bluuebunny/crossref_metadata_2025_split huggingface dataset:
Semimature Stage: A Checkpoint in a Dendritic Cell Maturation Program That Allows for Functional Reversion after Signal-Regulatory Protein-α Ligation and Maturation Signals
Authors: Braun Deborah , Galibert Laurent , Nakajima Toshiharu , Saito Hirohisa , Quang Van Vu , Rubio Manuel , Sarfati Marika 
Published: April 2014

Abstract
CD47 on live cells actively engages signal-regulatory protein-α (SIRP-α) on phagocytes and delivers a negative signal that prevents their elimination. We evaluated the biological consequences of SIRP-α ligation on the dendritic cell (DC) response to maturation signals and the potential interplay with the IL-10/IL-10R inhibitory pathway. At first, CD47/SIRP-α allowed the generation of mature migratory DCs not producing IL-12, IFN-γ-inducible protein-10, and CCL19. Rather, they secreted neutrophils attracting chemokine CXCL5 and IL-1β, reflecting a partial block in functional DC maturation. Afterward, semimature DCs functionally regressed in an IL-10-independent fashion toward cells that retrieved the cardinal features of immature DCs: re-expression of CCR5, loss of DC-lysosome-associated membrane protein, high endocytosis, and impaired allostimulatory functions. The global gene expression profile of IL-10 and SIRP-α-ligated DC demonstrated two distinct molecular pathways. IL-10R and SIRP-α expression were reciprocally down-regulated by CD47 and IL-10, respectively. These results emphasize that the SIRP-α pathway might be part of the molecular machinery used by the DC to dampen or resolve an inflammatory response in an IL-10-independent manner.
Molecular Basis of TCR Selectivity, Cross-Reactivity, and Allelic Discrimination by a Bacterial Superantigen: Integrative Functional and Energetic Mapping of the SpeC-Vβ2.1 Molecular Interface
Authors: Rahman A. K. M. Nur-ur , Herfst Christine A. , Moza Beenu , Shames Stephanie R. , Chau Luan A. , Bueno Clara , Madrenas Joaquín , Sundberg Eric J. , McCormick John K. 
Published: April 2014

Abstract
Superantigens activate large fractions of T cells through unconventional interactions with both TCR β-chain V domains (Vβs) and MHC class II molecules. The bacterial superantigen streptococcal pyrogenic exotoxin C (SpeC) primarily stimulates human Vβ2+ T cells. Herein, we have analyzed the SpeC-Vβ2.1 interaction by mutating all SpeC residues that make contact with Vβ2.1 and have determined the energetic and functional consequences of these mutations. Our comprehensive approach, including mutagenesis, functional readouts from both bulk T cell populations, and an engineered Vβ2.1+ Jurkat T cell, as well as surface plasmon resonance binding analysis, has defined the SpeC “functional epitope” for TCR engagement. Although only two SpeC residues (Tyr15 and Arg181) are critical for activation of virtually all human CD3+ T cells, a larger cluster of four hot spot residues are required for interaction with Vβ2.1. Three of these residues (Tyr15, Phe75, and Arg181) concentrate their binding energy on the CDR2 loop residue Ser52a, a noncanonical residue insertion found only in Vβ2 and Vβ4 chains. Plasticity of this loop is important for recognition by SpeC. Although SpeC interacts with the Vβ2.1 hypervariable CDR3 loop, our data indicate these contacts have little to no influence on the functional interaction with Vβ2.1. These studies also provide a molecular basis for selectivity and cross-reactivity of SpeC-TCR recognition and reveal a degree of fine specificity in these interactions, whereby certain SpeC mutants are capable of distinguishing between different alleles of the same Vβ domain subfamily.
NAK-Associated Protein 1 Participates in Both the TLR3 and the Cytoplasmic Pathways in Type I IFN Induction
Authors: Sasai Miwa , Shingai Masashi , Funami Kenji , Yoneyama Mitsutoshi , Fujita Takashi , Matsumoto Misako , Seya Tsukasa 
Published: April 2014

Abstract
TLR3 and the cytoplasmic helicase family proteins (retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5)) serve as dsRNA pattern-recognition receptors. In response to poly(I:C), a representative of dsRNA, and viral infection, they have been shown to activate the transcription factor IFN regulatory factor (IRF)-3, which in turn induces activation of the IFN-β promoter. RIG-I/MDA5 recognizes dsRNA in the cytoplasm, whereas TLR3 resides in the cell surface membrane or endosomes to engage in extracytoplasmic recognition of dsRNA. Recent reports suggest that TLR3 induces cellular responses in epithelial cells in response to respiratory syncytial virus (RSV). The modus for TLR3 activation by RSV, however, remains unresolved. By small interference RNA gene-silencing technology and human cell transfectants, we have revealed that knockdown of NAK-associated protein 1 (NAP1) leads to the down-regulation of IFN-β promoter activation &gt;24 h after poly(I:C) or virus (RSV and vesicular stomatitis virus) treatment. NAP1 is located downstream of the adapter Toll-IL-1R homology domain-containing adapter molecule (TICAM)-1 (Toll/IL-1R domain-containing adapter-inducing IFN-β) in the TLR3 pathway, but TICAM-1 and TLR3 did not participate in the IRF-3 and IFN-β promoter activation by RSV infection. Virus-mediated activation of the IFN-β promoter was largely abrogated by the gene silencing of IFN-β promoter stimulator-1 (mitochondria antiviral signaling (MAVS), VISA, Cardif), the adapter of the RIG-I/MDA5 dsRNA-recognition proteins. In both the TLR and virus-mediated IFN-inducing pathways, IκB kinase-related kinase ε and TANK-binding kinase 1 participated in IFN-β induction. Thus, RSV as well as other viruses induces replication-mediated activation of the IFN-β promoter, which is intracellularly initiated by the RIG-I/MDA5 but not the TLR3 pathway. Both the cytoplasmic and TLR3-mediated dsRNA recognition pathways converge upon NAP1 for the activation of the IRF-3 and IFN-β promoter.
High Mobility Group B1 Protein Suppresses the Human Plasmacytoid Dendritic Cell Response to TLR9 Agonists
Authors: Popovic Petar J. , DeMarco Richard , Lotze Michael T. , Winikoff Steven E. , Bartlett David L. , Krieg Arthur M. , Guo Z. Sheng , Brown Charles K. , Tracey Kevin J. , Zeh Herbert J. 
Published: April 2014

Abstract
Plasmacytoid dendritic cells (PDC) are innate immune effector cells that are recruited to sites of chronic inflammation, where they modify the quality and nature of the adaptive immune response. PDCs modulate adaptive immunity in response to signals delivered within the local inflammatory milieu by pathogen- or damage-associated molecular pattern, molecules, and activated immune cells (including NK, T, and myeloid dendritic cells). High mobility group B1 (HMGB1) is a recently identified damage-associated molecular pattern that is released during necrotic cell death and also secreted from activated macrophages, NK cells, and mature myeloid dendritic cells. We have investigated the effect of HMGB1 on the function of PDCs. In this study, we demonstrate that HMGB1 suppresses PDC cytokine secretion and maturation in response to TLR9 agonists including the hypomethylated oligodeoxynucleotide CpG- and DNA-containing viruses. HMGB1-inhibited secretion of several proinflammatory cytokines including IFN-α, IL-6, TNF-α, inducible protein-10, and IL-12. In addition, HMGB1 prevented the CpG induced up-regulation of costimulatory molecules on the surface of PDC and potently suppressed their ability to drive generation of IFN-γ-secreting T cells. Our observations suggest that HMGB1 may play a critical role in regulating the immune response during chronic inflammation and tissue damage through modulation of PDC function.
Thiocyanate-Dependent Induction of Endothelial Cell Adhesion Molecule Expression by Phagocyte Peroxidases: A Novel HOSCN-Specific Oxidant Mechanism to Amplify Inflammation
Authors: Wang Jian-Guo , Mahmud Shawn A. , Nguyen Julia , Slungaard Arne 
Published: April 2014

Abstract
Both eosinophil peroxidase (EPO) and neutrophil myeloperoxidase (MPO) preferentially oxidize SCN− to generate HOSCN, a weak, sulfhydryl-reactive oxidant, as a major physiologic product. We here show that HOSCN is a uniquely potent phagocyte oxidant inducer of E-selectin, ICAM-1, and VCAM-1 expression in HUVEC as detected by Western blot and flow cytometry. EMSA and inhibitor studies show that HOSCN up-regulation of these adhesion molecules is transcriptionally mediated through a mechanism that is dependent upon activation of the NF-κB p65/p50 transcription factor and constitutively suppressed by PI3K-Akt pathway activity. HUVEC monolayers exposed to HOSCN bind 8-fold more neutrophils and 3- to 4-fold more Aml14.3D10 cells (a differentiated cell line model of mature eosinophils) than control monolayers. Blocking Ab studies confirm the involvement of E-selectin and ICAM-1 but not VCAM-1 in neutrophil adhesion and of all three in Aml14.3D10 adhesion. Intraperitoneal injection of HOSCN evoked an 8-fold increase in neutrophil peritoneal extravasation. In addition to NF-κB, HOSCN also activates the potentially proinflammatory transcription factors Stat4, CDP, GRE, CBF, Ets-1/PEA3, and TFIID, a pattern easily distinguishable from that induced by LPS. These results suggest that phagocyte peroxidases function to amplify inflammation through a novel, HOSCN-specific oxidant mechanism.
Induction of Vascular Leakage and Blood Pressure Lowering through Kinin Release by a Serine Proteinase from Aeromonas sobria
Authors: Imamura Takahisa , Kobayashi Hidemoto , Khan Rasel , Nitta Hidetoshi , Okamoto Keinosuke 
Published: April 2014

Abstract
Aeromonas sobria causes septic shock, a condition associated with high mortality. To study the mechanism of septic shock by A. sobria infection, we examined the vascular leakage (VL) activity of A. sobria serine proteinase (ASP), a serine proteinase secreted by this pathogen. Proteolytically active ASP induced VL mainly in a bradykinin (BK) B2 receptor-, and partially in a histamine-H1 receptor-dependent manner in guinea pig skin. The ASP VL activity peaked at 10 min to 1.8-fold of the initial activity with an increased BK B2 receptor dependency, and attenuated almost completely within 30 min. ASP produced VL activity from human plasma apparently through kallikrein/kinin system activation, suggesting that ASP can generate kinin in humans. Consistent with the finding that a major part of the ASP-induced VL was reduced by a potent kallikrein inhibitor, soybean trypsin inhibitor that does not affect ASP enzymatic activity, ASP activated prekallikrein but not factor XII to generate kallikrein in a dose- and incubation time-dependent manner. ASP produced more VL activity directly from human low m.w. kininogen than high m.w. kininogen when both were used at their normal plasma concentrations. Intra-arterial injection of ASP into guinea pigs lowered blood pressure specifically via the BK B2 receptor. These data suggest that ASP induces VL through prekallikrein activation and direct kinin release from kininogens, which is a previously undescribed mechanism of A. sobria virulence and could be associated with the induction of septic shock by infection with this bacterium. ASP-specific inhibitors, and kinin receptor antagonists, might prove useful for the treatment or prevention of this fatal disease.
Oncostatin M-Induced IL-6 Expression in Murine Fibroblasts Requires the Activation of Protein Kinase Cδ
Authors: Smyth David C. , Kerr Christine , Richards Carl D. 
Published: April 2014

Abstract
Oncostatin M (OSM) is an IL-6/LIF cytokine family member whose role has been identified in a range of biological activities in vitro, including up-regulation of inflammatory gene expression and regulation of connective tissue metabolism. However, the mechanisms through which OSM regulates cellular responses are not completely understood. In this study, we show that activation of the calcium-independent or novel protein kinase C (PKC) isoform PKCδ is a critical event during OSM-mediated up-regulation of IL-6 expression in murine fibroblasts. The pan-PKC inhibitor GF109203X (bisindolylmaleimide I) reduced secretion of IL-6; however, use of Go6976, an inhibitor of calcium-dependent PKC enzymes, did not. The PKCδ-selective inhibitory compound rottlerin abrogated expression of IL-6 transcript and protein, but only reduced PKCδ activity when used at higher concentrations as determined by kinase activity assay, suggesting rottlerin may inhibit IL-6 expression in a PKCδ-independent manner. However, silencing of PKCδ protein expression, but not the related novel isoform PKCε, by use of RNA interference (i.e., small interfering RNA) demonstrated that PKCδ is required for murine OSM (mOSM) induction of IL-6 protein secretion. Furthermore, inhibition of PI3K by use of LY294002 reduces expression of IL-6 at both the mRNA and protein level in murine fibroblasts, and we suggest that PI3K is required for activation of PKCδ. Knockdown of phosphoinositide-dependent kinases PDK-1 or Akt1 using small interfering RNA strategies did not influence mOSM-induced IL-6 expression, suggesting mOSM uses a PI3K–PKCδ pathway of activation independent of these kinases. Our findings illustrate a novel signaling network used by mOSM that may be important for its mediation of inflammatory processes.
Cyclooxygenase Regulates Cell Surface Expression of CXCR3/1-Storing Granules in Human CD4+ T Cells
Authors: Gasser Olivier , Schmid Thomas A. , Zenhaeusern Gabriela , Hess Christoph 
Published: April 2014

Abstract
Efficient migration of CD4+ T cells into sites of infection/inflammation is a prerequisite to protective immunity. Inappropriate recruitment, on the other hand, contributes to inflammatory pathologies. The chemokine/chemokine receptor system is thought to orchestrate T cell homing. In this study, we show that most circulating human CD4+ T cells store the inflammatory chemokine receptors CXCR3 and CXCR1 within a distinct intracellular compartment. Equipped with such storage granules, CD4+ T cells coexpressing both receptors increased from only 1% ex vivo to ∼30% within minutes of activation with PHA or exposure to the cyclooxygenase (COX) substrate arachidonic acid. Up-regulation was TCR independent and reduced by COX inhibitors at concentrations readily reached in vivo. The inducible inflammatory CXCR3highCXCR1+ phenotype identified nonpolarized cells, was preferentially triggered on CCR7+CD4+ T cells, and conferred increased chemotactic responsiveness. Thus, inducible CXCR3/1 expression occurs in a large fraction of CD4+ T cells. Its dependency on COX may explain a number of established, and point toward novel, effects of COX inhibitors.
Costimulation via CD55 on Human CD4+ T Cells Mediated by CD97
Authors: Capasso Melania , Durrant Lindy G. , Stacey Martin , Gordon Siamon , Ramage Judith , Spendlove Ian 
Published: April 2014

Abstract
Decay-accelerating factor (CD55) is a complement regulatory protein, which is expressed by most cells to protect them from complement-mediated attack. CD55 also binds CD97, an EGF-TM7 receptor constitutively expressed on granulocytes and monocytes and rapidly up-regulated on T and B cells upon activation. Early results suggested that CD55 could further enhance T cell proliferation induced by phorbol ester treatment. The present study demonstrates that coengagement of CD55, using either cross-linking mAbs or its natural ligand CD97, and CD3 results in enhanced proliferation of human peripheral blood CD4+ T cells, expression of the activation markers CD69 and CD25, and secretion of IL-10 and GM-CSF. Recently, an increase in T cell responsiveness in CD55−/− mice was shown to be mediated by a lack of complement regulation. In this study, we show that direct stimulation of CD55 on CD4+ T cells with CD97 can modulate T cell activation but does not interfere with CD55-mediated complement regulation. Our results support a multifaceted role for CD55 in human T cell activation, constituting a further link between innate and adaptive immunity.
Paucity of V-D-D-J Rearrangements and VH Replacement Events in Lupus Prone and Nonautoimmune TdT−/− and TdT+/+ Mice
Authors: Watson Lisa C. , Moffatt-Blue Chantelle S. , McDonald R. Zachary , Kompfner Elizabeth , Ait-Azzouzene Djemel , Nemazee David , Theofilopoulos Argyrios N. , Kono Dwight H. , Feeney Ann J. 
Published: April 2014

AbstractCDR3 regions containing two D segments, or containing the footprints of VH replacement events, have been reported in both mice and humans. However, the 12–23 bp rule for V(D)J recombination predicts that D-D rearrangements, which would occur between 2 recombination signal sequences (RSSs) with 12-bp spacers, should be extremely disfavored, and the cryptic RSS used for VH replacement is very inefficient. We have previously shown that newborn mice, which lack TdT due to the late onset of its expression, do not contain any CDR3 with D-D rearrangements. In the present study, we test our hypothesis that most D-D rearrangements are due to fortuitous matching of the second apparent D segment by TdT-introduced N nucleotides. We analyzed 518 sequences from adult MRL/lpr- and C57BL/6 TdT-deficient B cell precursors and found only two examples of CDR3 with D-D rearrangements and one example of a potential VH replacement event. We examined rearrangements from pre-B cells, marginal zone B cells, and follicular B cells from mice congenic for the Lbw5 (Sle3/5) lupus susceptibility loci and from other strains of mice and found very few examples of CDR3 with D-D rearrangements. We assayed B progenitor cells, and cells enriched for receptor editing, for DNA breaks at the “cryptic heptamer” but such breaks were rare. We conclude that many examples of apparent D-D rearrangements in the mouse are likely due to N additions that fortuitously match short stretches of D genes and that D-D rearrangements and VH replacement are rare occurrences in the mouse.
The Histone Methyltransferase Suv39h1 Increases Class Switch Recombination Specifically to IgA
Authors: Bradley Sean P. , Kaminski Denise A. , Peters Antoine H. F. M. , Jenuwein Thomas , Stavnezer Janet 
Published: April 2014

AbstractAb class (isotype) switching allows the humoral immune system to adaptively respond to different infectious organisms. Isotype switching occurs by intrachromosomal DNA recombination between switch (S) region sequences associated with CH region genes. Although isotype-specific transcription of unrearranged (germline) CH genes is required for switching, recent results suggest that isotype specificity is also determined by the sequences of downstream (acceptor) S regions. In the current study, we identify the histone methyltransferase Suv39h1 as a novel Sα-specific factor that specifically increases IgA switching (Sμ-Sα recombination) in a transiently transfected plasmid S substrate, and demonstrate that this effect requires the histone methyltransferase activity of Suv39h1. Additionally, B cells from Suv39h1-deficient mice have an isotype-specific reduction in IgA switching with no effect on the level of germline Iα-Cα transcripts. Taken together, our results suggest that Suv39h1 activity inhibits the activity of a sequence-specific DNA-binding protein that represses switch recombination to IgA.
Resistance of C57BL/6 Mice to Amoebiasis Is Mediated by Nonhemopoietic Cells but Requires Hemopoietic IL-10 Production
Authors: Hamano Shinjiro , Asgharpour Amon , Stroup Suzanne E. , Wynn Thomas A. , Leiter Edward H. , Houpt Eric 
Published: April 2014

Abstract
Resistance to intestinal amoebiasis is mouse strain dependent. C57BL/6 (B6) mice clear Entamoeba histolytica within hours of challenge, whereas C3H and CBA strains are susceptible to infection and disease. In this study, we show using bone marrow (BM) chimeric mice that mouse strain-dependent resistance is mediated by nonhemopoietic cells; specifically, B6 BM → CBA recipients remained susceptible as measured by amoeba score and culture, whereas CBA BM → B6 recipients remained resistant. Interestingly, hemopoietic IL-10 was required for maintaining the resistance of B6 mice, in that B6 IL-10-deficient mice and IL-10−/− BM → wild-type recipients, but not IL-10+/+ BM → IL-10−/− recipients, exhibited higher amoeba scores than their wild-type controls. Additionally, C57BL/10 IL-10−/−Rag2−/− mice exhibited diminished amoeba scores and culture rates vs IL-10−/− mice, indicating that lymphocytes potentiated the susceptibility of IL-10-deficient mice. We conclude that nonhemopoietic cells mediate the natural resistance to intestinal amoebiasis of B6 mice, yet this resistance depends on hemopoietic IL-10 activity.
Wolbachia Endosymbiotic Bacteria of Brugia malayi Mediate Macrophage Tolerance to TLR- and CD40-Specific Stimuli in a MyD88/TLR2-Dependent Manner
Authors: Turner Joseph D. , Langley R. Stuart , Johnston Kelly L. , Egerton Gill , Wanji Samuel , Taylor Mark J. 
Published: April 2014

Abstract
Lymphatic filarial nematodes are able to down-regulate parasite-specific and nonspecific responses of lymphocytes and APC. Lymphatic filariae are reliant on Wolbachia endosymbiotic bacteria for development and survival. We tested the hypothesis that repeated exposure to Wolbachia endosymbionts would drive macrophage tolerance in vitro and in vivo. We pre-exposed murine peritoneal-elicited macrophages to soluble extracts of Brugia malayi female worms (BMFE) before restimulating with BMFE or TLR agonists. BMFE tolerized macrophages (in terms of IFN-β, IL-1β, IL-6, IL-12p40, and TNF-α inflammatory cytokine production) in a dose-dependent manner toward self, LPS, MyD88-dependent TLR2 or TLR9 ligands (peptidoglycan, triacyl lipopeptide, CpG DNA) and the MyD88-independent/TRIF-dependent TLR3 ligand, polyinosinic-polycytidylic acid. This was accompanied with down-regulation in surface expression of TLR4 and up-regulation of CD14, CD40, and TLR2. BMFE tolerance extended to CD40 activation in vitro and systemic inflammation following lethal challenge in an in vivo model of endotoxin shock. The mechanism of BMFE-mediated macrophage tolerance was dependent on MyD88 and TLR2 but not TLR4. Evidence that desensitization was driven by Wolbachia-specific ligands was determined by use of extracts from Wolbachia-depleted B. malayi, aposymbiotic filarial species, and a cell line stably infected with Wolbachia pipientis. Our data promote a role for Wolbachia in contributing toward the dysregulated and tolerized immunological phenotype that accompanies the majority of human filarial infections.
A Novel Approach to Characterize Clonality and Differentiation of Human Melanoma-Specific T Cell Responses: Spontaneous Priming and Efficient Boosting by Vaccination
Authors: Speiser Daniel E. , Baumgaertner Petra , Barbey Catherine , Rubio-Godoy Verena , Moulin Alexandre , Corthesy Patricia , Devevre Estelle , Dietrich Pierre-Yves , Rimoldi Donata , Liénard Danielle , Cerottini Jean-Charles , Romero Pedro , Rufer Nathalie 
Published: April 2014

Abstract
Despite major progress in T lymphocyte analysis in melanoma patients, TCR repertoire selection and kinetics in response to tumor Ags remain largely unexplored. In this study, using a novel ex vivo molecular-based approach at the single-cell level, we identified a single, naturally primed T cell clone that dominated the human CD8+ T cell response to the Melan-A/MART-1 Ag. The dominant clone expressed a high-avidity TCR to cognate tumor Ag, efficiently killed tumor cells, and prevailed in the differentiated effector-memory T lymphocyte compartment. TCR sequencing also revealed that this particular clone arose at least 1 year before vaccination, displayed long-term persistence, and efficient homing to metastases. Remarkably, during concomitant vaccination over 3.5 years, the frequency of the pre-existing clone progressively increased, reaching up to 2.5% of the circulating CD8 pool while its effector functions were enhanced. In parallel, the disease stabilized, but subsequently progressed with loss of Melan-A expression by melanoma cells. Collectively, combined ex vivo analysis of T cell differentiation and clonality revealed for the first time a strong expansion of a tumor Ag-specific human T cell clone, comparable to protective virus-specific T cells. The observed successful boosting by peptide vaccination support further development of immunotherapy by including strategies to overcome immune escape.