bluuebunny/crossref_metadata_2025_split huggingface dataset:
Telomerase mRNA-Transfected Dendritic Cells Stimulate Antigen-Specific CD8+ and CD4+ T Cell Responses in Patients with Metastatic Prostate Cancer
Authors: Su Zhen , Dannull Jens , Yang Benjamin K. , Dahm Philipp , Coleman Doris , Yancey Donna , Sichi Sylvia , Niedzwiecki Donna , Boczkowski David , Gilboa Eli , Vieweg Johannes 
Published: April 2014

AbstractTelomerase reverse transcriptase (hTERT) represents an attractive target for cancer immunotherapy because hTERT is reactivated in most human tumors. A clinical trial was initiated in which hTERT mRNA-transfected dendritic cells (DC) were administered to 20 patients with metastatic prostate cancer. Nine of these subjects received DC transfected with mRNA encoding a chimeric lysosome-associated membrane protein-1 (LAMP) hTERT protein, allowing for concomitant induction of hTERT-specific CD8+ and CD4+ T cell responses. Treatment was well tolerated. Intense infiltrates of hTERT-specific T cells were noted at intradermal injection sites after repeated vaccination. In 19 of 20 subjects, expansion of hTERT-specific CD8+ T cells was measured in the peripheral blood of study subjects, with 0.9–1.8% of CD8+ T cells exhibiting Ag specificity. Patients immunized with the chimeric LAMP hTERT vaccine developed significantly higher frequencies of hTERT-specific CD4+ T cells than subjects receiving DC transfected with the unmodified hTERT template. Moreover, CTL-mediated killing of hTERT targets was enhanced in the LAMP hTERT group, suggesting that an improved CD4+ response could augment a CTL response. Vaccination was further associated with a reduction of prostate-specific Ag velocity and molecular clearance of circulating micrometastases. Our findings provide a rationale for further development of hTERT-transfected DC vaccines in the treatment of prostate and other cancers.
An Integral Role for Heme Oxygenase-1 and Carbon Monoxide in Maintaining Peripheral Tolerance by CD4+CD25+ Regulatory T Cells
Authors: Brusko Todd M. , Wasserfall Clive H. , Agarwal Anupam , Kapturczak Matthias H. , Atkinson Mark A. 
Published: April 2014

Abstract
Over the past decade, a great deal of interest and attention has been directed toward a population of regulatory T cells (Treg) coexpressing the markers CD4 and CD25. The hallmark phenotype of this cell population resides in its ability to dominantly maintain peripheral tolerance and avert autoimmunity. Despite robust research interest in Treg, their mechanism of action and interaction with other cell populations providing immune regulation remains unclear. In this study, we present a model for Treg activity that implicates carbon monoxide, a by-product of heme oxygenase-1 activity, as an important and underappreciated facet in the suppressive capacity of Treg. Our hypothesis is based on recent evidence supporting a role for heme oxygenase-1 in regulating immune reactivity and posit carbon monoxide to function as a suppressive molecule. Potential roles for indoleamine 2,3-dioxygenase, costimulatory molecules, and cytokines in tolerance induction are also presented. This model, if validated, could act as a catalyst for new investigations into Treg function and ultimately result in novel methods to modulate Treg biology toward therapeutic applications.
Cutting Edge: In Vivo Blockade of Human IL-2 Receptor Induces Expansion of CD56bright Regulatory NK Cells in Patients with Active Uveitis
Authors: Li Zhuqing , Lim Wee Kiak , Mahesh Sankaranarayana P. , Liu Baoying , Nussenblatt Robert B. 
Published: April 2014

Abstract
In vivo blockade of the human IL-2R by mAb has been used for immunosuppression in transplantation, therapy for leukemia, and autoimmune diseases. In this study, we report that administration of a humanized IL-2R blocking Ab induced a 4- to 20-fold expansion of CD56bright regulatory NK cells in uveitis patients over time. The induced CD56bright regulatory NK cells from patients exhibited similar phenotype as those naturally occurring CD56bright cells. Patients with active uveitis had a significantly lower level of CD56bright NK cells compared with normal donors (p &lt; 0.01). In addition, the induced CD56bright cells could secrete large amounts of IL-10 whereas CD56dim NK cells could not, suggesting that the induction of the CD56bright cells may have a beneficial effect on the remission of active uveitis. Our observation may have implications to IL-2R blockade therapy and for the potential role of CD56bright regulatory NK cells in autoimmune diseases.
Inhibitors of TLR-9 Act on Multiple Cell Subsets in Mouse and Man In Vitro and Prevent Death In Vivo from Systemic Inflammation
Authors: Duramad Omar , Fearon Karen L. , Chang Bonnie , Chan Jean H. , Gregorio Josh , Coffman Robert L. , Barrat Franck J. 
Published: April 2014

Abstract
In parallel with the discovery of the immunostimulatory activities of CpG-containing oligodeoxynucleotides, several groups have reported specific DNA sequences that could inhibit activation by CpG-containing oligodeoxynucleotides in mouse models. We show that these inhibitory sequences, termed IRS, inhibit TLR-9-mediated activation in human as well as mouse cells. This inhibitory activity includes proliferation and IL-6 production by B cells, and IFN-α and IL-12 production by plasmacytoid dendritic cells. Our studies of multiple cell types in both mice and humans show the optimal IRS to contain a GGGG motif within the sequence, and the activity to require a phosphorothioate backbone. Although the GGGG motif readily itself leads to formation of a tetrameric oligodeoxynucleotide structure, inhibitory activity resides exclusively in the single-stranded form. When coinjected with a CpG oligodeoxynucleotide in vivo, IRS were shown to inhibit inflammation through a reduction in serum cytokine responses. IRS do not need to be injected at the same site to inhibit, demonstrating that rapid, systemic inhibition of TLR-9 can be readily achieved. IRS can also inhibit a complex pathological response to ISS, as shown by protection from death after massive systemic inflammation induced by a CpG-containing oligodeoxynucleotides.
An Essential Role for Phospholipase D in the Activation of Protein Kinase C and Degranulation in Mast Cells
Authors: Peng Ze , Beaven Michael A. 
Published: April 2014

Abstract
Activation of phospholipase D (PLD) and protein kinase C (PKC) as well as calcium mobilization are essential signals for degranulation of mast cells. However, the exact role of PLD in degranulation remains undefined. In this study we have tested the hypothesis that the PLD product, phosphatidic acid, and diacylglycerides generated therefrom might promote activation of PKC. Studies were conducted in two rodent mast cell lines that were stimulated with Ag via FcεRI and a pharmacologic agent, thapsigargin. Diversion of production of phosphatidic acid to phosphatidylbutanol (the transphosphatidylation reaction) by addition of l-butanol suppressed both the translocation of diacylglyceride-dependent isoforms of PKC to the membrane and degranulation. Tertiary-butanol, which is not a substrate for the transphosphatidylation, had a minimal effect on PKC translocation and degranulation, and 1-butanol itself had no effect on PKC translocation when PKC was stimulated directly with phorbol ester, 12-O-tetradecanoylphorbol-13-acetate. Also, in cells transfected with small inhibitory RNAs directed against PLD1 and PLD2, activation of PLD, generation of diacylglycerides, translocation of PKC, and degranulation were all suppressed. Phorbol ester, which did not stimulate degranulation by itself, restored degranulation when used in combination with thapsigargin whether PLD function was disrupted with 1-butanol or the small inhibitory RNAs. However, degranulation was not restored when cells were costimulated with Ag and phorbol ester. These results suggested that the production of phosphatidic acid by PLD facilitates activation of PKC and, in turn, degranulation, although additional PLD-dependent processes appear to be critical for Ag-mediated degranulation.
Histamine H4 Receptor Stimulation Suppresses IL-12p70 Production and Mediates Chemotaxis in Human Monocyte-Derived Dendritic Cells
Authors: Gutzmer Ralf , Diestel Carola , Mommert Susanne , Köther Brigitta , Stark Holger , Wittmann Miriam , Werfel Thomas 
Published: April 2014

Abstract
There is increasing evidence that histamine as an important mediator of immediate type allergic reactions also effects professional APCs. Recent reports showed effects of histamine on human monocyte-derived dendritic cells (MoDC) mediated primarily via histamine H1 receptors (H1R) and H2R. We show here that MoDC also express H3R and H4R at the mRNA and protein level. mRNA of the H3R is down-regulated and mRNA of the H4R is up-regulated during the differentiation from monocytes to MoDC. H4R or H2R stimulation suppressed IL-12p70 production in MoDC. Induction of cAMP was necessary for IL-12p70 inhibition mediated via the H2R. In contrast, H4R stimulation did not affect cAMP production but induced the transcription factor AP-1, and U0126, an inhibitor of AP-1 transactivation and MEK, rescued H4R mediated IL-12p70 suppression. Moreover, MoDC responded to a H4R agonist (and also to a H2R agonist) with increased F-actin polymerization and migration in modified Boyden chamber assays, suggesting a chemotactic effect of histamine via the H2R and the H4R. Thus, H4R stimulation on MoDC results in immunomodulatory and chemotactic effects. Histamine induces chemotaxis and IL-12p70 suppression via different receptors using different signaling pathways, which might be important for the pathogenesis of and therapeutic interventions in allergic diseases.
B Lymphocytes Participate in Cross-Presentation of Antigen following Gene Gun Vaccination
Authors: Hon Huiming , Oran Alp , Brocker Thomas , Jacob Joshy 
Published: April 2014

Abstract
Although endocytosed proteins are commonly presented via the class II MHC pathway to stimulate CD4+ T cells, professional APCs can also cross-present Ags, whereby these exogenous peptides can be complexed with class I MHC for cross-priming of CD8+ T cells. Whereas the ability of dendritic cells (DCs) to cross-present Ags is well documented, it is not known whether other APCs may also play a role, or what is the relative contribution of cross-priming to the induction of acquired immunity after DNA immunization. In this study, we compared immune responses generated after gene gun vaccination of mice with DNA vaccine plasmids driven by the conventional CMV promoter, the DC-specific CD11c promoter, or the keratinocyte-specific K14 promoter. The CD11c promoter achieved equivalent expression in CD11c+ DCs in draining lymph nodes over time, as did a conventional CMV-driven plasmid. However, immunization with DC-restricted DNA vaccines failed to generate protective humoral or cellular immunity to model Ags influenza hemagglutinin and OVA, despite the ability of CD11c+ cells isolated from lymph nodes to stimulate proliferation of Ag-specific T cells directly ex vivo. In contrast, keratinocyte-restricted vaccines elicited comparable T and B cell activity as conventional CMV promoter-driven vaccines, indicating that cross-priming plays a major role in the generation of immune responses after gene gun immunization. Furthermore, parallel studies in B cell-deficient μ-MT mice demonstrated that B lymphocytes, in addition to DCs, mediate cross-priming of Ag-specific T cells. Collectively, these data indicate that broad expression of the immunogen is required for optimal induction of protective acquired immunity.
Granulysin, a Cytolytic Molecule, Is Also a Chemoattractant and Proinflammatory Activator
Authors: Deng Anmei , Chen Sunxiao , Li Qing , Lyu Shu-chen , Clayberger Carol , Krensky Alan M. 
Published: April 2014

Abstract
Granulysin, a cationic protein produced by activated human CTL and NK cells, is cytolytic against microbial and tumor targets. In this study we show that granulysin also functions as a chemoattractant and activates monocytes to produce cytokines/chemokines. Although granulysin-mediated cytotoxicity occurs at micromolar concentrations, chemoattraction occurs in the nanomolar range, and immune activation occurs over a wide range of concentrations (nanomolar to micromolar). Granulysin causes a 2- to 7-fold increase in chemotaxis of monocytes, CD4+, and CD8+ memory (CD45RO) but not naive (CD45RA) T cells, NK cells, and mature, but not immature, monocyte-derived dendritic cells. Pertussis toxin treatment abrogates chemoattraction by granulysin, indicating involvement of G-protein-coupled receptor(s). At low concentrations (10 nM), granulysin promotes a 3- to 10-fold increase in MCP-1 and RANTES produced by monocytes and U937 cells, while a 2-fold increase in TNF-α production by LPS-stimulated monocytes requires higher concentrations of granulysin (micromolar). Taken together, these data indicate that the local concentration of granulysin is critical for the biologic activity, with high concentrations resulting in cytotoxicity while lower concentrations, presumably further from the site of granulysin release, actively recruit immune cells to sites of inflammation.
HIV-1 Trans-Activator of Transcription Substitutes for Oxidative Signaling in Activation-Induced T Cell Death
Authors: Gülow Karsten , Kamiński Marcin , Darvas Katalin , Süss Dorothee , Li-Weber Min , Krammer Peter H. 
Published: April 2014

Abstract
Termination of an immune response requires elimination of activated T lymphocytes by activation-induced cell death (AICD). In AICD, CD95 (Apo-1/Fas) ligand (L) triggers apoptosis of CD95-positive activated T lymphocytes. In AIDS patients, AICD is strongly enhanced and accelerated. We and others have previously shown that HIV-1 trans-activator of transcription (HIV-1 Tat) sensitizes T cells toward CD95-mediated apoptosis and up-regulates CD95L expression by affecting the cellular redox balance. In this study, we show that it is hydrogen peroxide (H2O2) that functions as an essential second messenger in TCR signaling. The H2O2 signal combined with simultaneous calcium (Ca2+) influx into the cytosol constitutes the minimal requirement for induction of CD95L expression. Either signal alone is insufficient. We further show that HIV-1 Tat interferes with TCR signaling and induces a H2O2 signal. H2O2 generated by HIV-1 Tat combines with CD4-dependent calcium influx and causes massive T cell apoptosis. Thus, our data provide an explanation for CD4+ T lymphocyte depletion during progression of AIDS.
IL-2 Increases Human Telomerase Reverse Transcriptase Activity Transcriptionally and Posttranslationally through Phosphatidylinositol 3′-Kinase/Akt, Heat Shock Protein 90, and Mammalian Target of Rapamycin in Transformed NK Cells
Authors: Kawauchi Kiyotaka , Ihjima Kimiko , Yamada Osamu 
Published: April 2014

Abstract
Human telomerase activity is induced by Ag receptor ligation in T and B cells. However, it is unknown whether telomerase activity is increased in association with activation and proliferation of NK cells. We found that telomerase activity in a human NK cell line (NK-92), which requires IL-2 for proliferation, was increased within 24 h after stimulation with IL-2. Levels of human telomerase reverse transcriptase (hTERT) mRNA and protein correlated with telomerase activity. ERK1/2 and Akt kinase (Akt) were activated by IL-2 stimulation. LY294002, an inhibitor of PI3K, abolished expression of hTERT mRNA and protein expression and abolished hTERT activity, whereas PD98059, which inhibits MEK1/2 and thus ERK1/2, had no effect. In addition, radicicol, an inhibitor of heat shock protein 90 (Hsp90), and rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), blocked IL-2-induced hTERT activity and nuclear translocation of hTERT but not hTERT mRNA expression. hTERT was coimmunoprecipitated with Akt, Hsp90, mTOR, and p70 S6 kinase (S6K), suggesting that these molecules form a physical complex. Immunoprecipitates of Akt, Hsp90, mTOR, and S6K from IL-2-stimulated NK-92 cells contained telomerase activity. Furthermore, the findings that Hsp90 and mTOR immunoprecipitates from primary samples contained telomerase activity are consistent with the results from NK-92 cells. These results indicate that IL-2 stimulation induces hTERT activation and that the mechanism of IL-2-induced hTERT activation involves transcriptional or posttranslational regulation through the pathway including PI3K/Akt, Hsp90, mTOR, and S6K in NK cells.
FcγRIIB Regulates Nasal and Oral Tolerance: A Role for Dendritic Cells
Authors: Samsom Janneke N. , van Berkel Lisette A. , van Helvoort Joop M. L. M. , Unger Wendy W. J. , Jansen Wendy , Thepen Theo , Mebius Reina E. , Verbeek Sjef S. , Kraal Georg 
Published: April 2014

Abstract
Mucosal tolerance prevents the body from eliciting productive immune responses against harmless Ags that enter the body via the mucosae, and is mediated by the induction of regulatory T cells that differentiate in the mucosa-draining lymph nodes (LN) under defined conditions of Ag presentation. In this study, we show that mice deficient in FcγRIIB failed to develop mucosal tolerance to OVA, and demonstrate in vitro and in vivo a critical role for this receptor in modulating the Ag-presenting capacity of dendritic cells (DC). In vitro it was shown that absence of FcγRIIB under tolerogenic conditions led to increased IgG-induced release of inflammatory cytokines such as MCP-1, TNF-α, and IL-6 by bone marrow-derived DC, and increased their expression of costimulatory molecules, resulting in an altered immunogenic T cell response associated with increased IL-2 and IFN-γ secretion. In vivo we could show enhanced LN-DC activation and increased numbers of Ag-specific IFN-γ-producing T cells when FcγRIIB−/− mice were treated with OVA via the nasal mucosa, inferring that DC modulation by FcγRIIB directed the phenotype of the T cell response. Adoptive transfer of CD4+ T cells from the spleen of FcγRIIB−/− mice to naive acceptor mice demonstrated that OVA-responding T cells failed to differentiate into regulatory T cells, explaining the lack of tolerance in these mice. Our findings demonstrate that signaling via FcγRIIB on DC, initiated by local IgG in the mucosa-draining LN, down-regulates DC activation induced by nasally applied Ag, resulting in those defined conditions of Ag presentation that lead to Tr induction and tolerance.
A Novel E3 Ubiquitin Ligase TRAC-1 Positively Regulates T Cell Activation
Authors: Zhao Haoran , Li Connie C. , Pardo Jorge , Chu Peter C. , Liao Charlene X. , Huang Jianing , Dong John G. , Zhou Xiulan , Huang Qi , Huang Betty , Bennett Mark K. , Molineaux Susan M. , Lu Henry , Daniel-Issakani Sarkiz , Payan Donald G. , Masuda Esteban S. 
Published: April 2014

Abstract
TRAC-1 (T cell RING (really interesting new gene) protein identified in activation screen) is a novel E3 ubiquitin ligase identified from a retroviral vector-based T cell surface activation marker screen. The C-terminal truncated TRAC-1 specifically inhibited anti-TCR-mediated CD69 up-regulation in Jurkat cells, a human T leukemic cell line. In this study, we show that TRAC-1 is a RING finger ubiquitin E3 ligase with highest expression in lymphoid tissues. Point mutations that disrupt the Zn2+-chelating ability of its amino-terminal RING finger domain abolished TRAC-1’s ligase activity and the dominant inhibitory effect of C-terminal truncated TRAC-1 on TCR stimulation. The results of in vitro biochemical studies indicate that TRAC-1 can stimulate the formation of both K48- and K63-linked polyubiquitin chains and therefore could potentially activate both degradative and regulatory ubiquitin-dependent pathways. Antisense oligonucleotides to TRAC-1 specifically reduced TRAC-1 mRNA levels in Jurkat and primary T cells and inhibited their activation in response to TCR cross-linking. Collectively, these results indicate that the E3 ubiquitin ligase TRAC-1 functions as a positive regulator of T cell activation.
A Major Role for Memory CD4 T Cells in the Control of Lymphopenia-Induced Proliferation of Naive CD4 T Cells
Authors: Bourgeois Christine , Kassiotis George , Stockinger Brigitta 
Published: April 2014

Abstract
In a state of lymphopenia, naive and memory CD4 T cells compete with each other for expansion at the expense of naive T cells. This competition prevents the proliferation as well as the phenotypic and functional conversion of naive T cells to “memory-like” T cells and may consequently prevent immune pathology frequently associated with lymphopenia-induced proliferation of naive cells. However, in T cell replete mice, memory T cells do not compete with naive T cells, indicating independent homeostatic control of naive and memory CD4 T cells in conditions that do not involve profound lymphopenia. Moreover, within the memory compartment, subsequent generation of new memory T cells precludes the survival of memory-like T cells. Thus, memory T cells have a major role in the control of lymphopenia-induced proliferation of naive cells because they inhibit both the generation of memory-like T cells and their persistence within the memory compartment.
Overexpression of IFN-Induced Protein 10 and Its Receptor CXCR3 in Myasthenia Gravis
Authors: Feferman Tali , Maiti Prasanta K. , Berrih-Aknin Sonia , Bismuth Jacky , Bidault Jocelyne , Fuchs Sara , Souroujon Miriam C. 
Published: April 2014

Abstract
Myasthenia gravis (MG) and its animal model, experimental autoimmune MG (EAMG), are autoimmune disorders in which the acetylcholine receptor (AChR) is the major autoantigen. Microarray technology was used to identify new potential drug targets for treatment of myasthenia that would reduce the need for the currently used nonspecific immunosuppression. The chemokine IFN-γ-inducible protein 10 (IP-10; CXCL10), a CXC chemokine, and its receptor, CXCR3, were found to be overexpressed in lymph node cells of EAMG rats. Quantitative real-time PCR confirmed these findings and revealed up-regulated mRNA levels of another chemoattractant that activates CXCR3, monokine induced by IFN-γ (Mig; CXCL9). TNF-α and IL-1β, which act synergistically with IFN-γ to induce IP-10, were also up-regulated. These up-regulations were observed in immune response effector cells, namely, lymph node cells, and in the target organ of the autoimmune attack, the muscle of myasthenic rats, and were significantly reduced after suppression of EAMG by mucosal tolerance induction with an AChR fragment. The relevance of IP-10/CXCR3 signaling in myasthenia was validated by similar observations in MG patients. A significant increase in IP-10 and CXCR3 mRNA levels in both thymus and muscle was observed in myasthenic patients compared with age-matched controls. CXCR3 expression in PBMC of MG patients was markedly increased in CD4+, but not in CD8+, T cells or in CD19+ B cells. Our results demonstrate a positive association of IP-10/CXCR3 signaling with the pathogenesis of EAMG in rats as well as in human MG patients.