bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Immunodominant, Ld-Restricted T Cell Response to Hepatitis B Surface Antigen (HBsAg) Efficiently Suppresses T Cell Priming to Multiple Dd-, Kd-, and Kb-Restricted HBsAg Epitopes
Authors: Schirmbeck Reinhold , Stober Detlef , El Kholy Shereen , Riedl Petra , Reimann Jörg 
Published: April 2014

AbstractMHC-I-restricted CTL responses of H-2d (Ld+ or Ld−) and F1 H-2dxb mice to hepatitis B surface Ag (HBsAg) are primed by either DNA vaccines or HBsAg particles. The Dd/S201–209 and Kd/S199–208 epitopes are generated by processing endogenous HBsAg; the Kb/S208–215 epitope is generated by processing exogenous HBsAg; and the Ld/S28–39 epitope is generated by exogenous as well as endogenous processing of HBsAg. DNA vaccination primed high numbers of CTL specific for the Ld/S28–39 HBsAg epitope, low numbers of CTL specific for the Dd/S201–209 or Kd/S199–208 HBsAg epitopes in BALB/c mice, and high numbers of Dd/S201–209- and Kd/S199–208-specific CTL in congenic H-2d/Ld− dm2 mice. In F1dxb mice, the Kd-, Dd-, and Kb-restricted CTL responses to HBsAg were strikingly suppressed in the presence but efficiently elicited in the absence of Ld/S28–39-specific CTL. Once primed, the Kd- and Dd-restricted CTL responses to HBsAg were resistant to suppression by immunodominant Ld/S28–39-specific CTL. The Ld-restricted immunodominant CTL reactivity to HBsAg can thus suppress priming to multiple alternative epitopes of HBsAg, independent of the processing pathway that generates the epitope, of the background of the mouse strain used, and of the presence/absence of different allelic variants of the K and D MHC class I molecules.
An Abortive Ligand-Induced Activation of CCR1-Mediated Downstream Signaling Event and a Deficiency of CCR5 Expression Are Associated with the Hyporesponsiveness of Human Naive CD4+ T Cells to CCL3 and CCL5
Authors: Sato Katsuaki , Kawasaki Hiroshi , Morimoto Chikao , Yamashima Naohide , Matsuyama Takami 
Published: April 2014

AbstractHuman memory CD4+ T cells respond better to inflammatory CCLs/CC chemokines, CCL3 and CCL5, than naive CD4+ T cells. We analyzed the regulatory mechanism underlying this difference. Memory and naive CD4+ T cells expressed similarly high levels of CCR1; however, CCR5 was only expressed in memory CD4+ T cells at low levels. Experiments using mAbs to block chemokine receptors revealed that CCR1 functioned as a major receptor for the binding of CCL5 in memory and naive CD4+ T cells as well as the ligand-induced chemotaxis in memory CD4+ T cells. Stimulation of memory CD4+ T cells with CCL5 activated protein tyrosine kinase-dependent cascades, which were significantly blocked by anti-CCR1 mAb, whereas this stimulation failed to induce these events in naive CD4+ T cells. Intracellular expressions of regulator of G protein signaling 3 and 4 were only detected in naive CD4+ T cells. Pretreatment of cell membrane fractions from memory and naive CD4+ T cells with GTP-γS inhibited CCL5 binding, indicating the involvement of G proteins in the interaction of CCL5 and its receptor(s). In contrast, CCL5 enhanced the GTP binding to Giα and Gqα in memory CD4+ T cells, but not in naive CD4+ T cells. Thus, a failure of the ligand-induced activation of CCR1-mediated downstream signaling event as well as a deficiency of CCR5 expression may be involved in the hyporesponsiveness of naive CD4+ T cells to CCL3 and CCL5.
Functional Analysis of the Human Complement Receptor 2 (CR2/CD21) Promoter: Characterization of Basal Transcriptional Mechanisms
Authors: Ulgiati Daniela , Pham Christine , Holers V. Michael 
Published: April 2014

AbstractHuman complement receptor (CR) type 2 (CR2/CD21) is a 145-kDa membrane protein encoded within the regulators of complement activation gene cluster localized on human chromosome 1q32. Understanding the mechanisms that regulate CR2 expression is important because CR2 is expressed during specific stages of B cell development, and several lines of evidence suggest a role for altered CR2 function or expression in a number of autoimmune diseases. Additionally, even modest changes in CR2 expression are likely to affect relative B cell responses. In this study we have delineated the transcriptional requirements of the human CR2 gene. We have studied the human CR2 proximal promoter and identified sites important for controlling the level of transcription in CR2-expressing cells. We have determined that four functionally relevant sites lie within very close proximity to the transcriptional initiation site. These sites bind the transcription factors USF1, an AP-2-like transcription factor, and Sp1.
VpreB1/VpreB2/λ5 Triple-Deficient Mice Show Impaired B Cell Development but Functional Allelic Exclusion of the IgH Locus
Authors: Shimizu Takeyuki , Mundt Cornelia , Licence Steve , Melchers Fritz , Mårtensson Inga-Lill 
Published: April 2014

Abstract
At the precursor B cell stage during bone marrow B cell development, Ig μH chain associates with surrogate L (SL) chain, which is encoded by the three genes VpreB1, VpreB2, and λ5, to form the pre-B cell receptor (pre-BCR). Surface expression of the pre-BCR is believed to signal both proliferation and allelic exclusion of the IgH locus. Mice which lack either VpreB1/VpreB2 or λ5 show a lack of precursor B cell expansion but normal IgH allelic exclusion. This would suggest that one of either λ5 or VpreB can make a pre-BCR-like complex which is still able to signal allelic exclusion but not proliferation. To investigate this, we established mice lacking all components of the SL chain. These mice showed severely impaired B cell development which was similar to that previously found in mice lacking either λ5 or VpreB1/VpreB2. Surprisingly, the IgH locus was still allelically excluded and thus the SL chain appears not to be involved in allelic exclusion.
Characterization of Mouse and Human B7-H3 Genes
Authors: Sun Mingyi , Richards Sabrina , Prasad Durbaka V. R. , Mai Xoi Muoi , Rudensky Alexander , Dong Chen 
Published: April 2014

Abstract
T cell activation and immune function are regulated by costimulatory molecules of the B7 superfamily. Human B7-H3 is a recent addition to this family and has been shown to mediate T cell proliferation and IFN-γ production. In this work we describe the identification of the mouse B7-H3 homolog, which is ubiquitously expressed in a variety of tissues. Activated CD4 and CD8 T cells express a putative receptor that can be recognized by soluble mouse B7-H3-Ig molecules. While the mouse B7-H3 gene was found to contain a single copy, we discovered a novel isoform of human B7-H3 (named as B7-H3b hereafter) with four Ig-like domains that results from gene duplication and differential splicing. B7-H3b is the major isoform expressed in several tissues. This structural information suggests a genetic variation of the B7-H3 gene in mammalian species.
B Cell Receptor- and β2-Adrenergic Receptor-Induced Regulation of B7-2 (CD86) Expression in B Cells
Authors: Kohm Adam P. , Mozaffarian Afsaneh , Sanders Virginia M. 
Published: April 2014

AbstractThe costimulatory molecule B7-2 (CD86) is expressed on the surface of APCs, including B cells. Considering the importance of B7-2 in regulating both T and B cell function, it may be important to understand the regulatory mechanisms governing its expression. We report in this study that stimulation of the B cell receptor (BCR) and/or a neurotransmitter receptor, the β2-adrenergic receptor (β2AR), may cooperate to regulate B cell-associated B7-2 expression in vitro and in vivo. β2AR stimulation further enhanced the level of BCR-induced B7-2 expression in B cells potentially via protein tyrosine kinase-, protein kinase A-, protein kinase C-, and mitogen-activated protein kinase-dependent mechanisms. Importantly, BCR and/or β2AR stimulation, but not histone hyperacetylation and DNA hypomethylation alone, increased B cell-associated B7-2 expression by increasing B7-2 mRNA stability, NF-κB nuclear binding, and NF-κB-dependent gene transcription. Thus, this study provides additional insight into the signaling intermediates and molecular mechanisms by which stimulation of the BCR and β2AR may regulate B cell-associated B7-2 expression.
A Founder Mutation in Artemis, an SNM1-Like Protein, Causes SCID in Athabascan-Speaking Native Americans
Authors: Li Lanying , Moshous Despina , Zhou Yungui , Wang Junhua , Xie Gang , Salido Eduardo , Hu Diana , de Villartay Jean-Pierre , Cowan Morton J. 
Published: April 2014

Abstract
Athabascan SCID (SCIDA) is an autosomal recessive disorder found among Athabascan-speaking Native Americans and is manifested by the absence of both T and B cells (T−B−NK+ SCID). We previously mapped the SCIDA gene to a 6.5-cM interval on chromosome 10p. SCIDA fibroblasts were found to have defective coding joint and reduced, but precise signal joint formation during V(D)J recombination. After excluding potential candidate genes, we conducted a combined positional candidate and positional cloning approach leading to the identification of nine novel transcripts in the refined SCIDA region. One of the transcripts showed significant homology with the mouse and yeast SNM1/PSO2 and was recently reported (Artemis) to be responsible for another T−B−NK+ SCID condition (radiation sensitive SCID) in 13 patients of primarily European origin. In our evaluation of this gene, we have identified a unique nonsense mutation in 21 SCIDA patients that is closely correlated to the founder haplotypes that we had previously identified. This nonsense founder mutation results in the truncation of the deduced protein product. The wild-type construct of the primary transcript can effectively complement the defective coding joint and reduced signal joint formation in SCIDA fibroblasts. The above results indicate that this SNM1-like gene (Artemis) is the gene responsible for SCIDA. We also discovered three additional alternative exons and detected at least six alternatively spliced SCIDA variants (SCIDA-V1, 2, 3, 4, 5, and 6) coexisting with the primary transcript in trace amounts. Finally, we found that the SCIDA primary transcript (Artemis) encodes a nuclear protein.
Signaling Through Integrin LFA-1 Leads to Filamentous Actin Polymerization and Remodeling, Resulting in Enhanced T Cell Adhesion
Authors: Porter Joanna C. , Bracke Madelon , Smith Andrew , Davies Derek , Hogg Nancy 
Published: April 2014

AbstractThe integrins can activate signaling pathways, but the final downstream outcome of these pathways is often unclear. This study analyzes the consequences of signaling events initiated by the interaction of the leukocyte integrin LFA-1 with its ligand, dimeric ICAM-1. We show that the active form of LFA-1 regulates its own function on primary human T cells by directing the remodeling of the F-actin cytoskeleton to strengthen T cell adhesion to ICAM-1. Confocal microscopy revealed that both F-actin bundling and overall levels of F-actin are increased in the ICAM-1-adhering T cells. This increase in F-actin levels and change in F-actin distribution was quantitated for large numbers of T cells using the technique of laser scanning cytometry and was found to be significant. The study went on to show that clustering of conformationally altered LFA-1 is essential for the changes in F-actin, and a model is proposed in which clustered, high-avidity T cell LFA-1, interacting with multivalent ICAM-1, causes LFA-1 signaling, which results in F-actin polymerization and higher-order F-actin bundling. The findings demonstrate that LFA-1 acts not only as an adhesion receptor but also as a signaling receptor by actively initiating the F-actin reorganization that is essential for many T cell-dependent processes.
Synaptic Transfer by Human γδ T Cells Stimulated with Soluble or Cellular Antigens
Authors: Espinosa Eric , Tabiasco Julie , Hudrisier Denis , Fournié Jean-Jacques 
Published: April 2014

AbstractB, αβ T, and NK lymphocytes establish immunological synapses (IS) with their targets to enable recognition. Transfer of target cell-derived Ags together with proximal molecules onto the effector cell appears also to occur through synapses. Little is known about the molecular basis of this transfer, but it is assumed to result from Ag receptor internalization. Because human γδ T cells recognize soluble nonpeptidic phosphoantigens as well as tumor cells such as Daudi, it is unknown whether they establish IS with, and extract molecules from, target cells. Using flow cytometry and confocal microscopy, we show in this work that Ag-stimulated human Vγ9/Vδ2 T cells conjugate to, and perform molecular transfer from, various tumor cell targets. The molecular transfer appears to be linked to IS establishment, evolves in a dose-dependent manner in the presence of either soluble or cellular Ag, and requires γδ TCR ligation, Src family kinase signaling, and participation of the actin cytoskeleton. Although CD45 exclusion characterized the IS performed by γδ T cells, no obvious capping of the γδ TCR was detected. The synaptic transfer mediated by γδ T cells involved target molecules unrelated to the cognate Ag and occurred independently of MHC class I expression by target cells. From these observations, we conclude thatm despite the particular features of γδ T cell activation, both synapse formation and molecular transfer of determinants belonging to target cell characterize γδ T cell recognition of Ags.
Mycobacterium tuberculosis Promotes Apoptosis in Human Neutrophils by Activating Caspase-3 and Altering Expression of Bax/Bcl-xL Via an Oxygen-Dependent Pathway
Authors: Perskvist Nasrin , Long Min , Stendahl Olle , Zheng Limin 
Published: April 2014

Abstract
In addition to direct bactericidal activities, such as phagocytosis and generation of reactive oxygen species (ROS), neutrophils can regulate the inflammatory response by undergoing apoptosis. We found that infection of human neutrophils with Mycobacterium tuberculosis (Mtb) induced rapid cell death displaying the characteristic features of apoptosis such as morphologic changes, phosphatidylserine exposure, and DNA fragmentation. Both a virulent (H37Rv) and an attenuated (H37Ra) strain of Mtb were equally effective in inducing apoptosis. Pretreatment of neutrophils with antioxidants or an inhibitor of NADPH oxidase markedly blocked Mtb-induced apoptosis but did not affect spontaneous apoptosis. Activation of caspase-3 was evident in neutrophils undergoing spontaneous apoptosis, but it was markedly augmented and accelerated during Mtb-induced apoptosis. The Mtb-induced apoptosis was associated with a speedy and transient increase in expression of Bax protein, a proapoptotic member of the Bcl-2 family, and a more prominent reduction in expression of the antiapoptotic protein Bcl-xL. Pretreatment with an inhibitor of NADPH oxidase distinctly suppressed the Mtb-stimulated activation of caspase-3 and alteration of Bax/Bcl-xL expression in neutrophils. These results indicate that infection with Mtb causes ROS-dependent alteration of Bax/Bcl-xL expression and activation of caspase-3, and thereby induces apoptosis in human neutrophils. Moreover, we found that phagocytosis of Mtb-induced apoptotic neutrophils markedly increased the production of proinflammatory cytokine TNF-α by human macrophages. Therefore, the ROS-dependent apoptosis in Mtb-stimulated neutrophils may represent an important host defense mechanism aimed at selective removal of infected cells at the inflamed site, which in turn aids the functional activities of local macrophages.
Protection fromStreptococcus pneumoniaeInfection by C-Reactive Protein and Natural Antibody Requires Complement But Not Fcγ Receptors
Authors: Mold Carolyn , Rodic-Polic Bojana , Du Clos Terry W. 
Published: April 2014

AbstractStreptococcus pneumoniae is an important human pathogen and the most common cause of community-acquired pneumonia. Both adaptive and innate immune mechanisms provide protection from infection. Innate immunity to S. pneumoniae in mice is mediated by naturally occurring anti-phosphocholine (PC) Abs and complement. The human acute-phase reactant C-reactive protein (CRP) also protects mice from lethal S. pneumoniae infection. CRP and anti-PC Ab share the ability to bind to PC on the cell wall C-polysaccharide of S. pneumoniae and to activate complement. CRP and IgG anti-PC also bind to FcγR. In this study, FcγR- and complement-deficient mice were used to compare the mechanisms of protection conferred by CRP and anti-PC Ab. Injection of CRP protected wild-type, FcRγ-chain-, FcγRIIb-, and FcγRIII-deficient mice from infection. Complement was required for the protective effect of CRP as cobra venom factor treatment eliminated the effect of CRP in both γ-chain-deficient and wild-type mice, and CRP failed to protect C3- or C4-deficient mice from infection. Unexpectedly, γ-chain-deficient mice were extremely sensitive to pneumococcal infection. This sensitivity was associated with low levels of natural anti-PC Ab. γ-chain-deficient mice immunized with nonencapsulated S. pneumoniae produced both IgM- and IgG PC-specific Abs, were protected from infection, and were able to clear the bacteria from the bloodstream. The protection provided by immunization was eliminated by complement depletion. The results show that in this model of systemic infection with highly virulent S. pneumoniae, protection from lethality by CRP and anti-PC Abs requires complement, but not FcγR.
Organ-Specific CD4+ T Cell Response DuringListeria monocytogenesInfection
Authors: Kursar Mischo , Bonhagen Kerstin , Köhler Anne , Kamradt Thomas , Kaufmann Stefan H. E. , Mittrücker Hans-Willi 
Published: April 2014

AbstractThe immune response against the intracellular bacterium Listeria monocytogenes involves both CD4+ and CD8+ T cells. We used the MHC class II-presented peptide listeriolysin189–201 to characterize the organ-specific CD4+ T cell response during infection. Systemic listeriosis resulted in a strong peptide-specific CD4+ T cell response with frequencies of 1/100 and 1/30 CD4+ splenocytes at the peak of primary and secondary response, respectively. This response was not restricted to lymphoid organs, because we detected specific CD4+ T cells in all tissues analyzed. However, the tissue distribution of the T cell response was dependent on the route of infection. After i.v. infection, the strongest CD4+ T cell response and the highest levels of memory cells were observed in spleen and liver, the major sites of L. monocytogenes replication. After oral infection, we detected a strong response in the liver, the lamina propria, and the intestinal epithelium. These tissues also harbored the highest frequencies of listeriolysin189–201-specific CD4+ memory T cells 5–8 wk post oral infection. Our results show that kinetics and magnitude of the CD4+ T cell response and the accumulation of CD4+ memory T cells depend on the route of infection and are regulated in a tissue-specific way.
Involvement of Suppressor of Cytokine Signaling-3 as a Mediator of the Inhibitory Effects of IL-10 on Lipopolysaccharide-Induced Macrophage Activation
Authors: Berlato Chiara , Cassatella Marco A. , Kinjyo Ichiko , Gatto Luana , Yoshimura Akihiko , Bazzoni Flavia 
Published: April 2014

AbstractPrevious studies have shown that IL-10 can induce the expression of the suppressor of cytokine signaling 3 (SOCS-3) mRNA in human monocytes and neutrophils, suggesting that the capacity of IL-10 to inhibit the expression of LPS-inducible proinflammatory genes may depend on SOCS-3 induction. However, no direct experimental evidence has been provided to support such hypothesis. Herein, we show that stable transfection of SOCS-3 into the mouse macrophage cell line J774 resulted in an inhibition of NO, TNF-α, IL-6, and GM-CSF secretion in response to LPS at levels similar to those exerted by IL-10 in LPS-stimulated wild-type J774. Constitutive SOCS-3 expression also down-regulated the mRNA expression of inducible NO synthase and IL-6 and impaired the production of TNF-α, mainly at a post-transcriptional level. In addition, SOCS-3-transfected cells displayed a constitutive expression of the IL-1R antagonist gene, consistent with the observation that IL-10 enhances IL-1R antagonist mRNA in LPS-stimulated wild-type cells. Furthermore, in peritoneal macrophages harvested from mice carrying heterozygous disruption of the SOCS-3 gene, IL-10 was less effective in repressing LPS-stimulated TNF-α and NO production. Taken together, our data show that SOCS-3 inhibits LPS-induced macrophage activation, strongly supporting the idea that it plays a role in the molecular mechanism by which IL-10 down-modulates the effector functions of LPS-activated macrophages. Finally, we show that forced expression of SOCS-3 significantly suppresses the ability of IL-10 to trigger tyrosine phosphorylation of STAT3. Therefore, SOCS-3 functions both as an LPS signal inhibitor and as a negative feedback regulator of IL-10/STAT3 signaling.
Nerve Growth Factor Activates Mast Cells Through the Collaborative Interaction with Lysophosphatidylserine Expressed on the Membrane Surface of Activated Platelets
Authors: Kawamoto Keiko , Aoki Junken , Tanaka Akane , Itakura Atsuko , Hosono Hiroyuki , Arai Hiroyuki , Kiso Yasuo , Matsuda Hiroshi 
Published: April 2014

AbstractEffect of nerve growth factor (NGF) on platelet-associated mast cell activation was investigated. Although neither NGF alone nor platelets alone induced significant 5-hydroxytriptamine (5-HT) release from rat peritoneal mast cells, marked 5-HT release was detected when costimulated with NGF and calcium ionophore-activated platelets. This response reached maximal levels as early as 5 min after the initiation of the coincubation and was completely blocked by anti-NGF Ab or by an inhibitor for a tyrosine kinase of the trkA NGF receptor. Paraformaldehyde-fixed platelets activated with either calcium ionophore or thrombin exhibited the collaborative ability, suggesting the possible involvement of some membrane molecules expressed on activated platelets in mast cell activation. Because activation of platelets induced expression of phosphatidylserine (PS) and/or lysoPS on membrane surface, and since lysoPS, unlike PS, initiated the NGF-induced 5-HT release, lysoPS expressed on activated platelets may be involved in the mast cell activation. Moreover, intradermal injection of NGF and activated platelets into the rat skin increased local vascular permeability. These findings suggested that NGF collaboratively worked with membrane lysoPS of activated platelets to induce mast cell activation. Thus, NGF released in response to inflammatory stimuli may contribute to mast cell activation in collaboration with locally activated platelets in the process of inflammations and tissue repair.