bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Role of Three Major New Zealand Black-Derived Loci Linked with Yaa-Induced Murine Lupus Nephritis
Authors: Kikuchi Shuichi , Fossati-Jimack Liliane , Moll Thomas , Amano Hirofumi , Amano Eri , Ida Akinori , Ibnou-Zekri Nabila , Laporte Catherine , Santiago-Raber Marie-Laure , Rozzo Stephen J. , Kotzin Brian L. , Izui Shozo 
Published: April 2014

Abstract
By assessing the development of Y-linked autoimmune acceleration (Yaa) gene-induced systemic lupus erythematosus in C57BL/6 (B6) × (New Zealand Black (NZB) × B6.Yaa)F1 backcross male mice, we mapped three major susceptibility loci derived from the NZB strain. These three quantitative trait loci (QTL) on NZB chromosomes 1, 7, and 13 differentially regulated three different autoimmune traits: anti-nuclear autoantibody production, gp70-anti-gp70 immune complex (gp70 IC) formation, and glomerulonephritis. Contributions to the disease traits were further confirmed by generating and analyzing three different B6.Yaa congenic mice, each carrying one individual NZB QTL. The chromosome 1 locus that overlapped with the previously identified Nba2 (NZB autoimmunity 2) locus regulated all three traits. A newly identified chromosome 7 locus, designated Nba5, selectively promoted anti-gp70 autoantibody production, hence the formation of gp70 IC and glomerulonephritis. B6.Yaa mice bearing the NZB chromosome 13 locus displayed increased serum gp70 production, but not gp70 IC formation and glomerulonephritis. This locus, called Sgp3 (serum gp70 production 3), selectively regulated the production of serum gp70, thereby contributing to the formation of nephritogenic gp70 IC and glomerulonephritis, in combination with Nba2 and Nba5 in NZB mice. Among these three loci, a major role of Nba2 was demonstrated, because B6.Yaa Nba2 congenic male mice developed the most severe disease. Finally, our analysis revealed the presence in B6 mice of an H2-linked QTL, which regulated autoantibody production. This locus had no apparent individual effect, but most likely modulated disease severity through interaction with NZB-derived susceptibility loci.
Cutting Edge: Bcl-3 Up-Regulation by Signal 3 Cytokine (IL-12) Prolongs Survival of Antigen-Activated CD8 T Cells
Authors: Valenzuela Javier O. , Hammerbeck Christopher D. , Mescher Matthew F. 
Published: April 2014

Abstract
Clonal expansion of T cells requires cell division and survival during the proliferative phase of the response. Naive murine CD8 T cells responding to Ag and costimulation undergo an abortive response characterized by impaired clonal expansion, failure to develop effector functions, and long-term tolerance. A third signal provided by IL-12 is required for full expansion, activation, and establishment of memory. The enhanced survival, and thus clonal expansion, supported by IL-12 is not due to increased Bcl-2 or Bcl-xL expression; both are maximally activated by signals 1 and 2. In contrast, Bcl-3, recently shown to enhance survival when ectopically expressed in T cells, is increased only when IL-12 is present. Furthermore, examination of Bcl-3-deficient CD8 T cells demonstrates that the increased survival caused by IL-12 depends upon Bcl-3. The time courses of expression suggest that Bcl-2 and Bcl-xL promote survival early in the response, whereas Bcl-3 acts later in the response.
LIGHT Is Constitutively Expressed on T and NK Cells in the Human Gut and Can Be Induced by CD2-Mediated Signaling
Authors: Cohavy Offer , Zhou Jaclyn , Ware Carl F. , Targan Stephan R. 
Published: April 2014

Abstract
The TNF superfamily cytokine, lymphotoxin-like inducible protein that competes with glycoprotein D for binding herpesvirus entry mediator on T cells (LIGHT; TNFSF14), can augment T cell responses inducing IFN-γ production and can drive pathological gut inflammation when expressed as a transgene in mouse T cells. LIGHT expression by human intestinal T cells suggests the possibility that LIGHT may play a key role in regulation of the mucosal immune system. A nonenzymatic method was developed for the isolation of T cells from the human lamina propria, permitting analysis of native cell surface protein expression. Cell surface LIGHT was constitutively expressed on mucosal T and NK cells and a subpopulation of gut-homing CD4+ T cells in the periphery. In addition, CD2-mediated stimulation induced efficient LIGHT expression on intestinal CD4+ T cells, but not on peripheral blood T cells, suggesting a gut-specific, Ag-independent mechanism for LIGHT induction. By contrast, herpesvirus entry mediator expression on gut T cells was unperturbed, implicating the transcriptional regulation of LIGHT as a mechanism modulating signaling activity in the gut. Quantitative analysis of LIGHT mRNA in a cohort of inflammatory bowel disease patients indicated elevated expression in biopsies from small bowel and from inflamed sites, implicating LIGHT as a mediator of mucosal inflammation.
Autocrine Regulation of T Cell Motility by Calreticulin-Thrombospondin-1 Interaction
Authors: Li Shu Shun , Forslöw Anna , Sundqvist Karl-Gösta 
Published: April 2014

AbstractThe mechanisms regulating T lymphocyte migration within the extracellular matrix are not understood. We show in this study that the thrombospondin-1 binding site of calreticulin, spanning aa 19–32, is a major triggering factor for T cell motility and migration within a three-dimensional collagen type 1 matrix, and that exogenous motogenic factors such as chemokines can stimulate migration via a calreticulin-thrombospondin-1 pathway. Endogenous calreticulin binding to the N-terminal domain of endogenous thrombospondin-1 elicited a motogenic signal to the T cells through the C-terminal domain of thrombospondin-1 and its cell surface receptor integrin-associated protein (CD47). Our data further revealed that thrombospondin-1 was expressed on the cell surface with a high turnover, and that PI3K and the Janus family of tyrosine kinases were required for T cell motility mediated through calreticulin, thrombospondin-1, and CD47. These results unveil an autocrine mechanism of calreticulin-thrombospondin-1-CD47 interaction for the control of T cell motility and migration within three-dimensional extracellular matrix substrata.
Phagocytosis-Induced Apoptosis in Macrophages Is Mediated by Up-Regulation and Activation of the Bcl-2 Homology Domain 3-Only Protein Bim
Authors: Kirschnek Susanne , Ying Songmin , Fischer Silke F. , Häcker Hans , Villunger Andreas , Hochrein Hubertus , Häcker Georg 
Published: April 2014

Abstract
Cell death by apoptosis is important in immune cell homeostasis and in the defense against infectious microorganisms. The physiological event of uptake and intracellular destruction of bacteria is a powerful apoptotic stimulus to macrophages and neutrophil granulocytes. In this study, we provide a molecular analysis of phagocytosis-induced apoptosis. Apoptosis was blocked by Bcl-2 in a mouse macrophage cell line and in primary mouse macrophages. Analysis of the upstream mechanisms revealed that apoptosis was triggered by the Bcl-2 homology domain 3-only protein Bim/Bod. Contact with bacteria or bacterial components induced a strong increase in Bim-expression through TLR and MyD88. Inhibition of the MAPK p38 and JNK reduced both up-regulation of Bim and apoptosis. Phosphorylation of Bim was further observed in mouse macrophages, which appeared to be the result of TLR-dependent phosphatase inhibition. Although TLR-induced Bim was, unlike Bim in resting cells, not bound to the microtubuli cytoskeleton, the up-regulation of Bim was not sufficient to cause apoptosis. A second signal was required that was generated in the process of phagocytosis. Phagocytosis-induced apoptosis was strongly reduced in Bim−/− macrophages. These data provide the molecular context of a form of apoptosis that may serve to dispose of terminally differentiated phagocytes.
Dysregulated B7-1 and B7-2 Expression on Nonobese Diabetic Mouse B Cells Is Associated with Increased T Cell Costimulation and the Development of Insulitis
Authors: Hussain Shabbir , Delovitch Terry L. 
Published: April 2014

Abstract
Little is known about the pathogenic role of B cell dysfunction in T cell-mediated autoimmune disease. We previously reported that B cell hyper-responsiveness, resistance to apoptosis, and accumulation in islets occur during the onset of insulitis, but not in type 1 diabetes (T1D), in NOD mice. In this study we extended these studies to further determine how islet-infiltrated B cells contribute to this inflammatory insulitis. We demonstrate the presence of an increased percentage of B7-1+ and a decreased percentage of B7-2+ B cells in the spleen of autoimmune disease-prone NOD and nonobese diabetes-resistant mice compared with the spleen of nonautoimmune disease-prone C57BL/6 and BALB/c mice. An age-dependent differential expression of B7-1 and B7-2 was associated with the development of insulitis and CD4+CD25+ T cell deficiency in autoimmune disease-prone mice. Whereas BCR and LPS stimulation increased B7-2 expression on B cells from autoimmune disease-prone and nonautoimmune disease-prone mice, LPS-induced B7-1 expression was higher on NOD than C57BL/6 B cells. Interestingly, increased expression of B7-1 and B7-2 was found on islet-infiltrated B cells, and this increase was associated with enhanced T cell costimulation. Islet-infiltrated B cells were shown to be a source of TNF-α production in islets. B7 blockade of BCR-stimulated NOD B cells by anti-B7-1 and anti-B7-2 mAbs during coadoptive transfer with diabetogenic T cells into NOD.scid mice protected these recipients from T1D. These results suggest that increased B7-1 and B7-2 expression on islet-infiltrated NOD B cells is associated with increased T cell costimulation and the development of inflammatory insulitis in NOD mice.
Vaccination with an Acidic Polymerase Epitope of Influenza Virus Elicits a Potent Antiviral T Cell Response but Delayed Clearance of an Influenza Virus Challenge
Authors: Crowe Sherry R. , Miller Shannon C. , Shenyo Rachael M. , Woodland David L. 
Published: April 2014

Abstract
The mechanisms underlying epitope selection and the potential impact of immunodominance hierarchies on peptide-based vaccines are not well understood. Recently, we have shown that two immunodominant MHC class I-restricted epitopes, NP366–374/Db (nucleoprotein (NP)) and PA224–233/Db (acidic polymerase (PA)), which drive the CD8+ T cell response to influenza virus infection in C57BL/6 mice, are differentially expressed on infected cells. Whereas NP appears to be strongly expressed on all infected cells, PA appears to be strongly expressed on dendritic cells but only weakly expressed on nondendritic cells. Thus, the immune response to influenza virus may involve T cells specific for epitopes, such as PA, that are poorly expressed at the site of infection. To examine the consequences of differential Ag presentation on peptide vaccination, we compared the kinetics of the T cell response and influenza virus clearance in mice vaccinated with the NP or PA peptide. Vaccination with either the NP or PA peptide resulted in accelerated and enhanced Ag-specific T cell responses at the site of infection following influenza virus challenge. These T cells were fully functional in terms of their ability to produce IFN-γ and TNF-α and to mediate cytolytic activity. Despite this enhancement of the Ag-specific T cell response, PA vaccination had a detrimental effect on the clearance of influenza virus compared with unvaccinated or NP-vaccinated mice. These data suggest that differential Ag presentation impacts the efficacy of T cell responses to specific epitopes and that this needs to be considered for the development of peptide-based vaccination strategies.
Identification of Antigen-Capturing Cells as Basophils
Authors: Mack Matthias , Schneider Martin A. , Moll Cordula , Cihak Josef , Brühl Hilke , Ellwart Joachim W. , Hogarth Mark P. , Stangassinger Manfred , Schlöndorff Detlef 
Published: April 2014

Abstract
Binding of intact Ag is a hallmark of Ag-specific B cells. Apart from B cells, a small number of non-B cells can bind Ag with comparable efficacy as B cells and are found in the peripheral blood, spleen, and bone marrow of mice. This population has been observed for a long time and recently named “Ag-capturing cells.” Their identity remained enigmatic. In this study, we show that these cells are basophilic granulocytes. Their ability to capture Ags is dependent on surface IgE receptors and on Ag-specific plasma IgE molecules appearing after immunization. Several surface markers including surface bound IgE, IL-3R, CD45, CD16/32, and the chemokine receptor CCR2 were used to clearly identify these cells. Cross-linkage of surface Igs results in the release of large amounts of IL-4 and IL-6. The data identify basophils as Ag-capturing cells and support the concept of basophils as important regulators of humoral immune responses.
Langerhans Cells Derived from Genetically Modified Human CD34+ Hemopoietic Progenitors Are More Potent Than Peptide-Pulsed Langerhans Cells for Inducing Antigen-Specific CD8+ Cytolytic T Lymphocyte Responses
Authors: Yuan Jianda , Latouche Jean-Baptiste , Reagan John L. , Heller Glenn , Riviere Isabelle , Sadelain Michel , Young James W. 
Published: April 2014

AbstractSustained Ag expression by human dendritic cells (DCs) is an attractive means of optimizing Ag presentation for stimulating durable cellular immunity. To establish proof of principle, we used Langerhans cell (LC) progeny of retrovirally transduced CD34+ hemopoietic progenitor cells to stimulate responses against the HLA-A*0201-restricted influenza matrix peptide (fluMP). Retroviral transduction of CD34+ hemopoietic progenitor cells, during pre-expansion by thrombopoietin, c-kit ligand, and FLT-3 ligand, on recombinant fibronectin, but in the absence of FCS, resulted in gene expression by 20–30% of the LCs. Expression persisted at least 28 days, with little decline (&lt;30%) over that time. Retroviral transduction did not alter the phenotype or potent immunogenicity of normal mature DCs. FluMP-transduced LCs stimulated a 130-fold expansion of T cells reactive with HLA-A*0201-fluMP tetramers, even at LC:T cell ratios of 1:100–150 and lower, whereas fluMP-pulsed LCs stimulated only a 30-fold expansion. FluMP-transduced LCs also stimulated higher IFN-γ secretion (100–123 spot-forming cells/105 CD8+ T cells) than did fluMP-pulsed LCs (10–91 spot-forming cells/105 CD8+ T cells). CD8+ T cells stimulated by transduced LCs did not react preferentially with retrovirally transduced targets, indicating that the responses targeted only the immunizing influenza and not the retroviral vector Ags, even though these could have provided nonspecific helper epitopes presented by the transduced LCs. These data demonstrate that gene-transduced LCs maintain the activated phenotype as well potent immunogenicity typical of mature DCs. LCs genetically modified to express fluMP are also more potent stimulators of Ag-specific CD8+ T cell responses than are peptide-pulsed LCs.
CpG Oligodeoxynucleotides Enhance Neonatal Resistance to Listeria Infection
Authors: Ito Shuichi , Ishii Ken J. , Gursel Mayda , Shirotra Hidekazu , Ihata Atsushi , Klinman Dennis M. 
Published: April 2014

Abstract
Infection by Listeria monocytogenes causes serious morbidity and mortality during the neonatal period. Previous studies established that immunostimulatory CpG oligodeoxynucleotides (ODN) can increased the resistance of adult mice to many infectious pathogens, including Listeria. This work examines the capacity of CpG ODN to stimulate a protective immune response in newborns. Results indicate that dendritic cells, macrophages, and B cells from 3-day-old mice respond to CpG stimulation by secreting IFN-γ, IL-12, and/or TNF-α. Spleen cells from CpG-treated neonates produce large amounts of cytokine and NO when exposed to bacteria in vitro. Newborns treated with CpG ODN are protected from lethal Listeria challenge and generate Ag-specific CD4 and CD8 T cells that afford long-term protection against subsequent infection. These results demonstrate that cellular elements of the neonatal immune system respond to stimulation by CpG ODN, thereby reducing host susceptibility to infectious pathogens.
Targeted Disruption of the2B4Gene in Mice Reveals an In Vivo Role of 2B4 (CD244) in the Rejection of B16 Melanoma Cells
Authors: Vaidya Swapnil V. , Stepp Susan E. , McNerney Megan E. , Lee Jae-Kyung , Bennett Michael , Lee Kyung-Mi , Stewart Colin L. , Kumar Vinay , Mathew Porunelloor A. 
Published: April 2014

AbstractMurine 2B4 (CD244) is a cell surface receptor expressed on all NK cells, γδ-T cells, a subset of CD8+ T cells, and all CD14+ monocytes. 2B4 binds to CD48 with high affinity, and cross-linking 2B4 with anti-2B4 Ab in vitro causes activation of NK cells. To study its physiological role, we have generated, by gene targeting, mice deficient in the expression of this cell surface molecule. The expression of lymphoid cell surface markers on PBMC and splenocytes of mice homozygous for the mutation in 2B4 (2B4−/−) is identical to that in wild-type mice. However, thymocytes from female 2B4−/− mice, but not male 2B4−/− mice, have an increase in the immature CD4−/CD8− population. To investigate the in vivo role of 2B4, wild-type and 2B4−/− mice were injected with CD48+ and CD48− metastatic B16 melanoma cells. Wild-type mice rejected CD48+ melanoma poorly compared with CD48− tumor cells, suggesting that ligation of 2B4 by CD48 on melanoma cells is inhibitory. In keeping with this, male 2B4−/− mice showed enhanced ability to reject CD48+ melanoma cells. However, female 2B4−/− mice poorly rejected both CD48+ and CD48− melanoma cells, revealing a gender-specific and CD48-independent defect in mice lacking 2B4. In vitro and in vivo experiments reveal a complex role of NK cells in gender specificity.
Human CD4+ Effector Memory T Cells Persisting in the Microenvironment of Lung Cancer Xenografts Are Activated by Local Delivery of IL-12 to Proliferate, Produce IFN-γ, and Eradicate Tumor Cells
Authors: Broderick Lori , Yokota Sandra J. , Reineke Joshua , Mathiowitz Edith , Stewart Carleton C. , Barcos Maurice , Kelleher Raymond J. , Bankert Richard B. 
Published: April 2014

Abstract
The implantation of small pieces of human primary lung tumor biopsy tissue into SCID mice results in a viable s.c. xenograft in which the tissue architecture, including tumor-associated leukocytes, tumor cells, and stromal cells, is preserved in a functional state. By monitoring changes in tumor volume, gene expression patterns, cell depletion analysis, and the use of function-blocking Abs, we previously established in this xenograft model that exogenous IL-12 mobilizes human tumor-associated leukocytes to kill tumor cells in situ by indirect mechanisms that are dependent upon IFN-γ. In this study immunohistochemistry and FACS characterize the early cellular events in the tumor microenvironment induced by IL-12. By 5 days post-IL-12 treatment, the constitutively present human CD45+ leukocytes have expanded and infiltrated into tumor-rich areas of the xenograft. Two weeks post-treatment, there is expansion of the human leukocytes and complete effacement of the tumor compared with tumor progression and gradual loss of most human leukocytes in control-treated xenografts. Immunohistochemical analyses reveal that the responding human leukocytes are primarily activated or memory T cells, with smaller populations of B cells, macrophages, plasma cells, and plasmacytoid dendritic cells capable of producing IFN-α. The predominant cell population was also characterized by FACS and was shown to have a phenotype consistent with a CD4+ effector memory T cell. We conclude that quiescent CD4+ effector memory T cells are present within the tumor microenvironment of human lung tumors and can be reactivated by the local and sustained release of IL-12 to proliferate and secrete IFN-γ, leading to tumor cell eradication.
Quality of Recombinant Protein Determines the Amount of Autoreactivity Detected against the Tumor-Associated Epithelial Cell Adhesion Molecule Antigen: Low Frequency of Antibodies against the Natural Protein
Authors: Schmetzer Oliver , Moldenhauer Gerhard , Riesenberg Rainer , Pires José Ricardo , Schlag Peter , Pezzutto Antonio 
Published: April 2014

AbstractThe human epithelial cell adhesion molecule (EpCAM) is expressed on normal epithelial cells and is overexpressed in most carcinomas. EpCAM-targeted immunotherapy has been tried in several clinical studies. High titers of autoantibodies against EpCAM have been reported by different authors. We have generated large amounts of purified protein in S2 Drosophila cells (S2-EpCAM) with a purity of &gt;96%. In contrast, the protein produced in baculovirus-dependent systems (baculo-EpCAM) that has been used in previous studies shows a purity of 79%. 1H nuclear magnetic resonance spectrum of S2-EpCAM is typical of folded protein, whereas the baculo-EpCAM sample shows a spectrum corresponding to a partially unfolded protein. Using S2-EpCAM, denatured S2-EpCAM, and baculo-EpCAM, we measured EpCAM Abs of different isotypes in the serum of healthy controls and cancer patients. We found Ab titers against EpCAM in a much lower percentage of sera as published previously, and support the hypothesis that Ab reactivity in some published studies might be due to reactivity against denatured protein, to contaminating proteins in the baculovirus preparations, and to reactivity with BSA. Tetanus toxoid-reactive IgG Abs are present in 1000-fold higher titers compared with EpCAM-reactive Abs. Only IgA Abs were found in higher proportions and in higher concentrations than tetanus toxoid-specific Abs. Our study shows that EpCAM only rarely induces autoantibodies against native protein and emphasizes the importance of using extremely purified Ag preparations when evaluating Abs against tumor-associated Ags.
Tristetraprolin Down-Regulates IL-2 Gene Expression through AU-Rich Element-Mediated mRNA Decay
Authors: Ogilvie Rachel L. , Abelson Michelle , Hau Heidi H. , Vlasova Irina , Blackshear Perry J. , Bohjanen Paul R. 
Published: April 2014

Abstract
Posttranscriptional regulation of IL-2 gene expression at the level of mRNA decay is mediated by an AU-rich element (ARE) found in the 3′-untranslated region. We hypothesized that the ARE-binding protein tristetraprolin (TTP) regulates T lymphocyte IL-2 mRNA decay by interacting with the IL-2 ARE and targeting the transcript for decay. rTTP protein expressed in HeLa cells bound specifically to the IL-2 ARE with high affinity in a gel shift assay. In primary human T lymphocytes, TTP mRNA and protein expression were induced by TCR and CD28 coreceptor stimulation. Using a gel shift assay, we identified a cytoplasmic RNA-binding activity that was induced by TCR and CD28 coreceptor stimulation and bound specifically to the IL-2 ARE sequence. Using anti-TTP Abs, we showed by supershift that this inducible activity contained TTP. We also showed that insertion of the IL-2 ARE sequence into the 3′-untranslated region of a β-globin reporter construct conferred TTP-dependent mRNA destabilization on the β-globin reporter. To determine whether TTP also regulates IL-2 gene expression in vivo, we examined IL-2 expression in primary cells from wild-type and TTP knockout mice. Compared with their wild-type counterparts, TCR- and CD28-activated splenocytes and T cells from TTP knockout mice overexpressed IL-2 mRNA and protein. Also, IL-2 mRNA was more stable in activated splenocytes from TTP knockout mice compared with wild-type mice. Taken together, these data suggest that TTP functions to down-regulate IL-2 gene expression through ARE-mediated mRNA decay.