bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vβ6+ T Cells Are Obligatory for Vaccine-Induced Immunity to Histoplasma capsulatum
Authors: Deepe George S. , Gibbons Reta 
Published: April 2014

Abstract
We examined TCR usage to a protective fragment of heat shock protein 60 from the fungus, Histoplasma capsulatum. Nearly 90% of T cell clones from C57BL/6 mice vaccinated with this protein were Vβ6+; the remainder were Vβ14+. Amino acid motifs of the CDR3 region from Vβ6+ cells were predominantly IxGGG, IGG, or SxxGG, whereas it was uniformly SFSGG for Vβ14+ clones. Short term T cell lines from Vβ6+-depleted mice failed to recognize Ag, and no T cell clones could be generated. To determine whether Vβ6+ cells were functionally important, we eliminated them during vaccination. Depletion of Vβ6+ cells abrogated protection in vivo and upon adoptive transfer of cells into TCR αβ−/− mice. Transfer of a Vβ6+, but not a Vβ14+, clone into TCR αβ−/− mice prolonged survival. Cytokine generation by Ag-stimulated splenocytes from immunized mice depleted of Vβ6+ cells was similar to that of controls. The efficacy of the Vβ6+ clone was associated with elevated production of IFN-γ, TNF-α, and GM-CSF compared with that of the Vβ14+ clone. More Vβ6+ cells were present in lungs and spleens of TCR αβ−/− on day 3 postinfection compared with Vβ14+ cells. Thus, a single Vβ family was essential for vaccine-induced immunity. Moreover, the mechanism by which Vβ6+ contributed to protective immunity differed between unfractionated splenocytes and T cell clones.
The Role of IL-4 in Heligmosomoides polygyrus-Induced Alterations in Murine Intestinal Epithelial Cell Function
Authors: Shea-Donohue Terez , Sullivan Carolyn , Finkelman Fred D. , Madden Kathleen B. , Morris Suzanne C. , Goldhill Jon , Piñeiro-Carrero Victor , Urban Joseph F. 
Published: April 2014

Abstract
IL-4 and IL-13 promote gastrointestinal worm expulsion, at least in part, through effects on nonlymphoid cells, such as intestinal epithelial cells. The role of IL-4/IL-13 in the regulation of intestinal epithelial function during Heligmosomoides polygyrus (Hp) infection was investigated in BALB/c mice infected with Hp or treated with a long-lasting formulation of recombinant mouse IL-4/αIL-4 complexes (IL-4C) for 7 days. Separate groups of BALB/c mice were drug-cured of initial infection and later reinfected and treated with anti-IL-4R mAb, an antagonist of IL-4 and IL-13 receptor binding, or with a control mAb. Segments of jejunum were mounted in Ussing chambers, and short circuit current responses to acetylcholine, histamine, serotonin, PGE2, and glucose were determined. Although only modest changes in epithelial cell function were observed during primary Hp infection, IL-4C or a secondary Hp infection each induced more dramatic changes, including increased mucosal permeability, reduced sodium-linked glucose absorption, and increased Cl− secretory response to PGE2. Some, but not all, effects of IL-4C and Hp infection were dependent on enteric nerves. Hp-induced changes in epithelial function were attenuated or prevented by anti-IL-4R mAb. Thus, IL-4/IL-13 mediate many of the effects of Hp infection on intestinal epithelial cell function and do so both through direct effects on epithelial cells and through indirect, enteric nerve-mediated prosecretory effects. These immune system-independent effector functions of IL-4/IL-13 may be important for host protection against gastrointestinal nematodes.
Differential Requirements for Core2 Glucosaminyltransferase for Endothelial L-Selectin Ligand Function In Vivo
Authors: Sperandio Markus , Forlow S. Bradley , Thatte Jayant , Ellies Lesley G. , Marth Jamey D. , Ley Klaus 
Published: April 2014

Abstract
L-selectin is a calcium-dependent lectin on leukocytes mediating leukocyte rolling in high endothelial venules and inflamed microvessels. Many selectin ligands require modification of glycoproteins by leukocyte core2 β1,6-N-acetylglucosaminyltransferase (Core2GlcNAcT-I). To test the role of Core2GlcNAcT-I for L-selectin ligand biosynthesis, we investigated leukocyte rolling in venules of untreated and TNF-α-treated cremaster muscles and in Peyer’s patch high endothelial venules (HEV) of Core2GlcNAcT-I null (core2−/−) mice. In the presence of blocking mAbs against P- and E-selectin, L-selectin-mediated leukocyte rolling was almost completely abolished in cremaster muscle venules of core2−/− mice, but not littermate control mice. By contrast, leukocyte rolling in Peyer’s patch HEV was not significantly different between core2−/− and control mice. To probe L-selectin ligands more directly, we injected L-selectin-coated beads. These beads showed no rolling in cremaster muscle venules of core2−/− mice, but significant rolling in controls. In Peyer’s patch HEV, beads coated with a low concentration of L-selectin showed reduced rolling in core2−/− mice. Beads coated with a 10-fold higher concentration of L-selectin rolled equivalently in core2−/− and control mice. Our data show that endothelial L-selectin ligands relevant for rolling in inflamed microvessels of the cremaster muscle are completely Core2GlcNAcT-I dependent. In contrast, L-selectin ligands in Peyer’s patch HEV are only marginally affected by the absence of Core2GlcNAcT-I, but are sufficiently functional to support L-selectin-dependent leukocyte rolling in Core2GlcNAcT-I-deficient mice.
Sensitized Mast Cells Migrate Toward the Agen: A Response Regulated by p38 Mitogen-Activated Protein Kinase and Rho-Associated Coiled-Coil-Forming Protein Kinase
Authors: Ishizuka Tamotsu , Okajima Fumikazu , Ishiwara Mitsuteru , Iizuka Kunihiko , Ichimonji Isao , Kawata Tadayoshi , Tsukagoshi Hideo , Dobashi Kunio , Nakazawa Tsugio , Mori Masatomo 
Published: April 2014

Abstract
Although mast cells accumulate within the mucosal epithelial layer of patients with allergic rhinitis and bronchial asthma, the responsible chemotactic factors are undefined. We investigated whether mast cells sensitized with Ag-specific IgE migrate toward the Ag. MC/9 mast cells sensitized with anti-DNP IgE migrated toward DNP-conjugated human serum albumin. This migration was directional, and the degree was stronger than that induced by stem cell factor. IL-3 and stem cell factor-dependent cultured mast cells derived from mouse bone marrow also migrated toward the Ag. Subsequent migration mediated by the FcεRI was significantly inhibited by incubating the cells with Y-27632, a Rho-associated coiled-coil-forming protein kinase inhibitor, or with SB203580, a p38 mitogen-activated protein kinase (MAPK) inhibitor. Both p38 MAPK and MAPK-activated protein kinase (MAPKAPK)2 were activated following FcεRI aggregation, and activation of MAPKAPK2 was almost completely inhibited by 10μM SB203580. Wortmannin or a low concentration of SB203580 partially inhibited MAPKAPK2, but did not block mast cell migration. In contrast, Y-27632 did not affect the activation of MAPKAPK2. These results indicate that Ag works not only as a stimulant for allergic mediators from IgE-sensitized mast cells, but also as a chemotactic factor for mast cells. Both p38 MAPK activation and Rho-dependent activation of Rho-associated coiled-coil-forming protein kinase may be required for FcεRI-mediated cell migration.
Up-Regulation of IL-10R1 Expression Is Required to Render Human Neutrophils Fully Responsive to IL-10
Authors: Crepaldi Luca , Gasperini Sara , Lapinet José A. , Calzetti Federica , Pinardi Cristina , Liu Ying , Zurawski Sandra , de Waal Malefyt René , Moore Kevin W. , Cassatella Marco A. 
Published: April 2014

AbstractWe have recently shown that IL-10 fails to trigger Stat3 and Stat1 tyrosine phosphorylation in freshly isolated human neutrophils. In this study, we report that IL-10 can nonetheless induce Stat3 tyrosine phosphorylation and the binding of Stat1 and Stat3 to the IFN-γ response region or the high-affinity synthetic derivative of the c-sis-inducible element in neutrophils that have been cultured for at least 3 h with LPS. Similarly, the ability of IL-10 to up-regulate suppressor of cytokine signaling (SOCS)-3 mRNA was dramatically enhanced in cultured neutrophils and, as a result, translated into the SOCS-3 protein. Since neutrophils’ acquisition of responsiveness to IL-10 required de novo protein synthesis, we assessed whether expression of IL-10R1 or IL-10R2 was modulated in cultured neutrophils. We detected constitutive IL-10R1 mRNA and protein expression in circulating neutrophils, at levels which were much lower than those observed in autologous monocytes or lymphocytes. In contrast, IL-10R2 expression was comparable in both cell types. However, IL-10R1 (but not IL-10R2) mRNA and protein expression was substantially increased in neutrophils stimulated by LPS. The ability of IL-10 to activate Stat3 tyrosine phosphorylation and SOCS-3 synthesis and to regulate IL-1 receptor antagonist and macrophage-inflammatory protein 1β release in LPS-treated neutrophils correlated with this increased IL-10R1 expression, and was abolished by neutralizing anti-IL-10R1 and anti-IL-10R2 Abs. Our results demonstrate that the capacity of neutrophils to respond to IL-10, as assessed by Stat3 tyrosine phosphorylation, SOCS-3 expression, and modulation of cytokine production, is very dependent on the level of expression of IL-10R1.
Cutting Edge: Culture with High Doses of Viral Peptide Induces Previously Unprimed CD8+ T Cells to Produce Cytokine
Authors: Riberdy Janice M. , Zirkel Amy , Surman Sherri , Hurwitz Julia L. , Doherty Peter C. 
Published: April 2014

Abstract
Culturing naive T cells with 50 μM selected HIV-1 envelope peptides for 6 days in the presence of IL-2 drives the emergence of a substantial CD8+ population that secretes IFN-γ following short-term stimulation with 1 μM peptide. This response is H-2Kb restricted, epitope specific, and requires the continuing presence of peptide. The same effect was found for known H-2Db-restricted peptides from two influenza virus proteins. The great majority of these influenza-specific CD8+IFN-γ+ T cells neither stained with the cognate tetramer nor expressed the TCR Vβ bias that is characteristic of the CD8+ set expanded in vivo during an infection. Thus, multipoint binding of low affinity TCRs on naive CD8+ T cells can drive peptide-specific cytokine production. However, at least for two influenza-derived epitopes, the avidity of the TCR-MHC peptide interaction appears to be insufficient to stabilize a tetrameric complex of MHC class I glycoprotein plus peptide on the lymphocyte surface.
Cutting Edge: Dichotomy of Homing Receptor Dependence by Mucosal Effector B Cells: αE Versus L-Selectin
Authors: Csencsits Keri L. , Walters Nancy , Pascual David W. 
Published: April 2014

Abstract
The common mucosal immune system may be compartmentalized because lymphocyte homing to the upper respiratory tract appears to be mediated by L-selectin interactions rather than α4β7 interactions, as is the case for gut-associated lymphoreticular tissue. To assess the role of L-selectin in effector B cell immunity, L-selectin-deficient mice were intranasally immunized with cholera toxin (CT), and mucosal immune responses were compared with C57BL/6 mice. The absence of L-selectin correlated with a reduction in CT-specific secretory-IgA responses in nasal passages and reproductive tract, but not intestinal lamina propria. Cell sorting experiments showed that an L-selectin-dependent subset was responsible for CT-specific responses in nasal passages and reproductive tract, whereas an αEβ7+ B cell subset was responsible for L-selectin-independent intestinal immunity. This study provides evidence for compartmentalization of the common mucosal immune system into “intestinal” vs “nonintestinal” effector sites.
Cutting Edge: Myeloid Complement C3 Enhances the Humoral Response To Peripheral Viral Infection
Authors: Verschoor Admar , Brockman Mark A. , Knipe David M. , Carroll Michael C. 
Published: April 2014

AbstractHSV-1 is the causative agent of cutaneous lesions, commonly referred to as cold sores. Primary exposure to the virus ordinarily occurs through the periphery, in particular through abraded skin or mucosal membranes. Under certain circumstances (e.g., in neonatals or AIDS patients), the infection becomes disseminated, often with severe consequences. Spread of HSV-1 is limited by virus-specific Ab. The development of an efficient humoral response to the virus is dependent on innate immunity component complement C3. The liver is the major source of C3, but there are also extrahepatic origins of C3 such as lymphoid macrophages. In the present study, the significance of C3 synthesis by bone marrow-derived cells was assessed by the transfer of wild-type bone marrow into irradiated C3-deficient mice. Using these chimeric mice, extrahepatic C3 was determined sufficient to initiate specific Ab and memory responses to a peripheral HSV-1 infection.
Cutting Edge: Amelioration of Kidney Disease in a Transgenic Mouse Model of Lupus Nephritis by Administration of the Caspase Inhibitor Carbobenzoxy-Valyl-Alanyl-Aspartyl-(β-o-methyl)-Fluoromethylketone
Authors: Seery John P. , Cattell Victoria , Watt Fiona M. 
Published: April 2014

Abstract
Systemic lupus erythematosus (SLE) is a common, potentially fatal, non-organ-specific autoimmune disorder. Immune complex-mediated kidney disease is the major cause of mortality. Apoptotic cells in the epidermis are a possible source of self Ags, and apoptosis of endothelial cells and lymphocytes is thought to contribute to end-organ damage. We have previously shown that female transgenic mice expressing IFN-γ in the epidermis develop inflammatory skin disease and features of SLE that have striking parallels with the human condition. We have now tested the effects of a pan-caspase inhibitor, carbobenzoxy-valyl-alanyl-aspartyl-(β-o-methyl)-fluoromethylketone, on disease progression. Daily s.c. administration of carbobenzoxy-valyl-alanyl-aspartyl-(β-o-methyl)-fluoromethylketone to female transgenic mice over a 3-wk period resulted in significant amelioration of both glomerular and interstitial renal damage, independent of the effects on autoantibody levels or skin inflammation. We propose that apoptosis inhibitors could be beneficial in the treatment of human SLE.
Technical Note: Linkage Disequilibrium and Disease-Associated CTLA4 Gene Polymorphisms
Authors: Holopainen Päivi M. , Partanen Jukka A. 
Published: April 2014

Abstract
CTLA4 and CD28 are important regulators of T lymphocyte activation. Gene region 2q33 carrying genes for both CTLA4 and CD28 has been shown to be linked to many autoimmune diseases. Disease associations with particular CTLA4 gene polymorphisms have been reported. Recently, first lines of evidence emerged for functional effects of CTLA4 gene polymorphisms. Two independent studies reported a reduced inhibitory function of CTLA4 in individuals with certain CTLA4 genotypes: those with a high number of microsatellite repeats in one study and those with allele +49*G in exon 1 in the other one. We analyzed the strength of linkage disequilibrium between the three known CTLA4 polymorphisms among 577 independent chromosomes. Our results show that the polymorphisms previously suggested to be the functional risk factors nearly always occur together in a very frequent haplotype. Due to this strong linkage disequilibrium, we conclude that the previous reports studying merely a single polymorphism could not distinguish which variation actually caused the functional difference. Hence, either mutagenesis approaches or studies with data on all linked polymorphisms are still needed to determine the genuine functional risk polymorphism in this gene region.
Role of CD47 in the Induction of Human Naive T Cell Anergy
Authors: Avice Marie-Noëlle , Rubio Manuel , Sergerie Martin , Delespesse Guy , Sarfati Marika 
Published: April 2014

AbstractWe recently reported that CD47 ligation inhibited IL-2 release by umbilical cord blood mononuclear cells activated in the presence of IL-12, but not IL-4, preventing the induction of IL-12Rβ2 expression and the acquisition of Th1, but not the Th2 phenotype. Here we show that in the absence of exogenous cytokine at priming, CD47 ligation of umbilical cord blood mononuclear cells promotes the development of hyporesponsive T cells. Naive cells were treated with CD47 mAb for 3 days, expanded in IL-2 for 9–12 days, and restimulated by CD3 and CD28 coengagement. Effector T cells generated under these conditions were considered to be anergic because they produced a reduced amount of IL-2 at the single-cell level and displayed an impaired capacity 1) to proliferate, 2) to secrete Th1/Th2 cytokines, and 3) to respond to IL-2, IL-4, or IL-12. Moreover, CD47 mAb strongly suppressed IL-2 production and IL-2Rα expression in primary cultures and IL-2 response of activated naive T cells. Induction of anergy by CD47 mAb was IL-10 independent, whereas inclusion of IL-2 and IL-4, but not IL-7, at priming fully restored T cell activation. Furthermore, CD28 costimulation prevented induction of anergy. Thus, CD47 may represent a potential target to induce anergy and prevent undesired Th0/Th1 responses such as graft vs host diseases, allograft rejection, or autoimmune diseases.
A CD19-Dependent Signaling Pathway Regulates Autoimmunity in Lyn-Deficient Mice
Authors: Hasegawa Minoru , Fujimoto Manabu , Poe Jonathan C. , Steeber Douglas A. , Lowell Clifford A. , Tedder Thomas F. 
Published: April 2014

AbstractCD19 and the Src family protein tyrosine kinases (PTKs) are important regulators of intrinsic signaling thresholds in B cells. Regulation is achieved by cross-talk between Src family PTKs and CD19; Lyn is essential for CD19 phosphorylation, while CD19 establishes an Src family PTK activation loop that amplifies kinase activity. However, CD19-deficient (CD19−/−) B cells are hyporesponsive to transmembrane signals, while Lyn-deficient (Lyn−/−) B cells exhibit a hyper-responsive phenotype resulting in autoimmunity. To identify the outcome of interactions between CD19 and Src family PTKs in vivo, B cell function was examined in mice deficient for CD19 and Lyn (CD19/Lyn−/−). Remarkably, CD19 deficiency suppressed the hyper-responsive phenotype of Lyn−/− B cells and autoimmunity characterized by serum autoantibodies and immune complex-mediated glomerulonephritis in Lyn−/− mice. Consistent with Lyn and CD19 each regulating conventional B cell development, B1 cell development was markedly reduced by Lyn deficiency, with further reductions in the absence of CD19 expression. Tyrosine phosphorylation of Fyn and other cellular proteins induced following B cell Ag receptor ligation was dramatically reduced in CD19/Lyn−/− B cells relative to Lyn−/− B cells, while Syk phosphorylation was normal. In addition, the enhanced intracellular Ca2+ responses following B cell Ag receptor ligation that typify Lyn deficiency were delayed by the loss of CD19 expression. BCR-induced proliferation and humoral immune responses were also markedly inhibited by CD19/Lyn deficiency. These findings demonstrate that while the CD19/Lyn amplification loop is a major regulator of signal transduction thresholds in B lymphocytes, CD19 regulation of other Src family PTKs also influences B cell function and the development of autoimmunity.
The TNF Superfamily Members LIGHT and CD154 (CD40 Ligand) Costimulate Induction of Dendritic Cell Maturation and Elicit Specific CTL Activity
Authors: Morel Yannis , Truneh Alemseged , Sweet Raymond W. , Olive Daniel , Costello Régis T. 
Published: April 2014

AbstractLIGHT is a recently identified member of the TNF superfamily that is up-regulated upon activation of T cells. Herpesvirus entry mediator, one of its receptors, is constitutively expressed on immature dendritic cells (DCs). In this report, we demonstrate that LIGHT induces partial DC maturation as demonstrated by Ag presentation and up-regulation of adhesion and costimulatory molecules. LIGHT-stimulated DCs show reduced macropinocytosis and enhanced allogeneic stimulatory capacity but fail to produce significant amounts of IL-12, IL-6, IL-1β, or TNF-α compared with unstimulated DCs. However, LIGHT cooperates with CD154 (CD40 ligand) in DC maturation, with particular potentiation of allogeneic T cell proliferation and cytokine secretion of IL-12, IL-6, and TNF-α. Moreover, LIGHT costimulation allows DCs to prime in vitro-enhanced specific CTL responses. Our results suggest that LIGHT plays an important role in DC-mediated immune responses by regulating CD154 signals and represents a potential tool for DC-based cancer immunotherapy.
IFN-γ Induces the Apoptosis of WEHI 279 and Normal Pre-B Cell Lines by Expressing Direct Inhibitor of Apoptosis Protein Binding Protein with Low pI
Authors: Yoshikawa Hideshi , Nakajima Yasuo , Tasaka Kachio 
Published: April 2014

AbstractInterferon-γ plays a crucial role in induction of Th1 response but is predominantly a negative regulator of B cell differentiation and Th2 response, so it is a key molecule in determining cellular or humoral immunity. In this study, we demonstrate that IFN-γ induces apoptosis in WEHI 279 mouse B cells and IL-7-dependent mouse pre-B cells by disrupting mitochondrial membrane potential and cytochrome c release via down-regulation of Bcl-2 and Bcl-xL. Furthermore, this apoptotic signal is promoted by the de novo synthesis of endogenous direct inhibitor of apoptosis protein binding protein with low pI (DIABLO) by IFN-γ and its release from mitochondria into the cytosol. Inhibition of DIABLO expression by antisense oligonucleotide is sufficient to decrease caspase activities and DNA fragmentation, but not cytochrome c release from mitochondria, suggesting that DIABLO plays a critical role in promoting apoptotic signals downstream of mitochondrial events. Thus, these findings demonstrate a signaling pathway during B cell apoptosis induced by IFN-γ and possible mechanisms by which B cell differentiation is negatively regulated by Th1-type cytokines.
Double-Stranded RNA Regulates IL-4 Expression
Authors: Kehoe Kelly E. , Brown Melissa A. , Imani Farhad 
Published: April 2014

AbstractdsRNA, as genomic fragment, replicative intermediate, or stem and loop structure in cells infected by viruses, can act to signal the immune system of the presence of viral infections. Although most viral infections are associated with strong Th1 immune responses, Th2-type responses have also been observed. In this study, we characterize the effects of dsRNA on the induction of Th2 responses in human lymphocytes. We report that in addition to the well-known Th1-inducing capabilities of dsRNA, treatment of human lymphocytes with low concentrations of dsRNA (0.1–1 μg/ml) leads to the expression of the prototypic Th2 cytokine IL-4. This induction was accompanied with the concentration-dependent activation of NF-κB and NF-AT2 but not NF-AT1. In addition, dsRNA can directly activate an IL-4 promoter-driven chloramphenicol acetyltransferase reporter gene in transiently transfected Jurkat cells. These results are the first demonstration of a non-TCR-associated activator of NF-AT in human cells and suggest that dsRNA directly influences IL-4 gene expression through its effect on NF-AT activation. Our data provide support for the idea that dsRNA at low concentrations in vivo may induce a Th2-dominant response that is not optimal for protective immunity to the virus.