantly, the 4-1BB-4-1BBL pathway is a well known target for anti-cancer immunotherapy. Here we present the 2.3-Å crystal structure of the extracellular domain of human 4-1BBL. The ectodomain forms a homotrimer with an extended, three-bladed propeller structure that differs from trimers formed by other members of the tumor necrosis factor (TNF) superfamily. Based on the 4-1BBL structure, we modeled its complex with 4-1BB, which was consistent with images obtained by electron microscopy, and verified the binding site by site-directed mutagenesis. This structural information will facilitate the development of immunotherapeutics targeting 4-1BB.
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Role of endogenous 4‐1BB in the development of systemic lupus erythematosus
Immunology, 2007Co-Authors: Dass S. Vinay, Jae H. Choi, Beom K. Choi, Byoung S. KwonAbstract:Summary Systemic lupus erythematosus (SLE) is characterized by the production of autoantibodies directed against nuclear antigens including nucleosomes and DNA. To determine the role of T-cell costimulatory molecule 4-1BB in the regulation of SLE, MRL-Faslpr (lpr) mice deficient in 4-1BB (lpr/4-1BB–/–) were generated and their disease phenotype was compared to that of control lpr mice. The main finding of this study is that the lpr/4-1BB–/– mice had more pronounced skin lesions which appeared earlier, increased lymphadenopathy, increased renal damage, and higher mortality than 4-1BB-intact control lpr mice. The increased severity of lesions in lpr/4-1BB–/– mice was closely associated with increases in CD4+ T, CD3+ B220+ double-negative T cells, serum immunoglobulin, anti-dsDNA autoantibodies, and tissue immunoglobulin deposits. These data suggest that the 4-1BB−4-1BB Ligand signalling pathway plays an important role in SLE and that deletion of 4-1BB confers susceptibility to lpr mice, leading to accelerated induction of disease and early mortality.
Robert S. Mittler - One of the best experts on this subject based on the ideXlab platform.
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Regulation of T Cell-Dependent Humoral Immunity Through CD137(4-1BB) Mediated Signals
CD137 Pathway: Immunology and Diseases, 2020Co-Authors: Robert S. Mittler, Becker Hewes, Juergen FoellAbstract:CD137 (4-1BB), a member of the tumor necrosis factor receptor (TNFR) superfamily is an activation-inducible type I transmembrane protein receptor expressed on activated T cells, Natural Killer cells (NK), macrophages (Mφ), and dendritic cells (DC). Its Ligand, 4-1BB-L, is a member of the tumor necrosis factor (TNF) superfamily a type II transmembrane protein that is expressed on antigen presenting cells (APC). Ligand-induced trimerization of CD137 activates multiple signaling pathways in T cells that result in transcriptional activation, enhanced T cell activation and survival. Agonistic anti-CD137 mAbs can replace the need for 4-1BB Ligand-mediated receptor crosslinking either in vitro or in vivo. 4-1BB-L specific mAbs can drive cytokine production in APCs; anti-4-1BB Ligand mAbs that can block receptor-Ligand binding also prevent CD137-mediated T cell costimulation. However, unlike agonistic mAbs to other T cell costimulatory receptors, signaling by anti-CD137 specific mAbs can also suppress the T cellmediated immune responses. CD137 receptor-proximal and downstream signals in T cells have been largely elucidated. However, this is not the case for anti-CD137induced immune suppression. Given that NK cells and dendritic cells express this receptor, it is not clear whether T cells are the cell targets during anti-CD137 mAb induced immune suppression. In this review we discuss CD137-mediated immune suppression and its role in regulating T-dependent B cell responses and to some extent APC function in normal, autoimmune, and tumor bearing mice.
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Anti-CD137 antibodies in the treatment of autoimmune disease and cancer.
Immunologic research, 2020Co-Authors: Robert S. Mittler, Juergen Foell, Megan Mccausland, Simona Strahotin, Abhijit Bapat, L Becker HewesAbstract:CD137 (4-1BB), is an inducible T-cell costimulatory receptor and a member of the tumor necrosis factor receptor (TNFR) superfamily. It is expressed on activated T cells and activated natural killer (NK) cells, but is constitutively expressed on a population of splenic dendritic cells (DCs). The natural counter receptor for CD137 is 4-1BB Ligand, a member of the TNF superfamily that is weakly expressed on naïve or resting B cells, macrophages, and DCs. Upon activation, the level of 4-1BBL expression increases on these cells. In T cells CD137-induced signals lead to the recruitment of TRAF family members and activation of several kinases, including ASK-1, MKK, MAPK3/ MAPK4, p38, and JNK/SAPK. Kinase activation is then followed by the activation and nuclear translocation of several transcription factors, including ATF-2, Jun, and NF-kappaB. CD137-mediated T-cell costimulation as measured by enhanced proliferation and cytokine production can be induced by anti-CD137 monoclonal antibodies (MAbs) or by employing immobilized 4-1BB Ligand. In addition to augmenting suboptimal TCR-induced proliferation, CD137-mediated signaling protects T cells, and in particular, CD8+ T cells from activation-induced cell death (AICD). Although studies with CD137-deficient or 4-1BBL-deficient mice failed to demonstrate any loss of essential immunological function, or other noteworthy deficits, we have found that 4-1BBL-deficient mice failed to generate a strong antiviral immune response following lymphocytic choriomeningitis virus (LCMV) peptide vaccination. We further found that although compromised, the immune response to LCMV vaccination in these mice could be fully restored by injecting them with anti-CD137 MAbs at the time of vaccination. Finally, we have found that injecting normal mice with anti-CD137 MAbs had profound effects on their ability to develop immune responses to allo- and autoantigens. The results of these studies discussed in this article provide a rationale for assessing the potential use of anti-CD137 MAbs for therapeutic purposes.
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factor receptor superfamily, with the high-affinity IgE receptor Costimulation of mast cells by 4-1BB, a member of the tumor necrosis
2020Co-Authors: Yuko Kawakami, Byoung S. Kwon, Michael Croft, Robert S. Mittler, Hong Hong, Carl F. Ware, Toshiaki Hajime Nishimoto, Mari Maeda-yamamotoAbstract:Abstract Mast cells are the major effector cell type for immediate hypersensitivity and other forms of allergic reactions. Expression of 4-1BB, a member of the tumor necrosis factor receptor superfamily, is induced at mRNA and protein levels upon stimulation through the high-affinity receptor for IgE (FceRI). In this study, we present evidence that agonistic anti-4-1BB antibodies can enhance FceRI-induced cytokine production and secretion. Consistent with this, 4-1BB-deficient mast cells exhibit reduced degranulation and cytokine production upon FceRI stimulation. Analysis of 4-1BB Ligand (4-1BBL)-deficient cells supported this notion. As a potential mechanism for these defects, we identified a defect in Ca 2+ flux induced by FceRI stimulation. The defective Ca 2+ flux could be accounted for by the reduced activity of Lyn/Btk/phospholipase C-γ2 pathway and constitutive interactions between 4-1BB and Lyn. Therefore, FceRI-inducible 4-1BB plays a costimulatory function together with FceRI stimulation.From bloodjournal.hematologylibrary.org by guest on June 12, 2013. For personal use only.
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engagement of 4 1bb inhibits the development of experimental allergic conjunctivitis in mice
Journal of Immunology, 2005Co-Authors: Atsuki Fukushima, Robert S. Mittler, Hideo Yagita, Tomoko Yamaguchi, Waka Ishida, Kazuyo Fukata, Hisayuki UenoAbstract:The 4-1BB receptor acts as a costimulator in CD8 + T cell activation. Agonistic stimulation through this molecule by treatment with anti-4-1BB Abs has been demonstrated to inhibit various experimentally induced diseases in animals. However, the effect of anti-4-1BB Abs on experimental allergic diseases has not been reported. We investigated the effect of anti-4-1BB Abs on the development and progression of experimental allergic conjunctivitis in mice. To examine the effects of Abs during the induction or effector phase, actively immunized mice or passively immunized mice by splenocyte transfer were treated with agonistic anti-4-1BB Abs, blocking anti-4-1BB Ligand Abs, or normal rat IgG. Eosinophil infiltration into the conjunctiva was significantly reduced in wild-type mice by the anti-4-1BB Ab treatment during either induction or effector phase. Th2 cytokine production by splenocytes and total serum IgE were significantly reduced by the anti-4-1BB Ab treatment, while IFN-γ production was increased. The anti-4-1BB Ab treatment induced a relative increase of CD8-positive cell numbers in the spleens. Moreover, inhibition of eosinophil infiltration by the treatment with anti-4-1BB Abs was also noted in actively immunized IFN-γ knockout mice. Taken altogether, in vivo treatment with agonistic anti-4-1BB Abs in either induction or effector phase inhibits the development of experimental allergic conjunctivitis, and this inhibition is likely to be mediated by suppression of Th2 immune responses rather than up-regulation of IFN-γ.
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Costimulation of mast cells by 4-1BB, a member of the tumor necrosis factor receptor superfamily, with the high-affinity IgE receptor
Blood, 2005Co-Authors: Hajime Nishimoto, Byoung S. Kwon, Robert S. Mittler, Hong Hong, Karen G. Potter, Mari Maeda-yamamoto, Tatsuya Kinoshita, Yuko Kawakami, Carl F. WareAbstract:Mast cells are the major effector-cell type for immediate hypersensitivity and other forms of allergic reactions. Expression of 4-1BB, a member of the tumor necrosis factor receptor superfamily, is induced at mRNA and protein levels on stimulation through the high-affinity receptor for immunoglobulin E (IgE; FcϵRI). In this study, we present evidence that agonistic anti-4-1BB antibodies can enhance FcϵRI-induced cytokine production and secretion. Consistent with this, 4-1BB-deficient mast cells exhibit reduced degranulation and cytokine production on FcϵRI stimulation. Analysis of 4-1BB Ligand (4-1BBL)-deficient cells supported this notion. As a potential mechanism for these defects, we identified a defect in Ca2+ flux induced by FcϵRI stimulation. The defective Ca2+ flux could be accounted for by the reduced activity of Lyn/Btk/phospholipase C-γ2 pathway and constitutive interactions between 4-1BB and Lyn. Therefore, FcϵRI-inducible 4-1BB plays a costimulatory function together with FcϵRI stimulation.
P A Kiener - One of the best experts on this subject based on the ideXlab platform.
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Serum levels of sCD137 (4-1BB) Ligand are prognostic factors for progression in acute myeloid leukemia but not in non-Hodgkin's lymphoma
European Journal of Haematology, 2006Co-Authors: N. Hentschel, P A Kiener, Helmut R. Salih, Matthias Krusch, Hans-jochem Kolb, Helga SchmetzerAbstract:: CD178 (Fas/APO-1 Ligand) and CD137 Ligand (CD137L) have previously been described in sera of patients with various malignancies and play an important role in the pathogenesis of various diseases. Recently, we demonstrated that low levels of soluble (s) CD137L and high levels of sCD178 correlate significantly with a long progression free survival in patients with myelodysplastic syndrome (MDS). In this study, we correlated sCD137L and sCD178 levels in sera of 42 samples of patients with acute myeloid leukemia (AML) and 46 samples of patients with non-Hodgkin's lymphoma (NHL) with stages, subtypes, and the clinical course of the diseases and determined cut-off values with maximum probability for significant differentiation between cases with higher/lower probability for progress free survival. In contrast to patients with MDS, surprisingly no correlation between sCD178 levels and different subtypes and stages or with prognosis in AML or NHL were observed. Regarding sCD137L, NHL-patients displayed lower levels compared with AML. Statistically significant higher median levels of sCD137L are present in patients with undifferentiated AML (M1/M2, 1470 pg/mL), poor cytogenetic risk (288 pg/mL) and higher levels of BM-blasts (186 pg/mL) compared with patients with monocytoid AML (M4/M5, 89 pg/mL), intermediate cytogenetic risk (59 pg/mL) and lower levels of BM-blasts (14 pg/mL) respectively. Furthermore, in AML patients sCD137L levels correlate significantly with the probabilities to achieve complete remission (CR), stay in CR or with progress of the disease. Taken together, our data demonstrate that sCD137L can be used as a prognostic factor not only in MDS but also in AML.
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4-1 BB Ligand--just another costimulating molecule?
International journal of clinical pharmacology and therapeutics, 2002Co-Authors: H. R. Salih, P A Kiener, V. NüsslerAbstract:Initially, scientific interest in the 4-1BB/4-1BB Ligand system focused on the role of the 4-1 BB (CD 137) receptor in the costimulation of T cells. More recently, evidence is accumulating that 4-1BBL is more than just the Ligand for a costimulatory molecule. In this review we discuss the functional properties of 4-1BB Ligand such as its preference for CD8 positive T cells and the differences to costimulation via the B7/CD28 system. Furthermore, the available data regarding its ability to transduce signals bidirectionally, i.e. also back into the Ligand bearing cell, its release as a soluble form following shedding from the cell surface, and its role in the interaction of tumor cells with the immune system are reviewed.
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Soluble CD137 (4-1BB) Ligand Is Released Following Leukocyte Activation and Is Found in Sera of Patients with Hematological Malignancies
Journal of Immunology, 2001Co-Authors: Helmut R. Salih, G. C. Starling, Helga Schmetzer, Christine Burke, Robert Dunn, R. Pelka-fleischer, Volkmar Nuessler, P A KienerAbstract: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.
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Constitutive Expression of Functional 4-1BB (CD137) Ligand on Carcinoma Cells
The Journal of Immunology, 2000Co-Authors: H. R. Salih, Deryk T Loo, S. G. Kosowski, V. F. Haluska, G. C. Starling, A. A. Aruffo, P. A. Trail, F Lee, P A KienerAbstract:Members of the TNF superfamily, including Fas, Fas Ligand, and CD40, have been shown to be expressed on tumor cells. In the studies described in this work, we report that another family member, the Ligand for 4-1BB (CD137), is expressed on various human carcinoma cell lines, on cells of solid tumors derived from these cell lines, and cells obtained from human tumors. Expression of 4-1BB Ligand (4-1BBL) mRNA was detected by both RT-PCR and Northern blot analysis, and expression of 4-1BBL protein was detected by Western blot analysis of whole cell lysates and by FACS analysis of tumor cells and cell lines. Incubation of tumor cells with a 4-1BB-Ig fusion protein led to the production of IL-8 by the cells, demonstrating that the 4-1BBL is functionally active and signals back into the tumor cells. Furthermore, 4-1BBL expressed on the carcinoma cells functioned as a costimulatory molecule for the production of cytokines (most notably IFN-gamma) in cocultures of T cells and tumor cells. These findings suggest that 4-1BBL expressed on carcinoma cells may significantly influence the outcome of a T cell-tumor cell interaction.
Tania H. Watts - One of the best experts on this subject based on the ideXlab platform.
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Endogenous 4-1BB Ligand Plays a Critical Role in Protection from Influenza-Induced Disease
Journal of Immunology, 2009Co-Authors: Bradley J. Sedgmen, Theo J. Moraes, Laura M. Snell, David J. Topham, Tania H. WattsAbstract:A critical issue during severe respiratory infection is whether it is the virus or the host response that does the most damage. In this study, we show that endogenous 4-1BBL plays a critical role in protecting mice from severe effects of influenza disease. During mild respiratory influenza infection in which virus is rapidly cleared, the inducible costimulatory receptor 4-1BB is only transiently induced on lung T cells and 4-1BB Ligand (4-1BBL) is completely dispensable for the initial CD8 T cell response and mouse survival. In contrast, during more severe respiratory influenza infection with prolonged viral load, 4-1BB expression on lung CD8 T cells is sustained, and 4-1BBL-deficient mice show decreased CD8 T cell accumulation in the lungs, decreased viral clearance, impaired lung function, and increased mortality. Transfer of an optimal number of naive Ag-specific T cells before infection protects wild-type but not 4-1BBL-deficient mice from an otherwise lethal dose of influenza virus. Transfer of T cells lacking the proapoptotic molecule Bim extends the lifespan of 4-1BBL-deficient mice by one to three days, suggesting that at least part of the role of 4-1BB/4-1BBL is to prolong effector cell survival long enough to clear virus. Intranasal delivery of 4-1BBL by recombinant adenovirus marginally improves survival of 4-1BBL-deficient mice at low dose, but exacerbates disease at high dose. These findings suggest a rationale for the evolutionary accumulation of inducible costimulatory molecules, thereby allowing the immune system to sustain the expression of molecules such as 4-1BB to a level commensurate with severity of infection.
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4-1BB Enhances Proliferation of Beryllium-Specific T Cells in the Lung of Subjects with Chronic Beryllium Disease
Journal of Immunology, 2008Co-Authors: Douglas G. Mack, Tania H. Watts, Allison K. Lanham, Brent E. Palmer, Lisa A. Maier, Andrew P. FontenotAbstract:In contrast to naive T cells, reactivation of memory cells is less dependent on CD28-mediated costimulation. We have shown that circulating beryllium-specific CD4+ T cells from chronic beryllium disease patients remain CD28-dependent, while those present in the lung no longer require CD28 for T cell activation. In the present study, we analyzed whether other costimulatory molecules are essential for beryllium-induced T cell function in the lung. Enhanced proliferation of a beryllium-responsive, HLA-DP2-restricted T cell line was seen after the induction of 4-1BB Ligand expression on the surface of HLA-DP2-expressing fibroblasts. Following beryllium exposure, CD4+ T cells from blood and bronchoalveolar lavage of chronic beryllium disease patients up-regulate 4-1BB expression, and the majority of beryllium-responsive, IFN-γ-producing CD4+ T cells in blood coexpress CD28 and 4-1BB. Conversely, a significant fraction of IFN-γ-producing bronchoalveolar lavage (BAL) T cells express 4-1BB in the absence of CD28. In contrast to blood, inhibition of the 4-1BB Ligand-4-1BB interaction partially blocked beryllium-induced proliferation of BAL CD4+ T cells, and a lack of 4-1BB expression on BAL T cells was associated with increased beryllium-induced cell death. Taken together, these findings suggest an important role of 4-1BB in the costimulation of beryllium-responsive CD4+ T cells in the target organ.
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Costimulation of human CD28- T cells by 4-1BB Ligand
European Journal of Immunology, 2003Co-Authors: Jacob Bukczynski, Tania H. WattsAbstract:The T cell surface protein CD28 provides a critical costimulatory signal for T cell activation. With age, humans accumulate increasing numbers of CD28– T cells, and this loss of CD28 expression is exacerbated certain disease states, such as HIV infection, autoimmune conditions or cancer. It is unclear whether CD28– T cells represent terminally differentiated effector cells or whether they remain sensitive to costimulation by CD28-independent pathways. Here, we demonstrate that 4–1BB Ligand can costimulate human CD28– T cells, resulting in cell division, inflammatory cytokine production, increased perforin levels, enhancement of cytolytic effector function, as well as the up-regulation of the anti-apoptotic protein Bcl-XL. Thus, human CD28– T cells can respond to costimulatory signals and as such become attractive targets for therapeutic intervention, particularly in chronic infectious and inflammatory diseases where large numbers of these cells accumulate.
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Temporal segregation of 4-1BB versus CD28-mediated costimulation: 4-1BB Ligand influences T cell numbers late in the primary response and regulates the size of the T cell memory response following influenza infection.
Journal of Immunology, 2002Co-Authors: Edward M. Bertram, Tania H. WattsAbstract:In this report, we demonstrate that CD28−/− mice are severely impaired in the initial expansion of Db/NP366-374-specific CD8 T cells in response to influenza virus infection, whereas 4-1BB Ligand (4-1BBL)−/− mice show no defect in primary T cell expansion to influenza virus. In contrast, 4-1BBL−/− mice show a decrease in Db/NP366-374-specific T cells late in the primary response. Upon secondary challenge with influenza virus, 4-1BBL−/− mice show a decrease in the number of Db/NP366-374-specific T cells compared to wild-type mice such that the level of the CD8 T cell expansion during the in vivo secondary response is reduced to the level of a primary response, with concomitant reduction of CTL effector function. In contrast, Ab responses, as well as secondary CD4 T cell responses, to influenza are unaffected by 4-1BBL deficiency. Thus, CD28 is critical for initial T cell expansion, whereas 4-1BB/4-1BBL signaling affects T cell numbers much later in the response and is essential for the survival and/or responsiveness of the memory CD8 T cell pool.
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4-1BB Ligand Induces Cell Division, Sustains Survival, and Enhances Effector Function of CD4 and CD8 T Cells with Similar Efficacy
Journal of Immunology, 2001Co-Authors: Jennifer L. Cannons, Mark A. Debenedette, Hideo Yagita, Birinder Ghumman, Ko Okumura, Tania H. WattsAbstract:A costimulatory member of the TNFR family, 4-1BB, is expressed on activated T cells. Although some reports have suggested that 4-1BB is primarily involved in CD8 T cell activation, in this report we demonstrate that both CD4 and CD8 T cells respond to 4-1BB Ligand (4-1BBL) with similar efficacy. CD4 and CD8 TCR transgenic T cells up-regulate 4-1BB, OX40, and CD27 and respond to 4-1BBL-mediated costimulation during a primary response to peptide Ag. 4-1BBL enhanced proliferation, cytokine production, and CTL effector function of TCR transgenic T cells. To compare CD4 vs CD8 responses to 4-1BBL under similar conditions of antigenic stimulation, we performed MLRs with purified CD4 or CD8 responders from CD28+/+ and CD28−/− mice. We found that CD8 T cells produced IL-2 and IFN-γ in a 4-1BBL-dependent manner, whereas under the same conditions the CD4 T cells produced IL-2 and IL-4. 4-1BBL promoted survival of CD4 and CD8 T cells, particularly at late stages of the MLR. CD4 and CD8 T cells both responded to anti-CD3 plus s4-1BBL with a similar cytokine profile as observed in the MLR. CD4 and CD8 T cells exhibited enhanced proliferation and earlier cell division when stimulated with anti-CD3 plus anti-CD28 compared with anti-CD3 plus 4-1BBL, and both subsets responded comparably to anti-CD3 plus 4-1BBL. These data support the idea that CD28 plays a primary role in initial T cell expansion, whereas 4-1BB/4-1BBL sustains both CD4 and CD8 T cell responses, as well as enhances cell division and T cell effector function.
Byoung Se Kwon - One of the best experts on this subject based on the ideXlab platform.
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Crystallization and preliminary X-ray crystallographic study of the extracellular domain of the 4-1BB Ligand, a member of the TNF family.
Acta crystallographica. Section F Structural biology and crystallization communications, 2005Co-Authors: Jung-sue Byun, Byoung Se KwonAbstract:The 4-1BB Ligand, a member of the tumour necrosis factor (TNF) family, is an important co-stimulatory molecule that plays a key role in the clonal expansion and survival of CD8+ T cells. Signalling through binding of the 4-1BB Ligand and 4-1BB has been reported to enhance CD8+ T-cell expansion and protect activated CD8+ T cells from death. The 4-1BB Ligand is an integral protein expressed on activated antigen-presenting cells. The extracellular domain of the 4-1BB Ligand fused with glutathione-S-transferase was expressed in Escherichia coli (Origami) and purified by using affinity and ion-exchange column chromatographic methods. Crystals of the 4-1BB Ligand were obtained at 290 K by the hanging-drop vapour-diffusion method. X-ray diffraction data were collected from these crystals to 2.8 A resolution and the crystals belong to space group C2, with unit-cell parameters a = 114.6, b = 73.8, c = 118.50 A, beta = 115.5 degrees.
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Crystallization and preliminary X-ray crystallographic study of the extracellular domain of the 4-1BB Ligand, a member of the TNF family
Acta Crystallographica Section F-structural Biology and Crystallization Communications, 2005Co-Authors: Jung-sue Byun, Byoung Se KwonAbstract:The 4-1BB Ligand, a member of the tumour necrosis factor (TNF) family, is an important co-stimulatory molecule that plays a key role in the clonal expansion and survival of CD8+ T cells. Signalling through binding of the 4-1BB Ligand and 4-1BB has been reported to enhance CD8+ T-cell expansion and protect activated CD8+ T cells from death. The 4-1BB Ligand is an integral protein expressed on activated antigen-presenting cells. The extracellular domain of the 4-1BB Ligand fused with glutathione-S-transferase was expressed in Escherichia coli (Origami) and purified by using affinity and ion-exchange column chromatographic methods. Crystals of the 4-1BB Ligand were obtained at 290 K by the hanging-drop vapour-diffusion method. X-ray diffraction data were collected from these crystals to 2.8 A resolution and the crystals belong to space group C2, with unit-cell parameters a = 114.6, b = 73.8, c = 118.50 A, β = 115.5°.
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Serum concentrations of soluble 4-1BB and 4-1BB Ligand correlated with the disease severity in rheumatoid arthritis
Experimental & Molecular Medicine, 2004Co-Authors: Hyo Won Jung, Seung Won Choi, Jung Il Choi, Byoung Se KwonAbstract:Rheumatoid arthritis (RA) is a multifactorial autoimmune disease whose etiopathogenesis is not well understood. Although soluble (s) forms of 4-1BB (s4-1BB) and 4-1BB legand (s4-1BBL) have been detected in the sera of RA patients, their significance is not known. We compared the serum levels of s4-1BB and s4-1BBL in RA patients with those in systemic lupus erythematosus (SLE) and Behcet's disease (BD) patients. Serum levels of s4-1BB and s4-1BBL were significantly higher in RA patients compared with healthy controls, SLE or BD patients, and the abundance was correlated with disease severity in patients with RA. The serum levels of s4-1BB in RA patients were inversely corroborated with 4-1BB expression levels on activated T lymphocytes. In addition, there was a correlation between serum levels of s4-1BB and s4-1BBL. The augmented secretion of s4-1BB and s4-1BBL levels into the serum may reflect the clinical symptoms of RA and levels of s4-1BB and s4-1BBL in sera at the time of diagnosis may be indicative of the severity and outcome of RA.
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4-1BB: Still in the Midst of Darkness
Molecules and Cells, 2000Co-Authors: Byungsuk Kwon, Chang Hoon Moon, Sangwook Kang, Byoung Se KwonAbstract:4-1BB is a member of the tumor necrosis factor receptor superfamily. The receptor functions mainly as a costimulatory molecule in T lymphocytes. In addition, several lines of evidence have shown that interactions between 4-1BB and its Ligand are involved in the antigen presentation process and the generation of cytotoxic T cells. Recent studies, however, have demonstrated that 4-1BB plays more diverse roles: Signals through 4-1BB are important for long-term survival of CD8^+ T cells and the induction of helper T cell anergy. Clinically, there is great interest in 4-1BB, because T-cell activation induced by anti-4-1BB monoclonal antibodies is highly efficient in the eradication of established tumor cells in mice. Now, since mice deficient in 4-1BB or the 4-1BB Ligand are available, subtle roles played by 4-1BB may be revealed in the near future.
