bluuebunny/crossref_metadata_2025_split huggingface dataset:
IFN-β Inhibits T Cell Activation Capacity of Central Nervous System APCs
Authors: Teige Ingrid , Liu Yawei , Issazadeh-Navikas Shohreh 
Published: April 2014

Abstract
We have previously investigated the physiological effects of IFN-β on chronic CNS inflammation and shown that IFN-β−/− mice develop a more severe experimental autoimmune encephalomyelitis than their IFN-β+/− littermates. This result was shown to be associated with a higher activation state of the glial cells and a higher T cell cytokine production in the CNS. Because this state suggested a down-regulatory effect of IFN-β on CNS-specific APCs, these results were investigated further. We report that IFN-β pretreatment of astrocytes and microglia (glial cells) indeed down-modulate their capacity to activate autoreactive Th1 cells. First, we investigated the intrinsic ability of glial cells as APCs and report that glial cells prevent autoreactive Th1 cells expansion while maintaining Ag-specific T cell effector functions. However, when the glial cells are treated with IFN-β before coculture with T cells, the effector functions of T cells are impaired as IFN-γ, TNF-α, and NO productions are decreased. Induction of the T cell activation marker, CD25 is also reduced. This suppression of T cell response is cell-cell dependent, but it is not dependent on a decrease in glial expression of MHC class II or costimulatory molecules. We propose that IFN-β might exert its beneficial effects mainly by reducing the Ag-presenting capacity of CNS-specific APCs, which in turn inhibits the effector functions of encephalitogenic T cells. This affect is of importance because activation of encephalitogenic T cells within the CNS is a prerequisite for the development of a chronic progressive CNS inflammation.
The Extracellular Membrane-Proximal Domain of Human Membrane IgE Controls Apoptotic Signaling of the B Cell Receptor in the Mature B Cell Line A20
Authors: Poggianella Monica , Bestagno Marco , Burrone Oscar R. 
Published: April 2014

Abstract
Ag engagement of BCR in mature B cells can deliver specific signals, which decide cell survival or cell death. Circulating membrane IgE+ (mIgE+) cells are found in extremely low numbers. We hypothesized that engagement of an εBCR in a mature isotype-switched B cell could induce apoptosis. We studied the role of the extracellular membrane-proximal domain (EMPD) of human mIgE upon BCR engagement with anti-Id Abs. Using mutants lacking the EMPD, we show that this domain is involved in controlling Ca2+ mobilization in immunoreceptors of both γ and ε isotypes, as well as apoptosis in signaling originated only from the εBCR. We mapped to the εCH4 ectodomain the region responsible for apoptosis in EMPD-deleted receptors. Ca2+ mobilization was not related to apoptotic signaling. This apoptotic pathway was caspase independent, involved ERK1/2 phosphorylation and was partially rescued by CD40 costimulation. We therefore conclude that the EMPD of human mIgE is a key control element of apoptotic signaling delivered through engagement of εBCR within the context of a mature B cell.
Protection from Type 1 Diabetes by Invariant NK T Cells Requires the Activity of CD4+CD25+ Regulatory T Cells
Authors: Ly Dalam , Mi Qing-Sheng , Hussain Shabbir , Delovitch Terry L. 
Published: April 2014

Abstract
Invariant NK T (iNKT) cells regulate immune responses, express NK cell markers and an invariant TCR, and recognize lipid Ags in a CD1d-restricted manner. Previously, we reported that activation of iNKT cells by α-galactosylceramide (α-GalCer) protects against type 1 diabetes (T1D) in NOD mice via an IL-4-dependent mechanism. To further investigate how iNKT cells protect from T1D, we analyzed whether iNKT cells require the presence of another subset(s) of regulatory T cells (Treg), such as CD4+CD25+ Treg, for this protection. We found that CD4+CD25+ T cells from NOD.CD1d−/− mice deficient in iNKT cell function similarly in vitro to CD4+CD25+ T cells from wild-type NOD mice and suppress the proliferation of NOD T responder cells upon α-GalCer stimulation. Cotransfer of NOD diabetogenic T cells with CD4+CD25+ Tregs from NOD mice pretreated with α-GalCer demonstrated that activated iNKT cells do not influence the ability of Tregs to inhibit the transfer of T1D. In contrast, protection from T1D mediated by transfer of activated iNKT cells requires the activity of CD4+CD25+ T cells, because splenocytes pretreated with α-GalCer and then inactivated by anti-CD25 of CD25+ cells did not protect from T1D. Similarly, mice inactivated of CD4+CD25+ T cells before α-GalCer treatment were also not protected from T1D. Our data suggest that CD4+CD25+ T cells retain their function during iNKT cell activation, and that the activity of CD4+CD25+ Tregs is required for iNKT cells to transfer protection from T1D.
Reduced Susceptibility of Recombinant Polyclonal Antibodies to Inhibitory Anti-Variable Domain Antibody Responses
Authors: Klitgaard Josephine L. , Coljee Vincent W. , Andersen Peter S. , Rasmussen Lone K. , Nielsen Lars S. , Haurum John S. , Bregenholt Søren 
Published: April 2014

Abstract
The immunogenicity of therapeutic Abs is a concern as anti-drug Abs may impact negatively on the pharmacodynamics and safety profile of Ab drugs. The factors governing induction of anti-drug Abs are not fully understood. In this study, we describe a model based on mouse-human chimeric Abs for the study of Ab immunogenicity in vivo. Six chimeric Abs containing human V regions and mouse C regions were generated from six human anti-Rhesus D Abs and the Ag-binding characteristics of the parental human Abs were retained. Analysis of the immune response toward the individual chimeric Abs revealed the induction of anti-variable domain Abs including anti-idiotypic Abs against some of these, thereby demonstrating the applicability of the model for studying anti-drug Ab responses in vivo. Immunization of BALB/c, C57, and outbred NMRI mice with a polyclonal composition consisting of all six chimeric Abs demonstrated that the immunogenicity of the individual Abs was haplotype dependent. Chimeric Abs, which were nonimmunogenic when administered individually, did not become immunogenic as part of the polyclonal composition, implying the absence of epitope spreading. Ex vivo Ab-binding studies established a clear correlation between the level of immunogenicity of the Abs comprised in the composition and the impact on the pharmacology of the Abs. These analyses demonstrate that under these conditions this polyclonal Ab composition was generally less susceptible to blocking Abs than the respective mAbs.
Evidence That Marginal Zone B Cells Possess an Enhanced Secretory Apparatus and Exhibit Superior Secretory Activity
Authors: Gunn Kathryn E. , Brewer Joseph W. 
Published: April 2014

Abstract
Marginal zone B (MZB) cells are the first splenic B cells to initiate Ab secretion against polysaccharide-encapsulated Ags in vivo. This swift MZB cell response can be reproduced in vitro as LPS treatment induces Ab secretion in as little as 12 h. Conversely, in vitro LPS treatment of splenic follicular B (FOB) cells results in Ab secretion after 2–3 days. The basis for these distinct response kinetics is not understood. We performed ex vivo analysis of resting and LPS-stimulated murine MZB and FOB cells and found that MZB cells express higher levels of the LPS TLR complex RP105/MD-1 and respond to much lower concentrations of LPS than do FOB cells. Furthermore, increasing doses of LPS do not accelerate the kinetics by which FOB cells transition into Ab secretion. Ultrastructural analysis of resting cells demonstrated that rough endoplasmic reticulum is more abundant in MZB cells than in FOB cells. Additionally, RT-PCR and immunoblot analyses revealed that numerous endoplasmic reticulum resident chaperones and folding enzymes are expressed at greater levels in resting MZB cells than in resting FOB cells. Although both LPS-stimulated MZB and FOB cells increase expression of these factors, MZB cells exhibit a more rapid increase that correlates with accelerated kinetics of Ab secretion and higher per cell output of secreted IgM. These data indicate that MZB cells are equipped for exquisite sensitivity to bacterial components like LPS and poised for rapid, robust Ab production, making MZB cells ideally suited as frontline defenders in humoral immunity.
Transgenic Expression of the Viral FLIP MC159 Causes lpr/gld-Like Lymphoproliferation and Autoimmunity
Authors: Woelfel Melissa , Bixby Jacqueline , Brehm Michael A. , Chan Francis Ka-Ming 
Published: April 2014

Abstract
Death receptor-induced programmed cell death (PCD) is crucial for the maintenance of immune homeostasis. However, interference of downstream death receptor signaling by genetic ablation or transgenic (Tg) expression of different apoptosis inhibitors often impairs lymphocyte activation. The viral FLICE (caspase-8)-like inhibitor proteins (v-FLIPs) are potent inhibitors of death receptor-induced apoptosis and programmed necrosis. We generated Tg mice expressing the v-FLIP MC159 from Molluscum contagiosum virus under the control of the H2Kb class I MHC promoter to examine the role of death receptor-induced PCD in the control of immune functions and homeostasis. We found that expression of MC159 led to lymphoproliferation and autoimmunity as exemplified by T and B lymphocyte expansion, accumulation of TCRαβ+CD3+B220+CD4−CD8− lymphocytes in secondary lymphoid organs, elevated serum Ig levels, and increased anti-dsDNA Ab titers. These phenotypes were caused by defective death receptor-induced apoptosis, but not by defective passive cell death in the absence of mitogenic stimulation. Lymphocyte activation was normal, as demonstrated by normal thymidine incorporation and CSFE dilution of T cells stimulated with anti-CD3 and anti-CD28 Abs. In addition, effector CD8+ T cell responses to acute and memory lymphocytic choriomeningitis virus infections were unaffected in the Tg mice. These phenotypes are reminiscent of the lpr and gld mice, and show that the v-FLIP MC159 is a bona fide PCD inhibitor that does not interfere with other essential lymphocyte functions. Thus, the MC159-Tg mice provide a model to study the effects of PCD in immune responses without hampering other important lymphocyte functions.
Evolution of the CD4 Family: Teleost Fish Possess Two Divergent Forms of CD4 in Addition to Lymphocyte Activation Gene-3
Authors: Laing Kerry J. , Zou Jun J. , Purcell Maureen K. , Phillips Ruth , Secombes Christopher J. , Hansen John D. 
Published: April 2014

Abstract
The T cell coreceptor CD4 is a transmembrane glycoprotein belonging to the Ig superfamily and is essential for cell-mediated immunity. Two different genes were identified in rainbow trout that resemble mammalian CD4. One (trout CD4) encodes four extracellular Ig domains reminiscent of mammalian CD4, whereas the other (CD4REL) codes for two Ig domains. Structural motifs within the amino acid sequences suggest that the two Ig domains of CD4REL duplicated to generate the four-domain molecule of CD4 and the related gene, lymphocyte activation gene-3. Here we present evidence that both of these molecules in trout are homologous to mammalian CD4 and that teleosts encode an additional CD4 family member, lymphocyte activation gene-3, which is a marker for activated T cells. The syntenic relationships of similar genes in other teleost and non-fish genomes provide evidence for the likely evolution of CD4-related molecules in vertebrates, with CD4REL likely representing the primordial form in fish. Expression of both CD4 genes is highest in the thymus and spleen, and mRNA expression of these genes is limited to surface IgM− lymphocytes. consistent with a role for T cell functionality. Finally, the intracellular regions of both CD4 and CD4REL possess the canonical CXC motif involved in the interaction of CD4 with p56LCK, implying that similar mechanisms for CD4+ T cell activation are present in all vertebrates. Our results therefore raise new questions about T cell development and functionality in lower vertebrates that cannot be answered by current mammalian models and, thus, is of fundamental importance for understanding the evolution of cell-mediated immunity in gnathosomes.
Requirements for Apoptotic Cell Contact in Regulation of Macrophage Responses
Authors: Lucas Mark , Stuart Lynda M. , Zhang Ailiang , Hodivala-Dilke Kairbaan , Febbraio Maria , Silverstein Roy , Savill John , Lacy-Hulbert Adam 
Published: April 2014

Abstract
An important consequence of macrophage engulfment of apoptotic cells is suppression of inflammatory responses, which was first defined by assay of TNF-α release stimulated by LPS. These effects are apparently mediated in part by paracrine effects of TGF-β released by the subset of stimulated macrophages that ingest apoptotic cells, which suppresses neighboring cells. However, the apoptotic cell-derived signal that stimulates TGF-β release, and the nature of any additional signals required for the anti-inflammatory response remain poorly defined. In this study, we investigate the requirements for apoptotic cell engagement of macrophage surface receptors in these responses. We show that the apoptotic cell receptors CD36 and αvβ3 contribute to apoptotic cell phagocytosis by mouse macrophages, but are not essential for anti-inflammatory responses, suggesting that the mechanisms of response and phagocytosis are separate. In further defining requirements for response, we confirm the importance of TGF-β in suppression by apoptotic cells, and identify an additional level of control of these effects. We show that LPS-stimulated mouse macrophage TNF-α release is only suppressed if macrophages have first contacted apoptotic cells, and hence, bystander macrophages are refractory to TGF-β released by phagocytosing macrophages. We conclude that the profound suppression of LPS-driven TNF-α release by macrophage populations requires hitherto obscure contact-dependent licensing of macrophage responsiveness to TGF-β by apoptotic cells.
Induction of RelB Participates in Endotoxin Tolerance
Authors: Yoza Barbara K. , Hu Jean Y.-Q. , Cousart Sue L. , Forrest Lolita M. , McCall Charles E. 
Published: April 2014

Abstract
Using a THP-1 human promonocyte model of endotoxin tolerance that simulates the sepsis leukocyte phenotype, we previously showed that tolerant cells remain responsive to LPS endotoxin with degradation of IκB in the cytosol and nuclear translocation and accumulation of p50 and p65 NF-κB transcription factors. Despite this, endotoxin-inducible NF-κB-dependent innate immunity genes, like IL-1β, remained transcriptionally unresponsive in the tolerant phenotype, similar to the endotoxin tolerance observed in sepsis patients. In this study, we examined this paradox and found that RelB, another member of the NF-κB family, is induced during the establishment of tolerance. RelB expression correlated with IL-1β repression, and sepsis patients showed increased RelB when compared with normal controls. Transient expression of RelB inhibited IL-1β in endotoxin-responsive cells. In the inverse experiment, small inhibitory RNAs decreased RelB expression in tolerant cells and restored endotoxin induction of IL-1β. When we examined tolerant cell extracts, we found transcriptionally inactive NF-κB p65/RelB heterodimers. Taken together, our findings demonstrate that RelB can repress proinflammatory gene expression, and suggest that RelB expression in sepsis patient blood leukocytes may play a role in the endotoxin-tolerant phenotype.
MaxiK Blockade Selectively Inhibits the Lipopolysaccharide-Induced IκB-α/NF-κB Signaling Pathway in Macrophages
Authors: Papavlassopoulos Martin , Stamme Cordula , Thon Lutz , Adam Dieter , Hillemann Doris , Seydel Ulrich , Schromm Andra B. 
Published: April 2014

Abstract
Macrophages have a pivotal function in innate immunity against bacterial infections. They are present in all body compartments and able to detect invading microorganisms with high sensitivity. LPS (endotoxin) of Gram-negative bacteria is among the most potent stimuli for macrophages and initiates a wide panel of cellular activation responses. The release of mediators such as TNF-α and ILs is essential for the initiation of a proinflammatory antibacterial response. Here, we show that blockade of the large-conductance Ca2+-activated potassium channel MaxiK (BK) inhibited cytokine production from LPS-stimulated macrophages at the transcriptional level. This inhibitory effect of channel blockade was specific to stimulation with LPS and affected neither stimulation of macrophages with the cytokine TNF-α nor LPS-induced activation of cells that do not express MaxiK. Investigation of the upstream intracellular signaling pathways induced by LPS revealed that the blockade of MaxiK selectively inhibited signaling pathways leading to the activation of the transcription factor NF-κB and the MAPK p38, whereas activation of ERK was unaffected. We present data supporting that proximal regulation of the inhibitory factor IκB-α is critically involved in the observed inhibition of NF-κB translocation. Using alveolar macrophages from rats, we could show that the necessity of MaxiK function in activation of NF-κB and subsequent cytokine production is not restricted to in vitro-generated monocyte-derived macrophages but also can be observed in primary cells. Thus, MaxiK appears to be a central molecule in the NF-κB-dependent inflammatory response of macrophages to bacterial LPS.
Mannose-Binding Lectin Contributes to the Severity of Guillain-Barré Syndrome
Authors: Geleijns Karin , Roos Anja , Houwing-Duistermaat Jeanine J. , van Rijs Wouter , Tio-Gillen Anne P. , Laman Jon D. , van Doorn Pieter A. , Jacobs Bart C. 
Published: April 2014

AbstractIn Guillain-Barré syndrome (GBS), complement activation plays a crucial role in the induction and extent of the postinfectious immune-mediated peripheral nerve damage. Mannose-binding lectin (MBL) activates the complement system via the lectin pathway after recognition of repetitive sugar groups on pathogens. We investigated whether the MBL2 genotype, serum MBL level, and MBL complex activity are associated with the development and severity of GBS. Single nucleotide polymorphisms in the promoter region (−550 H/L and −221 X/Y) and exon 1 (A/O) of the MBL2 gene were determined in 271 GBS patients and 212 healthy controls. The frequencies of the H allele, HY promoter haplotype, and HYA haplotype, which are related to high MBL activity, were all increased in GBS patients compared with healthy controls (p ≤ 0.03), particularly in severely affected GBS patients (MRC-sum score &lt;40) (p ≤ 0.02). Severe weakness was also associated with high MBL concentrations and MBL complex activity in sera from GBS patients (p &lt; 0.01). The MBL2 B allele was associated with functional deficiency and relatively mild weakness. These results support the hypothesis that complement activation mediated by MBL contributes to the extent of nerve damage in GBS, which is codetermined by the MBL2 haplotype.
Cutting Edge: IL-7-Independent Regulation of IL-7 Receptor α Expression and Memory CD8 T Cell Development
Authors: Klonowski Kimberly D. , Williams Kristina J. , Marzo Amanda L. , Lefrançois Leo 
Published: April 2014

Abstract
Expression of IL-7Rα on a subset of Ag-specific effector CD8 T cells is believed to identify memory cell precursors. However, whether IL-7 regulates IL-7Rα expression in vivo and is responsible for selective survival of IL-7Rα+ effector cells is unknown. Our results show that in the absence of IL-7, IL-7Rα expression was extinguished on the majority of CD8 T cells responding to virus infection, sustained on a subset of effector cells transitioning to memory, and expressed at high levels by memory cells. Additionally, an IL-7-deficient environment was capable of supporting bcl-2 up-regulation and memory cell development in response to virus infection. Thus, IL-7Rα regulation occurs independently of IL-7 in responding CD8 T cells, indicating that CD8 memory T cell precursors are not selected by IL-7/IL-7Rα interactions.
The Human CD77− B Cell Population Represents a Heterogeneous Subset of Cells Comprising Centroblasts, Centrocytes, and Plasmablasts, Prompting Phenotypical Revision
Authors: Högerkorp Carl-Magnus , Borrebaeck Carl A. K. 
Published: April 2014

Abstract
The process of becoming an Ig-producing plasma cell takes the mature B cell through the germinal center, where Ig genes are diversified through somatic hypermutation and class switch recombination. To more clearly define functional characteristics of the germinal center dark zone centroblasts and the light zone centrocytes, we have performed expression analysis of the CD77+ and CD77− populations, because CD77 has been accepted as a discriminator of centroblasts and centrocytes. Our results demonstrated that the CD77+ and the CD77− populations lack functional associated expression programs discriminating the two populations. Both populations are shown to be actively cycling and to share common features associated with cell cycle regulation and DNA maintenance. They are also shown to have an equally active DNA repair program, as well as components involved in somatic hypermutation and class switch recombination. Moreover, the data also demonstrated that the CD77− population comprises cells with an already initiated plasma cell differentiation program. Together this demonstrates that CD77 does not discriminate centroblasts and centrocytes and that the CD77− population represents a heterogeneous subset of cells, comprising centroblasts, centrocytes, and plasmablast.
A Large T Cell Invagination with CD2 Enrichment Resets Receptor Engagement in the Immunological Synapse
Authors: Singleton Kentner , Parvaze Nadia , Dama Kavyya R. , Chen Kenneth S. , Jennings Paula , Purtic Bozidar , Sjaastad Michael D. , Gilpin Christopher , Davis Mark M. , Wülfing Christoph 
Published: April 2014

AbstractT cell activation is driven by the TCR and complemented by costimulation. We have studied the dynamics of ligand-engagement of the costimulatory receptor CD2 in T cell/APC couples. Thousands of ligand-engaged CD2 molecules were included in a large T cell invagination at the center of the cellular interface within 1 min of cell couple formation. The structure and regulation of this invagination shared numerous features with phagocytosis and macropinocytosis. Three observations further characterize the invagination and the inclusion of CD2: 1) numerous ligand-engaged receptors were enriched in and internalized through the T cell invagination, none as prominently as CD2; 2) dissolution of the T cell invagination and CD2 engagement were required for effective proximal T cell signaling; and 3) the T cell invagination was uniquely sensitive to the affinity of the TCR for peptide-MHC. Based on this characterization, we speculate that the T cell invagination, aided by CD2 enrichment, internalizes parts of the TCR signaling machinery to reset T cell signaling upon agonist-mediated, stable APC contact.