bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential c-Myc Responsiveness to B Cell Receptor Ligation in B Cell-Negative Selection
Authors: Leider Nira , Melamed Doron 
Published: April 2014

Abstract
Responsiveness of c-Myc oncogene to B cell receptor ligation has been implicated in the induction of apoptosis in transformed and normal immature B cells. These studies provided compelling evidence to link the c-Myc oncogene with the process of negative selection in B-lymphocytes. However, in addition to apoptosis, B cell-negative selection has been shown to occur by secondary Ig gene rearrangements, a mechanism called receptor editing. In this study, we assessed whether differential c-Myc responsiveness to B cell receptor (BCR) ligation is associated with the mechanism of negative selection in immature B cells. Using an in vitro bone marrow culture system and an Ig-transgenic mouse model (3-83) we show here that c-Myc is expressed at low levels throughout B cell development and that c-Myc responsiveness to BCR ligation is developmentally regulated and increased with maturation. Furthermore, we found that the competence to mount c-Myc responsiveness upon BCR ligation is important for the induction of apoptosis and had no effect on the process of receptor editing. Therefore, this study suggests an important role of c-Myc in promoting and/or maintaining B cell development and that compartmentalization of B cell tolerance may also be developmentally regulated by differential c-Myc responsiveness.
Adenoviral Infection Decreases Mortality from Lipopolysaccharide-Induced Liver Failure Via Induction of TNF-α Tolerance
Authors: Yarovinsky Timur O. , Powers Linda S. , Butler Noah S. , Bradford Mary A. , Monick Martha M. , Hunninghake Gary W. 
Published: April 2014

AbstractEffects of adenoviral infection on in vivo responses to LPS mediated by TNF-α were evaluated in a murine model. Adenovirus-infected mice showed decreased mortality from fulminant hepatitis induced by administration of LPS or staphylococcal enterotoxin B in the presence of D-galactosamine. Importantly, TNF-α resistance genes within adenoviral E3 region were not required, because E1,E3-deleted vectors showed similar effects. Adenovirus-infected mice exhibited higher TNF-α levels after LPS stimulation, no difference in TNFR1 expression, and similar mortality from Fas-induced fulminant hepatitis. Decreased production of IL-6 and KC in response to exogenous TNF-α, in addition to protection from TNF-α, suggested that adenoviral infection results in TNF-α tolerance.
Effect of Promoter Methylation on the Regulation ofIFN-γ Gene During In Vitro Differentiation of Human Peripheral Blood T Cells into a Th2 Population
Authors: Yano Shingo , Ghosh Paritosh , Kusaba Hitoshi , Buchholz Meredith , Longo Dan L. 
Published: April 2014

AbstractThe carefully orchestrated events that result in a protective immune response are coordinated to a large extent by cytokines produced by Th1 and Th2 cell subsets. Th1 cells preferentially produce IL-2 and IFN-γ, resulting in a cellular response that helps to eliminate infected cells. In contrast, Th2 cells produce IL-4, IL-5, IL-6, and IL-10, stimulating an Ab response that attacks extracellular pathogens, thereby preventing the cells from becoming infected. To elucidate the mechanisms of differential regulation of cytokine genes by these two different subsets of T cells, we established an in vitro differentiation model of freshly isolated human peripheral blood T cells in which IFN-γ was used as an index gene to study the transcriptional regulation. The data presented here demonstrate that the IFN-γ promoter undergoes differential methylation during in vitro differentiation: the promoter becomes hypermethylated in Th2 cells, whereas it is hypomethylated in Th1 cells. Hypermethylation in Th2 cells results in chromatin condensation and exclusion of CREB proteins from the IFN-γ promoter. Treatment with 5-azacytidine, a demethylating agent, causes Th2 cells to reverse histone condensation and enables CREB recruitment to the hypomethylated promoter. This results in the increased production of IFN-γ. These data indicate the importance of promoter methylation in the regulation of the IFN-γ gene during differentiation.
Prime-Boost Vaccination with HIV-1 Gag Protein and Cytosine Phosphate Guanosine Oligodeoxynucleotide, Followed by Adenovirus, Induces Sustained and Robust Humoral and Cellular Immune Responses
Authors: Tritel Marc , Stoddard Amy M. , Flynn Barbara J. , Darrah Patricia A. , Wu Chang-you , Wille Ulrike , Shah Javeed A. , Huang Yue , Xu Ling , Betts Michael R. , Nabel Gary J. , Seder Robert A. 
Published: April 2014

AbstractA prophylactic vaccine for HIV-1 will probably require the induction and maintenance of both humoral and cellular immunity. One current strategy to achieve such long term immune responses is a prime-boost vaccination approach using a DNA priming inoculation, followed by recombinant viral boost. In this report we use a novel prime-boost approach in which the priming injections consist of recombinant HIV-1 Gag protein mixed with cytosine phosphate guanosine oligodeoxynucleotide (CpG ODN), followed by recombinant adenoviral boost expressing HIV-1 Gag. Analysis of the immune responses indicates that HIV-1 Gag protein plus CpG ODN immunization alone induces potent humoral as well as Th1 and CD8+ T cell responses. Boosting with recombinant adenovirus strikingly enhances CD8+, but not Th1, T cell responses, resulting in CD8+ T cell responses far greater in magnitude than Th1 responses. Furthermore, the Th1 and CD8+ T cell responses following prime-boost immunization were seen in both lymphoid and peripheral mucosal organs and were sustained over several months. Together, these data suggest a new immunization approach for elicitation of long term humoral and cellular immune responses.
Epitope-Enhanced Conserved HIV-1 Peptide Protects HLA-A2-Transgenic Mice Against Virus Expressing HIV-1 Antigen
Authors: Okazaki Takahiro , Pendleton C. David , Lemonnier François , Berzofsky Jay A. 
Published: April 2014

Abstract
HIV epitopes may have developed to be poor immunogens. As a counterapproach HIV vaccine strategy, we used epitope enhancement of a conserved HIV reverse transcriptase (RT) epitope for induction of antiviral protection in HLA-A2-transgenic mice mediated by human HLA-A2-restricted CTLs. We designed two epitope-enhanced peptides based on affinity for HLA-A2, one substituted in anchor residues (RT-2L9V) and the other also with tyrosine at position 1 (RT-1Y2L9V), and examined the balance between HLA binding and T cell recognition. CTL lines and bulk cultures in two HLA-A2-transgenic mouse strains showed that RT-2L9V was more effective in inducing CTL reactive with wild-type Ag than RT-1Y2L9V, despite the higher affinity of the latter, because the 1Y substitution unexpectedly altered T cell recognition. Accordingly, RT-2L9V afforded the greatest protection in vivo against a surrogate virus expressing HIV-1 RT mediated by HLA-A2-restricted CTL in a mouse in which all CTL are restricted to only the human HLA molecule. Such antiviral protection has not been previously achieved with an HLA epitope-enhanced vaccine. These findings define a critical balance between MHC affinity and receptor cross-reactivity required for effective epitope enhancement and also demonstrate construction and efficacy of such a component of a new generation vaccine.
Intracellular Mediators of Granulysin-Induced Cell Death
Authors: Okada Satoshi , Li Qing , Whitin John C. , Clayberger Carol , Krensky Alan M. 
Published: April 2014

Abstract
Granulysin, a molecule present in the granules of CTL and NK cells, is cytolytic against microbes and tumors. Granulysin induces apoptosis of mammalian cells by damaging mitochondria and causing the release of cytochrome c and apoptosis-inducing factor, resulting in DNA fragmentation. Here we show that Ca2+ and K+ channels as well as reactive oxygen species are involved in granulysin-mediated Jurkat cell death. The Ca2+ channel blockers, nickel and econazole, and the K+ channel blockers, tetraethylammonium chloride, apamin, and charybdotoxin, inhibit the granulysin-induced increase in intracellular Ca2+ ([Ca2+]i), the decrease in intracellular K+, and apoptosis. Thapsigargin, which releases Ca2+ from the endoplasmic reticulum, prevents a subsequent granulysin-induced increase in [Ca2+]i in Jurkat cells, indicating that the initial increase in [Ca2+]i is from intracellular stores. The rise in [Ca2+]i precedes a decrease in intracellular K+, and elevated extracellular K+ prevents granulysin-mediated cell death. In granulysin-treated cells, electron transport is uncoupled, and reactive oxygen species are generated. Finally, an increase in intracellular glutathione protects target cells from granulysin-induced lysis, indicating the importance of the redox state in granulysin-mediated cell death.
C1 Inhibitor Prevents Endotoxin Shock Via a Direct Interaction with Lipopolysaccharide
Authors: Liu Dongxu , Cai Shenghe , Gu Xiaogang , Scafidi Jennifer , Wu Xiao , Davis Alvin E. 
Published: April 2014

AbstractC1 inhibitor (C1INH) is beneficial in animal models of endotoxemia and sepsis. However, the mechanism(s) of C1INH protection remain(s) ill-defined. In this study, we demonstrated that both active C1INH and reactive center-cleaved, inactive C1INH protected mice from lethal Gram-negative endotoxemia. Both forms of C1INH blocked the LPS-binding protein-dependent binding of Salmonella typhimurium LPS to the murine macrophage cell line, RAW 264.7, and suppressed LPS-induced TNF-α mRNA expression. Inhibition of LPS binding to RAW 264.7 cells was reversed with anti-C1INH Ab and was more efficient when C1INH was incubated first with LPS rather than with the cells. C1INH also suppressed LPS-induced up-regulation of TNF-α mRNA in whole human blood. The interaction of C1INH with LPS was directly demonstrated both by ELISA and by nondenaturing PAGE, but deletion of the amino-terminal 97-aa residues abrogated this binding. Therefore, C1INH, in addition to its function as a serine protease inhibitor, has a novel anti-inflammatory function mediated via its heavily glycosylated amino-terminal non-serpin domain.
Apoptotic Cells and Innate Immune Stimuli Combine to Regulate Macrophage Cytokine Secretion
Authors: Lucas Mark , Stuart Lynda M. , Savill John , Lacy-Hulbert Adam 
Published: April 2014

Abstract
Macrophage interactions with apoptotic cells can suppress inflammatory responses, but cell death by apoptosis may also trigger inflammation. We now report that murine macrophages exposed to the combination of apoptotic cells and archetypal ligands for Toll-like receptors (TLRs) 2, 4, and 9 mount cytokine responses that differ importantly from those elicited by either class of stimulus alone. TLR ligands induced early and sustained secretion of TNF-α, macrophage-inflammatory protein (MIP) 1α and MIP-2 with later secretion of IL-10, IL-12, and TGF-β1; apoptotic cells alone stimulated late TGF-β1 secretion only. The combination of apoptotic cells and TLR ligands enhanced early secretion of TNF-α, MIP-1α, and MIP-2 and increased late TGF-β1 secretion, while suppressing late TNF-α, IL-10, and Il-12 by mechanisms which could nevertheless be overridden by IFN-γ. We propose that this combinatorial macrophage cytokine response to apoptotic cells and TLR ligands may contribute to recruitment and activation of innate immune defense when cell death occurs at infected inflamed sites while promoting later resolution with diminished engagement of adaptive immunity.
Inhibition of Rho Family GTPases Results in Increased TNF-α Production After Lipopolysaccharide Exposure
Authors: Monick Martha M. , Powers Linda S. , Butler Noah S. , Hunninghake Gary W. 
Published: April 2014

AbstractThese studies demonstrate that treatment of macrophages with lovastatin, a cholesterol-lowering drug that blocks farnesylation and geranylgeranylation of target proteins, increases LPS-induced TNF-α production. This is reversed by the addition of mevalonate, which bypasses the lovastatin block. Examination of membrane localization of RhoA, Cdc42, Rac1, and Ras demonstrated decreased membrane localization of the geranylgeranylated Rho family members (RhoA, Cdc42, and Rac1) with no change in the membrane localization of farnesylated Ras. LPS-induced TNF-α production in the presence of the Rho family-specific blocker (toxin B from Clostridium difficile) was significantly enhanced consistent with the lovastatin data. One intracellular signaling pathway that is required for TNF-α production by LPS is the extracellular signal-regulated kinase (ERK). Significantly, we found prolonged ERK activation after LPS stimulation of lovastatin-treated macrophages. When we inhibited ERK, we blocked the lovastatin-induced increase in TNF-α production. As a composite, these studies demonstrate a negative role for one or more Rho family GTPases in LPS-induced TNF-α production.
M-CSF Induces Vascular Endothelial Growth Factor Production and Angiogenic Activity From Human Monocytes
Authors: Eubank Tim D. , Galloway Michelle , Montague Christine M. , Waldman W. James , Marsh Clay B. 
Published: April 2014

AbstractThe impact of the immune response in malignancy is poorly understood. While immune cells can destroy transformed cells, the targeting and accumulation of monocytes and macrophages at tumor sites may promote tumor metastases. The growth factor M-CSF is important in promoting monocyte survival. Since M-CSF−/− mice are protected against tumor metastases, we hypothesized that M-CSF induced monocytes to produce angiogenic factors that facilitate metastases. In this study we demonstrate that recombinant human M-CSF induces freshly isolated normal human monocytes to produce and release the growth factor vascular endothelial growth factor (VEGF) in a dose-dependent manner, which peaked at 5 days in culture. VEGF released by these monocytes is biologically active, as cell-free supernatants from these M-CSF-stimulated monocytes induced tube formation in HUVEC. Network formation by these HUVECs after treatment with supernatants from monocytes stimulated with M-CSF were inhibited by anti-VEGF, but not by the isogenic control, Abs. Collectively, these data support an important role for M-CSF and monocytes in VEGF production and angiogenesis.
Immunoregulatory Role of Ocular Macrophages: The Macrophages Produce RANTES to Suppress Experimental Autoimmune Uveitis
Authors: Sonoda Koh-Hei , Sasa Yukio , Qiao Hong , Tsutsumi Chikako , Hisatomi Toshio , Komiyama Sohtaro , Kubota Toshiaki , Sakamoto Taiji , Kawano Yoh-Ichi , Ishibashi Tatsuro 
Published: April 2014

AbstractMurine experimental autoimmune uveitis (EAU) is a model of human uveitis. Ocular-infiltrating macrophages play a crucial role in the generation of tissue damage in EAU. In fact, several chemokines are actually produced in the inflamed eye. The aim of this study was to elucidate the role of ocular macrophage-derived chemokines in EAU. C57BL/6 mice were immunized with human interphotoreceptor retinoid binding protein peptide 1–20, and the EAU severity was scored at multiple time points based on microscopic fundus observations (retinal vascular dilatation and exudates) and histological examinations. The peak inflammatory response was observed 1 wk (day 16) after the beginning of macrophage infiltration to the eye (day 9). Ocular-infiltrating cells were enriched or depleted of macrophages by magnetic beads and analyzed by real-time RT-PCR for chemokine mRNA production. We found that only the macrophage-enriched cells from the eye produced RANTES, and thus proposed that macrophage-derived RANTES facilitated the ocular inflammations. In contrast to our postulate, neutralization of RANTES by specific Ab in vivo on days 9 and 13 exacerbated EAU. We also found that the ratio of ocular CD4/CD8 T cells was markedly increased after treatment. As a result, RANTES neutralization might exacerbate EAU by modulating the type of T cell subsets recruited to the eye. In conclusion, our data provide insight into the immunoregulatory role of macrophages and RANTES in the pathogenesis of ocular inflammation. Not all macrophage-derived chemokines cause local inflammation, since RANTES produced by ocular macrophages appears to suppress EAU.
Definition of TCR Epitopes for CTL-Mediated Attack of Cutaneous T Cell Lymphoma
Authors: Winter Dorian , Fiebiger Edda , Meraner Paul , Auer Herbert , Brna Christine , Strohal Robert , Trautinger Franz , Knobler Robert , Fischer Gottfried F. , Stingl Georg , Maurer Dieter 
Published: April 2014

AbstractTherapeutic vaccination against cutaneous T cell lymphoma (CTCL) requires the characterization of cancer cell-specific CTL epitopes. Despite reported evidence for tumor-reactive cytotoxicity in CTCL patients, the nature of the recognized determinants remains elusive. The clonotypic TCR of CTCL cells is a promising candidate tumor-specific Ag. In this study, we report that the clonotypic and framework regions of the TCRs expressed in the malignant T cell clones of six CTCL patients contain multiple peptides with anchor residues fitting the patients’ MHC class I molecules. We demonstrate that TCR peptide-specific T cells from the blood of healthy donors and patients can be induced to become cytotoxic effectors after repeated stimulation with 6 of 11 selected peptides with experimentally proven affinity for HLA-A*0201. Importantly, 4 of these 6 CTL lines reproducibly recognize and lyse autologous primary CTCL cells in MHC class I/CD8-dependent fashion. These tumoricidal CTL lines are directed against epitopes from V, hypervariable, and C regions of TCRα. We therefore conclude that recombined as well as V framework regions of the tumor cell TCRs contain predictable epitopes for CTL-mediated attack of CTCL cells. Our data further suggest that such peptides represent valuable tools for future anti-CTCL vaccination approaches.
Cutting Edge: Effector Memory CD8+ T Cells in the Lung Airways Retain the Potential to Mediate Recall Responses
Authors: Ely Kenneth H. , Roberts Alan D. , Woodland David L. 
Published: April 2014

Abstract
Previous studies have shown that long-lived memory CD8+ T cells persist in the lung airways following the resolution of a murine Sendai virus infection. These cells are CD11alow, noncytolytic, and do not proliferate in the lung airways raising the possibility that they are “end stage” or terminally differentiated memory cells. In this current report, we investigated the functional characteristics of these cells by analyzing their capacity to respond to secondary viral infection outside of the lung environment. We show that, after transfer into the bloodstream, CD11alow memory T cells from the lung airways can return to the secondary lymphoid tissue and respond to a secondary viral challenge. Furthermore, these cells re-express CD11a, which may contribute to their migratory and proliferative capacity. These data demonstrate that lung airway memory CD8+ T cells are not terminally differentiated cells and retain the capacity to mediate recall responses to infection.
Cutting Edge: Signaling and Cell Surface Expression of a μH Chain in the Absence of λ5: A Paradigm Revisited
Authors: Schuh Wolfgang , Meister Silke , Roth Edith , Jäck Hans-Martin 
Published: April 2014

Abstract
Pre-B cell receptor (pre-BCR) signals are essential for pro-B cells to mature efficiently into pre-B cells. The pre-BCR is an Ig-like transmembrane complex that is assembled from two μH chains (μHC) and two surrogate L chains consisting of the non-covalently associated polypeptides VpreB and λ5. In λ5−/− mice, pro-B cell maturation is impaired, but not completely blocked, implying that a μHC induces differentiation signals in the absence of λ5. Using a mouse model, in which transgenic μHC expression can be controlled by tetracycline, we show that in the absence of λ5, the transgenic μHC promotes in vivo differentiation of pro-B cells, induces IL-7-dependent cell growth, and is expressed on the surface of pre-B cells. Our findings not only show that an incomplete pre-BCR can initiate signals, but also challenge the paradigm that an IgHC must associate with an IgLC or a SLC to gain transport and signaling competency.
IFN-α Skews Monocyte Differentiation into Toll-Like Receptor 7-Expressing Dendritic Cells with Potent Functional Activities
Authors: Mohty Mohamad , Vialle-Castellano Alexandra , Nunes Jacques A. , Isnardon Daniel , Olive Daniel , Gaugler Béatrice 
Published: April 2014

Abstract
IFN-α is an important cytokine for the generation of a protective T cell-mediated immune response to viruses. In this study, we asked whether IFN-α can regulate the functional properties of dendritic cells (DCs). We show that monocytes cultured in the presence of GM-CSF and IFN-α can differentiate into DCs (IFN-α-derived DCs (IFN-DCs)). When compared with DCs generated in the presence of GM-CSF and IL-4 (IL-4-derived DCs), IFN-DCs exhibited a typical DC morphology and expressed, in addition to DC markers CD1a and blood DC Ag 4, a similar level of costimulatory and class II MHC molecules, but a significantly higher level of MHC class I molecules. After maturation with CD40 ligand, IFN-DCs up-regulated costimulatory, class I and II MHC molecules and expressed mature DC markers such as CD83 and DC-lysosome-associated membrane protein. IFN-DCs were endowed with potent functional activities. IFN-DCs secreted large amounts of the inflammatory cytokines IL-6, IL-10, TNF-α, IL-1β, and IL-18, and promoted a Th1 response that was independent of IL-12p70 and IL-18, but substantially inhibited by IFN-α neutralization. Furthermore, immature IFN-DCs induced a potent autologous Ag-specific immune response, as evaluated by IFN-γ secretion and expansion of CD8+ T cells specific for CMV. Also, IFN-DCs expressed a large number of Toll-like receptors (TLRs), including acquisition of TLR7, which is classically found on the natural type I IFN-producing plasmacytoid DCs. Like plasmacytoid DCs, IFN-DCs could secrete IFN-α following viral stimulation or TLR7-specific stimulation. Taken together, these results illustrate the critical role of IFN-α at the early steps of immune response to pathogens or in autoimmune diseases.
T/NK Bipotent Progenitors in the Thymus Retain the Potential to Generate Dendritic Cells
Authors: Shen Hui Qing , Lu Min , Ikawa Tomokatsu , Masuda Kyoko , Ohmura Koichiro , Minato Nagahiro , Katsura Yoshimoto , Kawamoto Hiroshi 
Published: April 2014

Abstract
We have previously shown that the earliest thymic progenitors retain the potential to generate T and NK cells and that they lose the bipotentiality to give rise to unipotent T and NK progenitors during the progression of intrathymic developmental stages. The present study examines the ability of these thymic progenitors for generation of dendritic cells (DC) with a new clonal assay that is capable of determining the developmental potential for DC in addition to T cells and NK cells. We found that the large majority of the T/NK bipotential progenitors in the earliest population of fetal thymus was able to generate DC. Although the DC potential is lost with the progression of the differentiation stage, some of the T/NK bipotential progenitors still retain their DC potential even at the CD44+CD25+ stage.