bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct Regulation of Integrin-Dependent T Cell Conjugate Formation and NF-κB Activation by the Adapter Protein ADAP
Authors: Burbach Brandon J. , Srivastava Rupa , Medeiros Ricardo B. , O'Gorman William E. , Peterson Erik J. , Shimizu Yoji 
Published: April 2014

Abstract
Following TCR stimulation, T cells utilize the hematopoietic specific adhesion and degranulation-promoting adapter protein (ADAP) to control both integrin adhesive function and NF-κB transcription factor activation. We have investigated the molecular basis by which ADAP controls these events in primary murine ADAP−/− T cells. Naive DO11.10/ADAP−/− T cells show impaired adhesion to OVAp (OVA aa 323–339)-bearing APCs that is restored following reconstitution with wild-type ADAP. Mutational analysis demonstrates that the central proline-rich domain and the C-terminal domain of ADAP are required for rescue of T:APC conjugate formation. The ADAP proline-rich domain is sufficient to bind and stabilize the expression of SKAP55 (Src kinase-associated phosphoprotein of 55 kDa), which is otherwise absent from ADAP−/− T cells. Interestingly, forced expression of SKAP55 in the absence of ADAP is insufficient to drive T:APC conjugate formation, demonstrating that both ADAP and SKAP55 are required for optimal LFA-1 function. Additionally, the ADAP proline-rich domain is required for optimal Ag-induced activation of CD69, CD25, and Bcl-xL, but is not required for assembly of the CARMA1/Bcl10/Malt1 (caspase-recruitment domain (CARD) membrane-associated guanylate kinase (MAGUK) protein 1/B-cell CLL-lymphoma 10/mucosa-associated lymphoid tissue lymphoma translocation protein 1) signaling complex and subsequent TCR-dependent NF-κB activity. Our results indicate that ADAP is used downstream of TCR engagement to delineate two distinct molecular programs in which the ADAP/SKAP55 module is required for control of T:APC conjugate formation and functions independently of ADAP/CARMA1-mediated NF-κB activation.
Hepatitis C Virus Infection Sensitizes Human Hepatocytes to TRAIL-Induced Apoptosis in a Caspase 9-Dependent Manner
Authors: Lan Lin , Gorke Sebastian , Rau Sibylle J. , Zeisel Mirjam B. , Hildt Eberhard , Himmelsbach Kiyoshi , Carvajal-Yepes Monica , Huber Roman , Wakita Takaji , Schmitt-Graeff Annette , Royer Cathy , Blum Hubert E. , Fischer Richard , Baumert Thomas F. 
Published: April 2014

Abstract
Apoptosis of infected cells represents a key host defense mechanism against viral infections. The impact of apoptosis on the elimination of hepatitis C virus (HCV)-infected cells is poorly understood. The TRAIL has been implicated in the death of liver cells in hepatitis-infected but not in normal liver cells. To determine the impact of TRAIL on apoptosis of virus-infected host cells, we studied TRAIL-induced apoptosis in a tissue culture model system for HCV infection. We demonstrated that HCV infection sensitizes primary human hepatocytes and Huh7.5 hepatoma cells to TRAIL induced apoptosis in a dose- and time-dependent manner. Mapping studies identified the HCV nonstructural proteins as key mediators of sensitization to TRAIL. Using a panel of inhibitors targeting different apoptosis pathways, we demonstrate that sensitization to TRAIL is caspase-9 dependent and mediated in part via the mitochondrial pathway. Sensitization of hepatocytes to TRAIL-induced apoptosis by HCV infection represents a novel antiviral host defense mechanism that may have important implications for the pathogenesis of HCV infection and may contribute to the elimination of virus-infected hepatocytes.
Extracellular Gelsolin Binds Lipoteichoic Acid and Modulates Cellular Response to Proinflammatory Bacterial Wall Components
Authors: Bucki Robert , Byfield Fitzroy J. , Kulakowska Alina , McCormick Margaret E. , Drozdowski Wieslaw , Namiot Zbigniew , Hartung Thomas , Janmey Paul A. 
Published: April 2014

Abstract
The various functions of gelsolin in extracellular compartments are not yet clearly defined but include actin scavenging and antiinflammatory effects. Gelsolin was recently reported to bind endotoxin (LPS) from various Gram-negative bacteria with high affinity. In this study we investigate whether gelsolin also interacts with bacterial wall molecules of Gram-positive bacteria such as lipoteichoic acid (LTA) and whether gelsolin’s interaction with bacterial lipids from Gram-negative or Gram-positive bacteria affects their cellular inflammatory responses. A peptide based on the PPI binding site of gelsolin (160–169) binds purified LTA at the same molecular ratio that it binds phosphatidylinositol 4,5-bisphosphate. The OD of recombinant human plasma gelsolin was found to decrease following the addition of purified LTA, and the binding of gelsolin to LTA inhibits F-actin depolymerization by gelsolin. Simultaneously, the ability of LTA to activate translocation of NF-κB, E-selectin expression, and adhesion of neutrophils to LTA-treated human aortic endothelial cells was compromised by gelsolin. Gelsolin was able to partially inhibit LPS- or LTA-induced release of IL-8 from human neutrophils but was unable to prevent Gram-positive Bacillus subtilis or Gram-negative Pseudomonas aeruginosa growth and had no effect on the antibacterial activity of the cathelicidin-derived antibacterial peptide LL37. These data suggest that extracellular gelsolin is involved in the host immune recognition of LTA or LPS following release of these molecules from the bacterial outer membrane during cell division or attack by drugs and immune components.
Platelet-Activating Factor Production in the Spinal Cord of Experimental Allergic Encephalomyelitis Mice via the Group IVA Cytosolic Phospholipase A2-Lyso-PAFAT Axis
Authors: Kihara Yasuyuki , Yanagida Keisuke , Masago Kayo , Kita Yoshihiro , Hishikawa Daisuke , Shindou Hideo , Ishii Satoshi , Shimizu Takao 
Published: April 2014

Abstract
Platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) plays a critical role in inflammatory disorders including experimental allergic encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Although PAF accumulation in the spinal cord (SC) of EAE mice and cerebrospinal fluid of MS patients has been reported, little is known about the metabolic processing of PAF in these diseases. In this study, we demonstrate that the activities of phospholipase A2 (PLA2) and acetyl-CoA:lyso-PAF acetyltransferase (LysoPAFAT) are elevated in the SC of EAE mice on a C57BL/6 genetic background compared with those of naive mice and correlate with disease severity. Correspondingly, levels of groups IVA, IVB, and IVF cytosolic PLA2s, group V secretory PLA2, and LysoPAFAT transcripts are up-regulated in the SC of EAE mice. PAF acetylhydrolase activity is unchanged during the disease course. In addition, we show that LysoPAFAT mRNA and protein are predominantly expressed in microglia. Considering the substrate specificity and involvement of PAF production, group IVA cytosolic PLA2 is likely to be responsible for the increased PLA2 activity. These data suggest that PAF accumulation in the SC of EAE mice is profoundly dependent on the group IVA cytosolic PLA2/LysoPAFAT axis present in the infiltrating macrophages and activated microglia.
IFN Consensus Sequence Binding Protein (Icsbp) Is Critical for Eosinophil Development
Authors: Milanovic Maja , Terszowski Grzegorz , Struck Daniela , Liesenfeld Oliver , Carstanjen Dirk 
Published: April 2014

Abstract
IFN consensus sequence binding protein (Icsbp) (IFN response factor-8) is a hematopoietic transcription factor with dual functions in myelopoiesis and immunity. In this study, we report a novel role of Icsbp in regulating the development of eosinophils. Loss of Icsbp in mice leads to a reduction of eosinophils in different tissues. During parasite infection with the nematode Nippostrongylus brasiliensis, Icsbp-deficient mice fail to mount eosinophilia despite a vigorous IL-5 response. Numbers of phenotypically defined eosinophil progenitors are decreased and those progenitors have, on a per-cell basis, reduced eosinophil differentiation potential. The transcription factor Gata1, crucial for eosinophil development, is reduced expressed in committed eosinophil progenitors in wells as mature eosinophils. These findings identify Icsbp as a novel transcription factor critical for the development of the eosinophil lineage.
Immune Cell Activation by Enterotoxin Gene Cluster (egc)-Encoded and Non-egc Superantigens from Staphylococcus aureus
Authors: Grumann Dorothee , Scharf Sandra S. , Holtfreter Silva , Kohler Christian , Steil Leif , Engelmann Susanne , Hecker Michael , Völker Uwe , Bröker Barbara M. 
Published: April 2014

Abstract
The species Staphylococcus aureus harbors 19 superantigen gene loci, six of which are located in the enterotoxin gene cluster (egc). Although these egc superantigens are far more prevalent in clinical S. aureus isolates than non-egc superantigens, they are not a prominent cause of toxic shock. Moreover, neutralizing Abs against egc superantigens are very rare, even among carriers of egc-positive S. aureus strains. In search of an explanation, we have tested two non-exclusive hypotheses: 1) egc and non-egc superantigens have unique intrinsic properties and drive the immune system into different directions and 2) egc and non-egc superantigens are released by S. aureus under different conditions, which shape the immune response. A comparison of three egc (SEI, SElM, and SElO) and three non-egc superantigens (SEB, SElQ, and toxic shock syndrome toxin-1) revealed that both induced proliferation of human PBMC with comparable potency and elicited similar Th1/Th2-cytokine signatures. This was supported by gene expression analysis of PBMC stimulated with one representative superantigen from each group (SEI and SEB). They induced very similar transcriptional changes, especially of inflammation-associated gene networks, corresponding to a very strong Th1- and Th17-dominated immune response. In contrast, the regulation of superantigen release differed markedly between both superantigen groups. Egc-encoded proteins were secreted by S. aureus during exponential growth, while non-egc superantigens were released in the stationary phase. We conclude that the distinct biological behavior of egc and non-egc superantigens is not due to their intrinsic properties, which are very similar, but caused by their differential release by S. aureus.
Lipoteichoic Acid Induces HO-1 Expression via the TLR2/MyD88/c-Src/NADPH Oxidase Pathway and Nrf2 in Human Tracheal Smooth Muscle Cells
Authors: Lee I-Ta , Wang Shyi-Wu , Lee Chiang-Wen , Chang Chia-Chi , Lin Chih-Chung , Luo Shue-Fen , Yang Chuen-Mao 
Published: April 2014

Abstract
Heme oxygenase (HO)-1 is a stress-inducible rate-limiting enzyme in heme degradation that confers cytoprotection against oxidative injury and provides a vital function in maintaining tissue homeostasis. Increasing reports have indicated that lipoteichoic acid (LTA) exerts as LPS as an immune system-stimulating agent and plays a role in the pathogenesis of severe inflammatory responses induced by Gram-positive bacterial infection. We report that LTA is an inducer of HO-1 expression mediated through the signaling pathways in human tracheal smooth muscle cells (HTSMCs). LTA-induced HO-1 protein levels, mRNA expression, and promoter activity were attenuated by transfection with dominant negative mutants of TLR2 and MyD88, by pretreatment with the inhibitors of c-Src (PP1), NADPH oxidase (diphenylene iodonium chloride (DPI) and apocynin (APO)), and reactive oxygen species (ROS) scavenger (N-acetyl-l-cysteine) or by transfection with small interfering RNAs of Src and NF-E2-related factor 2 (Nrf2). LTA-stimulated translocation of p47phox and Nrf2 or ROS production was attenuated by transfection with dominant negative mutants of TLR2, MyD88, and c-Src and by pretreatment with DPI or APO. Furthermore, LTA-induced TLR2, MyD88, TNFR-associated factor (TRAF)6, c-Src, and p47phox complex formation was revealed by immunoprecipitation using an anti-TLR2 or anti-c-Src Ab followed by Western blot analysis against an anti-TLR2, anti-MyD88, anti-TRAF6, anti-c-Src, or anti-p47phox Ab. These results demonstrated that LTA-induced ROS generation was mediated through the TLR2/MyD88/TRAF6/c-Src/NADPH oxidase pathway, in turn initiates the activation of Nrf2, and ultimately induces HO-1 expression in HTSMCs.
Differential Production of IL-23 and IL-12 by Myeloid-Derived Dendritic Cells in Response to TLR Agonists
Authors: Roses Robert E. , Xu Shuwen , Xu Min , Koldovsky Ursula , Koski Gary , Czerniecki Brian J. 
Published: April 2014

Abstract
The recently delineated role for IL-23 in enhancing Th-17 activity suggests that regulation of its expression is distinct from that of IL-12. We hypothesized that independent TLR-mediated pathways are involved in the regulation of IL-12 and IL-23 production by myeloid-derived dendritic cells (DCs). The TLR 2 ligand, lipoteichoic acid (LTA), the TLR 4 ligand, LPS, and the TLR 7/8 ligand, resimiquod (R848), induced production of IL-23 by DCs. None of these TLR ligands alone induced significant IL-12 production, except when combined with IFN-γ or other TLR ligands. Notably, IL-23 production in response to single TLR ligands was inhibited by IL-4. DCs treated with single TLR agonists induced IL-17A production by allogeneic and Ag-specific memory CD4+ T cells, an effect that was abrogated by IL-23 neutralization. Moreover, these DCs stimulated IL-17A production by tumor peptide-specific CD8+ T cells. In contrast, DCs treated with dual signals induced naive and memory Th1 responses and enhanced the functional avidity of tumor-specific CD8+ T cells. These results indicate that distinct microbial-derived stimuli are required to drive myeloid DC commitment to IL-12 or IL-23 production, thereby differentially polarizing T cell responses.
Despite Biased TRBV Gene Usage against a Dominant HLA B57-Restricted Epitope, TCR Diversity Can Provide Recognition of Circulating Epitope Variants
Authors: Simons Brenna C. , VanCompernolle Scott E. , Smith Rita M. , Wei Jie , Barnett Louise , Lorey Shelly L. , Meyer-Olson Dirk , Kalams Spyros A. 
Published: April 2014

Abstract
The role of epitope-specific TCR repertoire diversity in the control of HIV-1 viremia is unknown. Further analysis at the clonotype level is important for understanding the structural aspects of the HIV-1 specific repertoire that directly relate to CTL function and ability to suppress viral replication. In this study, we performed in-depth analysis of T cell clonotypes directed against a dominantly recognized HLA B57-restricted epitope (KAFSPEVIPMF; KF11) and identified common usage of the TCR β-chain TRBV7 in eight of nine HLA B57 subjects examined, regardless of HLA B57 subtype. Despite this convergent TCR gene usage, structural and functional assays demonstrated no substantial difference in functional or structural avidity between TRBV7 and non-TRBV7 clonotypes and this epitopic peptide. In a subject where TRBV7-usage did not confer cross-reactivity against the dominant autologous sequence variant, another circulating TCR clonotype was able to preferentially recognize the variant peptide. These data demonstrate that despite selective recruitment of TCR for a conserved epitope over the course of chronic HIV-1 infection, TCR repertoire diversity may benefit the host through the ability to recognize circulating epitope variants.
Human C3 Deficiency Associated with Impairments in Dendritic Cell Differentiation, Memory B Cells, and Regulatory T Cells
Authors: Ghannam Arije , Pernollet Martine , Fauquert Jean-Luc , Monnier Nicole , Ponard Denise , Villiers Marie-Bernadette , Péguet-Navarro Josette , Tridon Arlette , Lunardi Joel , Gerlier Denis , Drouet Christian 
Published: April 2014

Abstract
Primary C3 deficiency, a rare autosomal inherited disease (OMIM 120700), was identified in a 2-year-old male suffering from recurrent pyogenic infections from early infancy with undetectable total complement hemolytic activity (CH50) and C3 values. The nonconsanguineous parents and the two patients’ two siblings had 50% normal serum C3 concentration. The molecular abnormality associated a paternal allele coding C3 with the missense mutation p.Ser550Pro and an apparently null maternal allele, with production of a defective protein that could no longer be secreted. Vaccination of the child did not induce a long-term Ab response. Accordingly, switched memory IgD−CD27+ B cells were barely detected, amounting to only 2.3% of peripheral blood CD19+ cells. Cells were significantly defective in stimulating alloreactive responses. The in vitro development of immature dendritic cells and their maturation capacity were greatly impaired, with decreased CD1a expression and IL-12p70 secretion ability. These cells were unable to induce autologous B cell proliferation and Ig secretion in the presence of CD40L and C3. Finally, the regulatory T cell development ability of CD4+ T cells after CD3 and CD46 activation in the presence of IL-2 was significantly impaired. Thus, the association of important functional defects of dendritic cells, acquisition of B cell memory, and regulatory T cells with human C3 deficiency strongly supports a major role for C3 in bridging innate and adaptive immunity in humans.
Homeostatic Regulation of Blood Neutrophil Counts
Authors: von Vietinghoff Sibylle , Ley Klaus 
Published: April 2014

Abstract
Blood neutrophil counts are determined by the differentiation and proliferation of precursor cells, the release of mature neutrophils from the bone marrow, margination, trafficking and transmigration through the endothelial lining, neutrophil apoptosis, and uptake by phagocytes. This brief review summarizes the regulation of blood neutrophil counts, which is in part controlled by G-CSF, IL-17, and IL-23. Neutrophils are retained in the bone marrow through interaction of CXCL12 with its receptor CXCR4. The relevance of this mechanism is illustrated by rare diseases in which disrupting the desensitization of CXCR4 results in failure to release mature neutrophils from bone marrow. Although blood neutrophil numbers in inbred mouse strains and individual human subjects are tightly controlled, their large variation among outbred populations suggests genetic factors. One example is benign ethnic neutropenia, which is found in some African Americans. Reduced and elevated neutrophil counts, even within the normal range, are associated with excess all-cause mortality.
Cutting Edge: Inhibition of NF-κB-Mediated TSLP Expression by Retinoid X Receptor
Authors: Lee Hai-Chon , Headley Mark B. , Iseki Masanori , Ikuta Koichi , Ziegler Steven F. 
Published: April 2014

Abstract
The epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) has important roles in the initiation of allergic airway inflammation and the activation of dendritic cells. We have shown that the human TSLP gene is regulated in a NF-κB-dependent manner; however the factors that negatively regulate TSLP expression are not known. In this study we demonstrate that 9-cis-retinoic acid (9-cis-RA) is a negative regulator of TSLP expression in airway epithelial cells. This inhibition is manifested as a block in the IL-1β-mediated recruitment of NF-κB to the human TSLP promoter. 9-cis-RA-mediated inhibition is not restricted to TSLP gene expression but rather reflects a general inhibition of NF-κB activation, as other NF-κB-regulated-genes were also inhibited in a similar manner by 9-cis-RA treatment. Taken as a whole, these data demonstrate that inhibition of IL-1β-dependent genes by active retinoid X receptors involves antagonism of NF-κB signaling.
Cutting Edge: Autocrine TGF-β Sustains Default Tolerogenesis by IDO-Competent Dendritic Cells
Authors: Belladonna Maria L. , Volpi Claudia , Bianchi Roberta , Vacca Carmine , Orabona Ciriana , Pallotta Maria T. , Boon Louis , Gizzi Stefania , Fioretti Maria C. , Grohmann Ursula , Puccetti Paolo 
Published: April 2014

Abstract
CD8− and CD8+ dendritic cells (DCs) are distinct subsets of mouse splenic accessory cells with opposite but flexible programs of Ag presentation, leading to immunogenic and tolerogenic responses, respectively. In this study, we show that the default tolerogenic function of CD8+ DCs relies on autocrine TGF-β, which sustains the activation of IDO in response to environmental stimuli. CD8− DCs do not produce TGF-β, yet externally added TGF-β induces IDO and turns those cells from immunogenic into tolerogenic cells. The acquisition of a suppressive phenotype by CD8− DCs correlates with activation of the PI3K/Akt and noncanonical NF-κB pathways. These data are the first to link TGF-β signaling with IDO in controlling spontaneous tolerogenesis by DCs.
Cutting Edge: Immunity against a “Silent” Salivary Antigen of the Lyme Vector Ixodes scapularis Impairs Its Ability to Feed
Authors: Kotsyfakis Michalis , Anderson Jennifer M. , Andersen John F. , Calvo Eric , Francischetti Ivo M. B. , Mather Thomas N. , Valenzuela Jesus G. , Ribeiro José M. C. 
Published: April 2014

Abstract
Ixodes scapularis ticks transmit the Lyme disease agent in the United States. Although strong antitick immunity mediates tick rejection by certain vertebrates, only a few Ags have been molecularly characterized. We show that guinea pig vaccination against a secreted tick salivary immunomodulator, sialostatin L2, can lead to decreased feeding ability of I. scapularis nymphs. Increased rejection rate, prolonged feeding time, and apparent signs of inflammation were observed for nymphs attached to vaccinated animals, indicating a protective host immune response. Interestingly, sialostatin L2 humoral recognition does not take place upon repeated tick exposure in control animals, but only in the vaccinated animals that neutralize sialostatin L2 action. Therefore, we demonstrate an essential sialostatin L2 role upon nymphal infestation that can be blocked by vertebrate immunity and propose the discovery of similarly “silent” Ags toward the development of a multicomponent vaccine that will protect against tick bites and the pathogens they transmit.
Cutting Edge: Contact with Secondary Lymphoid Organs Drives Postthymic T Cell Maturation
Authors: Houston Evan G. , Nechanitzky Robert , Fink Pamela J. 
Published: April 2014

Abstract
T cell development, originally thought to be completed in the thymus, has recently been shown to continue for several weeks in the lymphoid periphery. The forces that drive this peripheral maturation are unclear. The use of mice transgenic for GFP driven by the RAG2 promoter has enabled the ready identification and analysis of recent thymic emigrants. Here, we show that recent thymic emigrant maturation is a progressive process and is promoted by T cell exit from the thymus. Further, we show that this maturation occurs within secondary lymphoid organs and does not require extensive lymphocyte recirculation.