bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-10 Mediates Sigma1 Receptor-Dependent Suppression of Antitumor Immunity
Authors: Zhu Li X. , Sharma Sherven , Gardner Brian , Escuadro Brian , Atianzar Kimberly , Tashkin Donald P. , Dubinett Steven M. 
Published: April 2014

Abstract
Sigma receptors are unique endoplasmic reticulum proteins that mediate signaling for a variety of drugs. We determined the effect of sigma1 receptor agonists on immune responses in a syngeneic lung cancer model. Sigma1 receptor agonists, including cocaine, up-regulated splenocyte IL-10 mRNA and protein production in vitro in a sigma receptor-dependent, pertussis toxin-sensitive manner. In vivo, sigma1 receptor agonists promoted tumor growth and induced IL-10 at the tumor site. Increased tumor growth was prevented by administration of specific Abs to IL-10 or by administration of specific sigma1 receptor antagonists. We report that sigma1 receptor ligands, including cocaine, augment tumor growth through an IL-10 dependent mechanism.
Infections That Induce Autoimmune Diabetes in BBDR Rats Modulate CD4+CD25+ T Cell Populations
Authors: Zipris Danny , Hillebrands Jan-Luuk , Welsh Raymond M. , Rozing Jan , Xie Jenny X. , Mordes John P. , Greiner Dale L. , Rossini Aldo A. 
Published: April 2014

AbstractViruses are believed to contribute to the pathogenesis of autoimmune type 1A diabetes in humans. This pathogenic process can be modeled in the BBDR rat, which develops pancreatic insulitis and type 1A-like diabetes after infection with Kilham’s rat virus (RV). The mechanism is unknown, but does not involve infection of the pancreatic islets. We first documented that RV infection of BBDR rats induces diabetes, whereas infection with its close homologue H-1 does not. Both viruses induced similar humoral and cellular immune responses in the host, but only RV also caused a decrease in splenic CD4+CD25+ T cells in both BBDR rats and normal WF rats. Surprisingly, RV infection increased CD4+CD25+ T cells in pancreatic lymph nodes of BBDR but not WF rats. This increase appeared to be due to the accumulation of nonproliferating CD4+CD25+ T cells. The results imply that the reduction in splenic CD4+CD25+ cells observed in RV-infected animals is virus specific, whereas the increase in pancreatic lymph node CD4+CD25+ cells is both virus and rat strain specific. The data suggest that RV but not H-1 infection alters T cell regulation in BBDR rats and permits the expression of autoimmune diabetes. More generally, the results suggest a mechanism that could link an underlying genetic predisposition to environmental perturbation and transform a “regulated predisposition” into autoimmune diabetes, namely, failure to maintain regulatory CD4+CD25+ T cell function.
Role of MHC Class I in Immune Surveillance of Mitochondrial DNA Integrity
Authors: Gu Yiping , Wang Chunjie , Roifman Chaim M. , Cohen Amos 
Published: April 2014

Abstract
Mitochondrial DNA is subject to increased rates of mutations due to its proximity to the source of reactive oxygen species. Here we show that increased MHC class I (MHC I) expression serves to alert the immune system to cells with mitochondrial mutations. MHC I is overexpressed in fibroblasts with mitochondrial dysfunction from patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes and in lymphocytes from purine nucleoside phosphorylase-deficient immune-deficient mice with mitochondrial DNA deletions. Consistent with a role of MHC I in the elimination of cells containing mitochondrial DNA mutations, mice deficient in MHC I accumulate mitochondrial DNA deletions in various tissues. These observations in both mice and humans suggest a role for the immune system in preventing reversion of mitochondrial DNA back into a parasitic state following deleterious mutations affecting mitochondrial oxidative phosphorylation.
Requirement of Species-Specific Interactions for the Activation of Human γδ T Cells by Pamidronate
Authors: Kato Yu , Tanaka Yoshimasa , Tanaka Hidenori , Yamashita Seiji , Minato Nagahiro 
Published: April 2014

Abstract
Human γδ T cells bearing Vγ2Vδ2-TCR recognize various kinds of small nonpeptide Ags, and activation of them by a nitrogen-containing bisphosphonate Ag, pamidronate, requires Ag presentation by cells other than γδ T cells, including many human tumor cells. Present results demonstrated that tumor cell lines of nonhuman origins pulsed with pamidronate failed to activate human γδ T cells without exception, whereas most if not all human tumor cell lines could do so. γδ T cells formed stable conjugates with pamidronate-pulsed human tumor cells and both conjugate formation and γδ T cell activation were inhibited significantly by anti-LFA-1 mAb, suggesting the requirement of LFA-1-mediated interaction with APC for efficient γδ T cell activation. Consistently, ICAM-1low tumor cell lines pulsed with pamidronate induced no or only weak activation of γδ T cells, whereas similarly treated ICAM-1high cell lines could activate them. One of the two ICAM-1low tumor cell lines pulsed with pamidronate induced strong γδ T cell activation after ICAM-1 gene transfer. However, another ICAM-1low human cell line as well as murine tumor cell lines pulsed with pamidronate remained totally defective in γδ T cell activation even after expression of human ICAM-1. These results suggested that activation of human γδ T cells by nonpeptide Ags required species-specific interactions in addition to LFA-1/ICAM-1-mediated cell adhesion with APC.
The Molecular Basis for the Lack of Immunostimulatory Activity of Vertebrate DNA
Authors: Stacey Katryn J. , Young Greg R. , Clark Francis , Sester David P. , Roberts Tara L. , Naik Shalin , Sweet Matthew J. , Hume David A. 
Published: April 2014

Abstract
Macrophages and B cells are activated by unmethylated CpG-containing sequences in bacterial DNA. The lack of activity of self DNA has generally been attributed to CpG suppression and methylation, although the role of methylation is in doubt. The frequency of CpG in the mouse genome is 12.5% of Escherichia coli, with unmethylated CpG occurring at ∼3% the frequency of E. coli. This suppression of CpG alone is insufficient to explain the inactivity of self DNA; vertebrate DNA was inactive at 100 μg/ml, 3000 times the concentration at which E. coli DNA activity was observed. We sought to resolve why self DNA does not activate macrophages. Known active CpG motifs occurred in the mouse genome at 18% of random occurrence, similar to general CpG suppression. To examine the contribution of methylation, genomic DNAs were PCR amplified. Removal of methylation from the mouse genome revealed activity that was 23-fold lower than E. coli DNA, although there is only a 7-fold lower frequency of known active CpG motifs in the mouse genome. This discrepancy may be explained by G-rich sequences such as GGAGGGG, which potently inhibited activation and are found in greater frequency in the mouse than the E. coli genome. In summary, general CpG suppression, CpG methylation, inhibitory motifs, and saturable DNA uptake combined to explain the inactivity of self DNA. The immunostimulatory activity of DNA is determined by the frequency of unmethylated stimulatory sequences within an individual DNA strand and the ratio of stimulatory to inhibitory sequences.
More Is Not Necessarily Better: Prozone-Like Effects in Passive Immunization with IgG
Authors: Taborda Carlos P. , Rivera Johanna , Zaragoza Oscar , Casadevall Arturo 
Published: April 2014

Abstract
Despite a century of study, the relationship between Ag-specific Ig concentration and protection remains poorly understood for the majority of pathogens. In certain conditions, administration of high Ab doses before challenge with an infectious agent can be less effective than smaller Ab doses, a phenomenon which is consistent with a prozone-like effect. In this study, the relationship between IgG1, IgG2a, IgG2b, and IgG3 dose, infective inocula, and protection was investigated in a mouse model of Cryptococcus neoformans infection. The activity of each IgG subclass ranged from protective to disease-enhancing depending on both the Ab dose and infective inocula used. Enhanced dissemination to the brain was observed in mice given a high IgG2a dose and a relatively low inoculum. Ab administration had immunomodulatory effects, with cytokine expression in lung, brain, and spleen varying as a function of the infective inoculum Ab dose and IgG subclass. In vitro studies did not predict or explain the mechanism of in vivo prozone-like effects, because all isotypes were opsonic and elicited NO release from macrophages. IgG2a was most efficient in inducing a macrophage oxidative burst. These results reveal that an individual Ab can be protective, nonprotective, or disease-enhancing depending on its concentration relative to a challenge inoculum. Our findings have implications for the potential contribution of Ab responses to defense against microbial diseases because Ab-mediated immunity may be protective, nonprotective, or even deleterious to the host.
Galectin-9 Induces Apoptosis Through the Calcium-Calpain-Caspase-1 Pathway
Authors: Kashio Yumiko , Nakamura Kazuhiro , Abedin Mohammad J. , Seki Masako , Nishi Nozomu , Yoshida Naoko , Nakamura Takanori , Hirashima Mitsuomi 
Published: April 2014

AbstractGalectin-9 (Gal-9) induced the apoptosis of not only T cell lines but also of other types of cell lines in a dose- and time-dependent manner. The apoptosis was suppressed by lactose, but not by sucrose, indicating that β-galactoside binding is essential for Gal-9-induced apoptosis. Moreover, Gal-9 required at least 60 min of Gal-9 binding and possibly de novo protein synthesis to mediate the apoptosis. We also assessed the apoptosis of peripheral blood T cells by Gal-9. Apoptosis was induced in both activated CD4+ and CD8+ T cells, but the former were more susceptible than the latter. A pan-caspase inhibitor (Z-VAD-FMK) inhibited Gal-9-induced apoptosis. Furthermore, a caspase-1 inhibitor (Z-YVAD-FMK), but not others such as Z-IETD-FMK (caspase-8 inhibitor), Z-LEHD-FMK (caspase-9 inhibitor), and Z-AEVD-FMK (caspase-10 inhibitor), inhibited Gal-9-induced apoptosis. We also found that a calpain inhibitor (Z-LLY-FMK) suppresses Gal-9-induced apoptosis, that Gal-9 induces calcium (Ca2+) influx, and that either the intracellular Ca2+ chelator BAPTA-AM or an inositol trisphosphate inhibitor 2-aminoethoxydiphenyl borate inhibits Gal-9-induced apoptosis. These results suggest that Gal-9 induces apoptosis via the Ca2+-calpain-caspase-1 pathway, and that Gal-9 plays a role in immunomodulation of T cell-mediated immune responses.
B7-H1 (Programmed Death-1 Ligand) on Dendritic Cells Is Involved in the Induction and Maintenance of T Cell Anergy
Authors: Selenko-Gebauer Nicole , Majdic Otto , Szekeres Andreas , Höfler Gerald , Guthann Elisabeth , Korthäuer Ulf , Zlabinger Gerhard , Steinberger Peter , Pickl Winfried F. , Stockinger Hannes , Knapp Walter , Stöckl Johannes 
Published: April 2014

Abstract
In an effort to identify immunoregulatory molecules on dendritic cells (DC), we generated and screened for mAbs capable of modulating the T cell stimulatory function of DC. A particularly interesting mAb was mAb DF272. It recognizes monocyte-derived DC, but not blood monocytes or lymphocytes, and has profound immunomodulatory effects on DC. Treatment of DC with intact IgG or Fab of mAb DF272 enhanced their T cell stimulatory capacity. This effect on DC was accompanied by neither an up-regulation of costimulatory molecules such as B7.1 (CD80), B7.2 (CD86), and MHC class II molecules nor by an induction of cytokine production, including IL-1, TNF-α, IL-10, and IL-12. Moreover, the well-established inhibitory function of IL-10-treated DC could be reverted with mAb DF272. Even T cells, anergized because of stimulation with IL-10-treated DC, could be reactivated and induced to proliferate upon stimulation with mAb DF272-treated DC. Furthermore, mAb DF272-treated DC favored the induction of a type-1 cytokine response in T cells and inhibited IL-10 production. By using a retrovirus-based cDNA expression library generated from DC, we cloned and sequenced the mAb DF272-defined cell surface receptor and could demonstrate that it is identical with B7-H1 (programmed death-1 ligand), a recently identified new member of the B7 family of costimulatory molecules. Our results thus demonstrate that the mAb DF272-defined surface molecule B7-H1 represents a unique receptor structure on DC that might play a role in the induction and maintenance of T cell anergy.
TGFβ1 Inhibits Ca2+-Calcineurin-Mediated Activation in Thymocytes
Authors: Bommireddy Ramireddy , Ormsby Ilona , Yin Moying , Boivin Gregory P. , Babcock George F. , Doetschman Thomas 
Published: April 2014

AbstractTGFβ1 is a polypeptide growth modulatory and differentiation factor involved in many biological processes including immune homeostasis and self-tolerance. Tgfb1 knockout mice die around weaning age due to severe inflammation in most major organ systems, but the mechanism underlying this disease is not understood. In this study we demonstrate that Tgfb1−/− CD4+CD8+ and CD4+CD8− thymocytes are hyperresponsive to receptor-mediated and receptor-independent mitogenic stimulation. A suboptimal concentration of ionomycin in the presence of PMA fully activates Tgfb1−/− thymocytes, whereas the inhibitors of Ca2+ influx and calcineurin, EGTA and FK506, eliminate the hyperresponsiveness. Hence, the hypersensitivity of Tgfb1−/− thymocytes is due to a lowered threshold for Ca2+-dependent activation. Further, we demonstrate that the hypersensitivity of thymocytes results from the absence of TGFβ1 and not from the inflammatory environment because the thymocytes are hyperresponsive in preinflammatory-stage Tgfb1−/− mice. Our results suggest for the first time that TGFβ1 functions to inhibit aberrant T cell expansion by maintaining intracellular calcium concentration levels low enough to prevent a mitogenic response by Ca2+-independent stimulatory pathways alone. Consequently, TGFβ1 prevents autoimmune disease through a Ca2+ regulatory pathway that maintains the activation threshold above that inducible by self-MHC-TCR interactions.
SS-A/Ro52, an Autoantigen Involved in CD28-Mediated IL-2 Production
Authors: Ishii Tomonori , Ohnuma Kei , Murakami Akikazu , Takasawa Naruhiko , Yamochi Tadanori , Iwata Satoshi , Uchiyama Masahiko , Dang Nam H. , Tanaka Hirotoshi , Morimoto Chikao 
Published: April 2014

Abstract
An autoantibody against SS-A/Ro52 (Ro52) is most frequently found in the sera of patients with Sjögren’s syndrome, systemic lupus erythematosus, and congenital heart block from anti-Ro52 Ab-positive mother. However, the physiological function of the autoantigen SS-A/Ro52 has not yet been elucidated. In this study, we describe the role of Ro52 protein in T cell activation. Overexpression of SS-A/Ro52 in Jurkat T cell resulted in enhanced IL-2 production following CD28 stimulation. Furthermore, transfection of anti-Ro52-specific small RNA duplexes partially blocked the expression of native and overexpressed Ro52 in Jurkat T cell, resulting in decreased IL-2 production via CD28 pathway in these cells. Finally, intracellular localization of Ro52 dramatically changed following CD28 stimulation. Our data reveal a novel function of Ro52 in CD28-mediated pathway, which eventually contributes to cytokine production and expression of the T cell biological programs.
Sphingosine-1-Phosphate Receptor Agonism Impairs the Efficiency of the Local Immune Response by Altering Trafficking of Naive and Antigen-Activated CD4+ T Cells
Authors: Xie Jenny H. , Nomura Naomi , Koprak Sam L. , Quackenbush Elizabeth J. , Forrest Michael J. , Rosen Hugh 
Published: April 2014

Abstract
FTY720 (2-amino-[2-(4-octylphenyl) ethyl]-1,3-propanediol hydrochloride) is an immunosuppressive agent that inhibits allograft rejection. We recently demonstrated that FTY-phosphate, the active metabolite of FTY720, acts as a full agonist for sphingosine-1-phosphate (S1P) receptors. Furthermore, activation of S1P receptors with their natural ligand, S1P, as well as pharmacological ligands leads to lymphopenia, probably due to sequestration of lymphocytes in secondary lymphoid organs. In the present study we used a local Ag-challenged mouse model to examine the effects of FTY720 on T cell activation in the draining lymph node (DLN) and on the release of activated T cells to the peripheral blood compartment. We showed that the number of Ag-activated CD4+ T cells in the DLN after injection of Ag and CFA into a footpad was dramatically reduced after FTY720 treatment. However, T cell proliferation, both in vitro and in vivo, was not impaired by FTY720. Our results suggest that the reduced efficiency of T cell responses in the DLN in response to a local Ag is probably due to a defective recirculation of naive T cells caused by FTY720 treatment. Furthermore, we found that the numbers of naive and Ag-activated CD4+ T cells in the peripheral blood of Ag-challenged mice were equally reduced with FTY720 treatment, suggesting that both T cell subsets are sequestered in the DLNs. Thus, FTY720 induces immunosuppression through inhibition of both the recirculation of naive T cells and the release of Ag-activated T cells from the DLN to lymph and to the blood compartment.
B Cell Complement Receptor 2 Transfer Reaction
Authors: Lindorfer Margaret A. , Jinivizian Hasmig B. , Foley Patricia L. , Kennedy Adam D. , Solga Michael D. , Taylor Ronald P. 
Published: April 2014

Abstract
The B cell C receptor specific for C3dg (CR2) shares a number of features with the primate E C receptor (CR1). Previously, we have demonstrated, both in vitro and in animal models, that immune complexes (IC) bound to primate E CR1, either via C opsonization or by means of bispecific mAb complexes, can be transferred to acceptor macrophages in a process that also removes CR1 from the E. We have now extended this paradigm, the transfer reaction, to include B cell CR2. We used both flow cytometry and fluorescence microscopy to demonstrate that IC bound to Raji cell CR2, either via C opsonization or through the use of an anti-CR2 mAb, are transferred to acceptor THP-1 cells. This reaction, which appears to require Fc recognition of IgG bound to Raji cell CR2, also leads to transfer of CR2. Additional support for the B cell transfer reaction is provided in a prototype study in a monkey model in which IC bound to B cell CR2 are localized to the spleen. These findings may have important implications with respect to defining the role of C in IC handling during the normal immune response.
The Possible Role of TGF-β-Induced Suppressors of Cytokine Signaling Expression in Osteoclast/Macrophage Lineage Commitment In Vitro
Authors: Fox Simon W. , Haque S. Jaharul , Lovibond Alison C. , Chambers Timothy J. 
Published: April 2014

Abstract
Osteoclast formation is dependent on the ability of TGF-β to enable receptor activator of NF-κB ligand (RANKL)-induced commitment of hemopoietic precursors to the osteoclastic lineage. The mechanism by which TGF-β enables formation is unknown. One possibility is that TGF-β opposes Janus kinase (JAK)/STAT signals generated by inhibitory cytokines such as IFN-β. The JAK/STAT pathway is activated by cytokines that induce resistance to osteoclast formation, such as IFN-γ and M-CSF, and the effect of these is opposed by TGF-β. Recently, a group of STAT-induced factors, termed suppressors of cytokine signaling (SOCS), has been identified that inhibit JAK/STAT signals. Therefore, we tested the ability of TGF-β to induce SOCS expression in osteoclast precursors and examined the effect of SOCS expression on osteoclast/macrophage lineage commitment. We found that while SOCS mRNA is undetectable in macrophages, osteoclasts express SOCS-3, and TGF-β up-regulates this expression. Furthermore, TGF-β rapidly induces sustained SOCS-3 expression in macrophage/osteoclast precursors. To determine whether SOCS-3 plays a role in osteoclast differentiation we expressed SOCS-3 in precursors using a retroviral system. We found that osteoclast differentiation was significantly enhanced in SOCS-3-infected precursors, and SOCS-3 expression enables formation in the presence of anti-TGF-β Ab. On the other hand, antisense knockdown of SOCS-3 strongly suppressed osteoclast formation and significantly blunted the response to TGF-β. Moreover, like TGF-β, SOCS-3 expression opposed the inhibitory effect of IFN-β. These data suggest that TGF-β-induced expression of SOCS-3 may represent a mechanism by which TGF-β suppresses inhibitory cytokine signaling, priming precursors for a role in bone resorption.
Lipopolysaccharide Promotes the Survival of Osteoclasts Via Toll-Like Receptor 4, but Cytokine Production of Osteoclasts in Response to Lipopolysaccharide Is Different from That of Macrophages
Authors: Itoh Kanami , Udagawa Nobuyuki , Kobayashi Kanichiro , Suda Koji , Li Xiaotong , Takami Masamichi , Okahashi Nobuo , Nishihara Tatsuji , Takahashi Naoyuki 
Published: April 2014

Abstract
Lipopolysaccharide is a pathogen that causes inflammatory bone loss. Monocytes and macrophages produce proinflammatory cytokines such as IL-1, TNF-α, and IL-6 in response to LPS. We examined the effects of LPS on the function of osteoclasts formed in vitro in comparison with its effect on bone marrow macrophages, osteoclast precursors. Both osteoclasts and bone marrow macrophages expressed mRNA of Toll-like receptor 4 (TLR4) and CD14, components of the LPS receptor system. LPS induced rapid degradation of I-κB in osteoclasts, and stimulated the survival of osteoclasts. LPS failed to support the survival of osteoclasts derived from C3H/HeJ mice, which possess a missense mutation in the TLR4 gene. The LPS-promoted survival of osteoclasts was not mediated by any of the cytokines known to prolong the survival of osteoclasts, such as IL-1β, TNF-α, and receptor activator of NF-κB ligand. LPS stimulated the production of proinflammatory cytokines such as IL-1β, TNF-α, and IL-6 in bone marrow macrophages and peritoneal macrophages, but not in osteoclasts. These results indicate that osteoclasts respond to LPS through TLR4, but the characteristics of osteoclasts are quite different from those of their precursors, macrophages, in terms of proinflammatory cytokine production in response to LPS.
Conservation of Nonpeptide Antigen Recognition by Rhesus Monkey Vγ2Vδ2 T Cells
Authors: Wang Hong , Lee Hoi K. , Bukowski Jack F. , Li Hongmin , Mariuzza Roy A. , Chen Zheng W. , Nam Ki-Hoan , Morita Craig T. 
Published: April 2014

Abstract
We have previously found that monkey Vγ2Vδ2+ T cells mount adaptive immune responses in response to Mycobacterium bovis bacillus Calmette-Guérin infections. We have now analyzed rhesus monkey γδ T cell responses to nonpeptide Ags and superantigens. Like human Vγ2Vδ2+ T cells, rhesus monkey γδ T cells are stimulated when exposed to prenyl pyrophosphate, bisphosphonate, and alkylamine Ags. Responsiveness was limited to γδ T cells expressing Vγ2Vδ2 TCRs. Rhesus monkey Vγ2Vδ2+ T cells also responded to the superantigen, staphyloccocal enterotoxin A. Sequencing of the rhesus monkey Vγ2Vδ2 TCR revealed a strong sequence homology to human Vγ2Vδ2 TCR that preserves important sequence motifs. Moreover, chimeric TCRs that pair human Vγ2 with monkey Vδ2 and monkey Vγ2 with human Vδ2 retain reactivity to nonpeptide Ags and B cell lymphomas. A molecular model of the rhesus monkey Vγ2Vδ2 TCR has a basic region in the complementarity-determining region 3 binding groove that is similar to that seen in the human Vγ2Vδ2 TCR and preserves the topology of the complementarity-determining region loops. Thus, recognition of nonpeptide prenyl pyrophosphate, bisphosphonate, and alkylamine Ags is conserved in primates suggesting that primates can provide an animal model for human γδ T cell Ag responses.