bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Viral System for Generating Antigen-Specific T Cells
Authors: Moran Timothy P. , Collier Martha , McKinnon Karen P. , Davis Nancy L. , Johnston Robert E. , Serody Jonathan S. 
Published: April 2014

Abstract
Dendritic cell (DC)-based vaccines are increasingly used for the treatment of patients with malignancies. Although these vaccines are typically safe, consistent and lasting generation of tumor-specific immunity has been rarely demonstrated. Improved methods for delivering tumor Ags to DCs and approaches for overcoming tolerance or immune suppression to self-Ags are critical for improving immunotherapy. Viral vectors may address both of these issues, as they can be used to deliver intact tumor Ags to DCs, and have been shown to inhibit the suppression mediated by CD4+CD25+ regulatory T cells. We have evaluated the potential use of Venezuelan equine encephalitis virus replicon particles (VRPs) for in vitro Ag delivery to human monocyte-derived DCs. VRPs efficiently transduced immature human DCs in vitro, with ∼50% of immature DCs expressing a vector-driven Ag at 12 h postinfection. VRP infection of immature DCs was superior to TNF-α treatment at inducing phenotypic maturation of DCs, and was comparable to LPS stimulation. Additionally, VRP-infected DC cultures secreted substantial amounts of the proinflammatory cytokines IL-6, TNF-α, and IFN-α. Finally, DCs transduced with a VRP encoding the influenza matrix protein (FMP) stimulated 50% greater expansion of FMP-specific CD8+ CTL when compared with TNF-α-matured DCs pulsed with an HLA-A*0201-restricted FMP peptide. Thus, VRPs can be used to deliver Ags to DCs resulting in potent stimulation of Ag-specific CTL. These findings provide the rationale for future studies evaluating the efficacy of VRP-transduced DCs for tumor immunotherapy.
Cutting Edge: Roles of Caspase-8 and Caspase-10 in Innate Immune Responses to Double-Stranded RNA
Authors: Takahashi Ken , Kawai Taro , Kumar Himanshu , Sato Shintaro , Yonehara Shin , Akira Shizuo 
Published: April 2014

Abstract
Upon viral infection, host cells trigger antiviral immune responses by inducing type I IFN and inflammatory cytokines. dsRNA generated during viral replication is recognized by the cytoplasmic RNA helicases retinoic acid-inducible gene I and melanoma differentiation-associated gene 5, which interact with an adaptor, IFN-β promoter stimulator-1, to activate the transcription factors NF-κB and IFN regulatory factor 3. In this article we demonstrate that caspase-8 and caspase-10 are involved in these pathways. Both caspases were cleaved during dsRNA stimulation, and overexpression of a cleaved form of these caspases activated NF-κB. Knockdown of caspase-10 or caspase-8 in a human cell line resulted in the reduction of inflammatory cytokine production. Cells derived from caspase-8-deficient mice also showed reduced expression of inflammatory cytokines as well as NF-κB activation. Furthermore, the Fas-associated death domain protein interacted with these two caspases and IFN-β promoter stimulator 1. These results indicate that caspase-8 and caspase-10 are essential components that mediate NF-κB-dependent inflammatory responses in antiviral signaling.
Immune Complex-Loaded Dendritic Cells Are Superior to Soluble Immune Complexes as Antitumor Vaccine
Authors: Schuurhuis Danita H. , van Montfoort Nadine , Ioan-Facsinay Andreea , Jiawan Reshma , Camps Marcel , Nouta Jan , Melief Cornelis J. M. , Verbeek J. Sjef , Ossendorp Ferry 
Published: April 2014

AbstractDendritic cells (DCs) play an important role in the induction of T cell responses. FcγRs, expressed on DCs, facilitate the uptake of complexed Ag, resulting in efficient MHC class I and MHC class II Ag presentation and DC maturation. In the present study, we show that prophylactic immunization with DCs loaded with Ag-IgG immune complexes (ICs) leads to efficient induction of tumor protection in mice. Therapeutic vaccinations strongly delay tumor growth or even prevent tumors from growing out. By depleting CD4+ and CD8+ cell populations before tumor challenge, we identify CD8+ cells as the main effector cells involved in tumor eradication. Importantly, we show that DCs that are preloaded in vitro with ICs are at least 1000-fold more potent than ICs injected directly into mice or DCs loaded with the same amount of noncomplexed protein. The contribution of individual FcγRs to Ag presentation, T cell response induction, and induction of tumor protection was assessed. We show that FcγRI and FcγRIII are capable of enhancing MHC class I-restricted Ag presentation to CD8+ T cells in vitro and that these activating FcγRs on DCs are required for efficient priming of Ag-specific CD8+ cells in vivo and induction of tumor protection. These findings show that targeting ICs via the activating FcγRs to DCs in vitro is superior to direct IC vaccination to induce protective tumor immunity in vivo.
Oral Nickel Tolerance: Fas Ligand-Expressing Invariant NK T Cells Promote Tolerance Induction by Eliciting Apoptotic Death of Antigen-Carrying, Effete B Cells
Authors: Nowak Michael , Kopp Frank , Roelofs-Haarhuis Karin , Wu Xianzhu , Gleichmann Ernst 
Published: April 2014

AbstractWhereas oral nickel administration to C57BL/6 mice (Nihigh mice) renders the animals tolerant to immunization with NiCl2 combined with H2O2 as adjuvant, as determined by ear-swelling assay, it fails to tolerize Jα18−/− mice, which lack invariant NKT (iNKT) cells. Our previous work also showed that Nihigh splenic B cells can adoptively transfer the nickel tolerance to untreated (Nilow) recipients, but not to Jα18−/− recipients. In this study, we report that oral nickel administration increased the nickel content of splenic Nihigh B cells and up-regulated their Fas expression while down-regulating expression of bcl-2 and Bcl-xL, thus giving rise to an Ag-carrying, apoptosis-prone B cell phenotype. Although oral nickel up-regulated Fas expression on B cells of both wild-type Nihigh and Jα18−/− Nihigh mice, only the former showed a reduced number of total B cells in spleen when compared with untreated, syngeneic mice, indicating that iNKT cells are involved in B cell homeostasis by eliciting apoptosis of effete B cells. Upon transfer of Nihigh B cells, an infectious spread of nickel tolerance ensues, provided the recipients are immunized with NiCl2/H2O2. As a consequence of immunization, Fas ligand-positive (FasL+) iNKT cells appeared in the spleen and apparently elicited apoptosis of Nihigh B cells. The apoptotic Nihigh B cells were taken up by splenic dendritic cells, which thereby became tolerogenic for nickel-reactive Nilow T cells. In conclusion, FasL+ iNKT cells may act as ready-to-kill sentinels of innate immunity, but at the same time assist in tolerance induction by eliciting Fas/FasL-mediated apoptosis of effete, Ag-containing B cells.
Targeted Disruption of CD38 Accelerates Autoimmune Diabetes in NOD/Lt Mice by Enhancing Autoimmunity in an ADP-Ribosyltransferase 2-Dependent Fashion
Authors: Chen Jing , Chen Yi-Guang , Reifsnyder Peter C. , Schott William H. , Lee Chul-Ho , Osborne Melissa , Scheuplein Felix , Haag Friedrich , Koch-Nolte Friedrich , Serreze David V. , Leiter Edward H. 
Published: April 2014

AbstractUbiquitously expressed CD38 and T cell-expressed ADP-ribosyltransferase 2 (ART2) are ectoenzymes competing for NAD substrate. CD38 exerts pleiotropic actions in hemopoietic and nonhemopoietic compartments via effects on calcium mobilization. ART2 is an ADP-ribosyltransferase on naive CD4+ and CD8+ T cells. ART2-catalyzed ADP-ribosylation of the P2X7 purinoreceptor elicits apoptosis. Transfer of a genetically disrupted CD38 allele into the autoimmune diabetes-prone NOD/Lt background accelerated diabetes onset in both sexes, whereas transfer of a disrupted ART2 complex had no effect. However, the fact that the accelerated pathogenesis mediated by CD38 deficiency required ART2 activity was demonstrated by combining both ART2 and CD38 deficiencies. Reciprocal bone marrow reconstitution studies demonstrated accelerated diabetes only when CD38-deficient bone marrow was transferred into CD38-deficient recipients. Neither decreases in β cell function nor viability were indicated. Rather, the balance between T-effectors and T-regulatory cells was disturbed in CD38-deficient but ART2-intact NOD mice. In these mice, significant reductions in total viable CD8+ T cells were observed. This was accompanied by an age-dependent increase in a diabetogenic CD8 clonotype. This in turn correlated with impaired T-regulatory development (10-fold reduction in Foxp3 mRNA expression). These changes were corrected when CD38 deficiency was combined with ART2 deficiency. Both ART2-deficient and CD38/ART2 combined deficient T cells were resistant to NAD-induced killing in vitro, whereas CD38-deficient but ART2-intact T cells showed increased sensitivity, particularly the CD4+CD25+ subset. Unexpectedly, diabetes development in the combined CD38/ART2 stock was strongly suppressed, possibly through epistatic interactions between genes linked to the targeted CD38 on Chromosome 5 and the ART2 complex on Chromosome 7.
Phospholipase Cγ2 Dosage Is Critical for B Cell Development in the Absence of Adaptor Protein BLNK
Authors: Xu Shengli , Huo Jianxin , Chew Weng-Keong , Hikida Masaki , Kurosaki Tomohiro , Lam Kong-Peng 
Published: April 2014

Abstract
B cell linker (BLNK) protein and phospholipase Cγ2 (PLCγ2) are components of the BCR signalosome that activate calcium signaling in B cells. Mice lacking either molecule have a severe but incomplete block in B lymphopoiesis. In this study, we generated BLNK−/−PLCγ2−/− mice to examine the effect of simultaneous disruption of both molecules on B cell development. We showed that BLNK−/−PLCγ2−/− mice had compounded defects in B cell maturation compared with either single mutant, suggesting that these two molecules cooperatively or synergistically signaled B lymphopoiesis. However, Ig H chain allelic exclusion was maintained in single and double mutants, indicating that signals propagated by BLNK and PLCγ2 were not involved in this process. Interestingly, in the absence of BLNK, B cell development was dependent on plcγ2 gene dosage. This was evidenced by the proportionate decrease in splenic B cell population and increase in bone marrow surface pre-BCR+ cells in PLCγ2-diploid, -haploid, and -null animals. Intracellular calcium signaling and ERK activation in response to BCR engagement were also proportionately decreased and delayed, respectively, with stepwise reduction of plcγ2 dosage in a BLNKnull background. Thus, these data indicate the importance of BLNK not only as a conduit to specifically channel BCR-signaling pathways and as a scaffold for the assembling of macromolecular complex, but also as an efficient aggregator or concentrator of PLCγ2 molecules to effect optimal signaling for B cell generation and activation.
Adaptive Islet-Specific Regulatory CD4 T Cells Control Autoimmune Diabetes and Mediate the Disappearance of Pathogenic Th1 Cells In Vivo
Authors: Weber Sarah E. , Harbertson Judith , Godebu Elana , Mros Guthrie A. , Padrick Ryan C. , Carson Bryan D. , Ziegler Steven F. , Bradley Linda M. 
Published: April 2014

Abstract
Adaptive regulatory T cells that develop from naive CD4 cells in response to exposure to Ag can act as immunotherapeutic agents to control immune responses. We show that effectors generated from murine islet-specific CD4 cells by TCR stimulation with IL-2 and TGF-β1 have potent suppressive activity. They prevent spontaneous development of type 1 diabetes in NOD mice and inhibit development of pancreatic infiltrates and disease onset orchestrated by Th1 effectors. These regulatory T cells do not require innate CD25+ regulatory cells for generation or function, nor do they share some characteristics typically associated with them, including expression of CD25. However, the adaptive population does acquire the X-linked forkhead/winged helix transcription factor, FoxP3, which is associated with regulatory T cell function and maintains expression in vivo. One mechanism by which they may inhibit Th1 cells is via FasL-dependent cytotoxicity, which occurs in vitro. In vivo, they eliminate Th1 cells in lymphoid tissues, where Fas/FasL interactions potentially play a role because Th1 cells persist when this pathway is blocked. The results suggest that adaptive regulatory CD4 cells may control diabetes in part by impairing the survival of islet-specific Th1 cells, and thereby inhibiting the localization and response of autoaggressive T cells in the pancreatic islets.
Early Growth Response Gene 1 Provides Negative Feedback to Inhibit Entry of Progenitor Cells into the Thymus
Authors: Schnell Frederick J. , Zoller Allison L. , Patel Seema R. , Williams Ifor R. , Kersh Gilbert J. 
Published: April 2014

Abstract
The size of the thymus can be greatly influenced by changes in the small number of early progenitors in the thymus. However, it is not known whether thymic cellularity feeds back to regulate the recruitment, survival, and expansion of progenitors. The transcription factor early growth response gene 1 (Egr1) has been implicated in controlling proliferation and survival in many cell types. We have previously shown that mice deficient in Egr1 have increased thymic cellularity. We now show that Egr1 regulates a negative feedback signal that controls the entry of cells into the thymus. Egr1-deficient mice have higher percentages of early T lineage progenitors in the thymus, yet Egr1-deficient mice have normal numbers of myelolymphoid progenitors in the bone marrow, and Egr1-deficient thymocytes show normal rates of apoptosis and proliferation at all stages of development. Evidence from mixed bone marrow chimeras shows that the ability of Egr1 to control progenitor recruitment is mediated by bone marrow-derived cells, but is not cell autonomous. Furthermore, Egr1-deficient thymuses have increased P-selectin expression. The data suggest that Egr1 mediates a feedback mechanism whereby the number of resident double negative thymocytes controls the entry of new progenitors into the thymus by regulating P-selectin expression on thymic endothelial cells.
Control of Autoimmune Myocarditis and Multiorgan Inflammation by Glucocorticoid-Induced TNF Receptor Family-Related Proteinhigh, Foxp3-Expressing CD25+ and CD25− Regulatory T Cells
Authors: Ono Masahiro , Shimizu Jun , Miyachi Yoshiki , Sakaguchi Shimon 
Published: April 2014

AbstractAnomalies of naturally occurring CD4+ regulatory T cells (Treg) cause severe autoimmune/inflammatory diseases in humans and rodents. The transcription factor Foxp3 is currently the most specific marker for natural CD4+ Treg, but it would be useful if other Treg markers, particularly cell surface molecules, could be elucidated. We demonstrate in this study that the vast majority of Foxp3-expressing CD4+ T cells (whether CD25+ or CD25−) show constitutive high-level expression of glucocorticoid-induced TNFR family-related gene/protein (GITR). Transfer of T cell or thymocyte suspensions depleted of GITRhigh cells produces in BALB/c nude mice a wider spectrum and more severe forms of autoimmune diseases than does transfer of similar cell suspensions depleted of CD25+CD4+ T cells only. Notably, mice that receive cells depleted of GITRhigh populations develop severe multiorgan inflammation that includes fatal autoimmune myocarditis resembling giant cell myocarditis in humans, accompanying high-titer anti-myosin autoantibodies. Similar transfer of GITRhigh-depleted cells from prediabetic NOD mice to NOD-SCID mice accelerates the development of diabetes and induces skeletal muscle myositis and other autoimmune/inflammatory diseases. We conclude that GITRhigh, Foxp3-expressing natural Treg, containing both CD25+ and CD25− cell populations, contribute to preventing a variety of autoimmune/inflammatory diseases, and depletion of these cells allows the activation of even weak or rare autoreactive T cells yielding widespread severe autoimmune disease. Diseases induced in this way include many which have been suspected of an autoimmune etiology in humans without much evidence. GITRhigh, Foxp3-expressing natural Treg represent a potential target for the treatment and prevention of these diseases.
STAT5-Mediated Signals Sustain a TCR-Initiated Gene Expression Program toward Differentiation of CD8 T Cell Effectors
Authors: Verdeil Grégory , Puthier Denis , Nguyen Catherine , Schmitt-Verhulst Anne-Marie , Auphan-Anezin Nathalie 
Published: April 2014

AbstractPoorly functional effector CD8 T cells are generated in some pathological situations, including responses to weakly antigenic tumors. To identify the molecular bases for such defective differentiation, we monitored gene expression in naive monoclonal CD8 T cells during responses to TCR ligands of different affinity. We further evaluated whether responses to weak Ags may be improved by addition of cytokines. Transient gene expression was observed for a cluster of genes in response to the weak TCR agonist. Strikingly, gene expression was stabilized by low dose IL-2. This IL-2-sustained gene cluster encoded notably transcripts for CD25, cytolytic effector molecules (granzyme B) and TNF-R family costimulatory molecules (glucocorticoid-induced TNF-R (GITR), OX40, and 4-1BB). IL-2-enhanced surface expression or function was also demonstrated in vivo for these genes. A constitutive active form of STAT5 mimicked the IL-2 effect by sustaining transcripts for the same gene cluster. Consistent with this, under conditions of low avidity TCR engagement and IL-2 treatment, endogenous STAT5 binding to 4-1BB and granzyme B promoters was demonstrated by chromatin immunoprecipitation. This study highlights those genes for which IL-2, via STAT5 activation, acts as a stabilizer of gene regulation initiated by TCR signals, contributing to the development of a complete CD8 T cell effector program.
Cloning and Characterization of Mannose-Binding Lectin from Lamprey (Agnathans)
Authors: Takahashi Momoe , Iwaki Daisuke , Matsushita Akiko , Nakata Munehiro , Matsushita Misao , Endo Yuichi , Fujita Teizo 
Published: April 2014

AbstractThe recognition of pathogens is mediated by a set of pattern recognition molecules that recognize conserved pathogen-associated molecular patterns shared by broad classes of microorganisms. Mannose-binding lectin (MBL) is one of the pattern recognition molecules and activates complement in association with MBL-associated serine protease (MASP) via the lectin pathway. Recently, an MBL-like lectin was isolated from the plasma of a urochordate, the solitary ascidian. This ascidian lectin has a carbohydrate recognition domain, but the collagen-like domain was replaced by another sequence. To elucidate the origin of MBLs, the aim of this study is to determine the structure and function of the MBL homolog in lamprey, the most primitive vertebrate. Using an N-acetylglucosamine (GlcNAc)-agarose column, MBL-like lectin (p25) was isolated from lamprey serum and cDNA cloning was conducted. From the deduced amino acid sequence this lectin has a collagenous region and a typical carbohydrate recognition domain. This lectin also binds mannose, glucose, and GlcNAc, but not galactose, indicating that it is structurally and functionally similar to the mammalian MBLs. Furthermore, it associated with lamprey MASPs, and the MBL-MASP activated lamprey C3 in fluid-phase and on the surface of pathogens. In conjunction with the phylogenetic analysis, it seems likely that the lamprey MBL is an ortholog of the mammalian MBL. Because acquired immunity seems to have been established only from jawed vertebrates onward, the lectin complement pathway in lamprey, as one of the major contributors to innate immunity, plays a pivotal role in defending the body against microorganisms.
Effect of d-Alanylation of (Lipo)Teichoic Acids of Staphylococcus aureus on Host Secretory Phospholipase A2 Action before and after Phagocytosis by Human Neutrophils
Authors: Hunt Catherine L. , Nauseef William M. , Weiss Jerrold P. 
Published: April 2014

Abstract
Invading bacteria such as Staphylococcus aureus induce mobilization of professional phagocytes (e.g., neutrophils) and extracellular antibacterial proteins (e.g., group IIA phospholipase A2 (gIIA PLA2)). Accumulation of gIIA PLA2 in inflammatory fluids confers potent extracellular antistaphylococcal activity and at lower concentrations promotes bacterial phospholipid degradation during phagocytosis of S. aureus by human neutrophils. d-alanylation of (lipo) teichoic acids of S. aureus increases bacterial resistance to gIIA PLA2 ∼100-fold, raising the possibility that the resistance of ingested S. aureus to related gV and gX secretory PLA2 present in human neutrophil granules depends on d-alanylation mediated by the dlt operon. However, we show that isogenic wild-type and dltA S. aureus are equally resistant to gV/X PLA2 during phagocytosis and when exposed to the purified enzymes. The fates of wild-type and dltA S. aureus exposed to serum and human neutrophils differed significantly only when extracellular gIIA PLA2 was also present before phagocytosis. The extreme potency of the gIIA PLA2 toward dltA S. aureus suggests that even small amounts of this extracellular enzyme mobilized early in inflammation could contribute substantially to the overall cytotoxicity of acute inflammatory exudates toward S. aureus when d-alanylation of (lipo)teichoic acids is limiting.
Contrasting Roles for Domain 4 of VCAM-1 in the Regulation of Cell Adhesion and Soluble VCAM-1 Binding to Integrin α4β1
Authors: Woodside Darren G. , Kram Ronda M. , Mitchell Jason S. , Belsom Tracie , Billard Matthew J. , McIntyre Bradley W. , Vanderslice Peter 
Published: April 2014

AbstractCell adhesion mediated by the interaction between integrin α4β1 and VCAM-1 is important in normal physiologic processes and in inflammatory and autoimmune disease. Numerous studies have mapped the α4β1 binding sites in VCAM-1 that mediate cell adhesion; however, little is known about the regions in VCAM-1 important for regulating soluble binding. In the present study, we demonstrate that 6D VCAM-1 (an alternatively spliced isoform of VCAM-1 lacking Ig-like domain 4) binds α4β1 with a higher relative affinity than does the full-length form of VCAM-1 containing 7 Ig-like extracellular domains (7D VCAM-1). In indirect binding assays, the EC50 of soluble 6D VCAM-1 binding to α4β1 on Jurkat cells (in 1 mM MnCl2) was 2 × 10−9 M, compared with 7D VCAM-1 at 11 × 10−9 M. When used in solution to inhibit α4β1 mediated cell adhesion, the IC50 of 6D VCAM-1 was 13 × 10−9 M, compared with 7D VCAM-1 measured at 150 × 10−9 M. Removal of Ig-like domains 4, 5, or 6, or simply substituting Asp328 in domain 4 of 7D VCAM-1 with alanine, caused increased binding of soluble 7D VCAM-1 to α4β1. In contrast, cells adhered more avidly to 7D VCAM-1 under shear force, as it induced cell spreading at lower concentrations than did 6D VCAM-1. Finally, soluble 6D VCAM-1 acts as an agonist through α4β1 by augmenting cell migration and inducing cell aggregation. These results indicate that the domain 4 of VCAM-1 plays a contrasting role when VCAM-1 is presented in solution or as a cell surface-expressed adhesive substrate.