bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Lymphocyte Receptor CD6 Interacts with Syntenin-1, a Scaffolding Protein Containing PDZ Domains
Authors: Gimferrer Idoia , Ibáñez Anna , Farnós Montse , Sarrias Maria-Rosa , Fenutría Rafael , Roselló Sandra , Zimmermann Pascale , David Guido , Vives Jordi , Serra-Pagès Carles , Lozano Francisco 
Published: April 2014

Abstract
CD6 is a type I membrane glycoprotein expressed on thymocytes, mature T and B1a lymphocytes, and CNS cells. CD6 binds to activated leukocyte cell adhesion molecule (CD166), and is considered as a costimulatory molecule involved in lymphocyte activation and thymocyte development. Accordingly, CD6 partially associates with the TCR/CD3 complex and colocalizes with it at the center of the mature immunological synapse (IS) on T lymphocytes. However, the signaling pathway used by CD6 is still mostly unknown. The yeast two-hybrid system has allowed us the identification of syntenin-1 as an interacting protein with the cytoplasmic tail of CD6. Syntenin-1 is a PDZ (postsynaptic density protein-95, postsynaptic discs large, and zona occludens-1) domain-containing protein, which functions as an adaptor protein able to bind cytoskeletal proteins and signal transduction effectors. Mutational analyses showed that certain amino acids of the most C-terminal sequence of CD6 (-YDDISAA) and the two postsynaptic density protein-95, postsynaptic discs large, and zona occludens-1 domains of syntenin-1 are relevant to the interaction. Further confirmation of the CD6-syntenin-1 interaction was obtained from pull-down and coimmunoprecipitation assays in mammalian cells. Image analyses also showed that syntenin-1 accumulates at CD6 caps and at the IS. Therefore, we propose that syntenin-1 may function as a scaffolding protein coupling CD6 and most likely other lymphocyte receptors to cytoskeleton and/or signaling effectors during IS maturation.
Failed Up-Regulation of the Inhibitory IgG Fc Receptor FcγRIIB on Germinal Center B Cells in Autoimmune-Prone Mice Is Not Associated with Deletion Polymorphisms in the Promoter Region of the FcγRIIB Gene
Authors: Rahman Ziaur S. M. , Manser Tim 
Published: April 2014

Abstract
FcγRIIB, a low-affinity FcR for IgG, inhibits BCR-mediated activation when these two receptors are cocross-linked by Ags and IgG-containing immune complexes. Although a role for FcγRIIB in the germinal center (GC) reaction has been proposed, conflicting results have been published regarding the levels of FcγRIIB expressed on GC B cells in normal and autoimmune-prone mice and humans. In the present study, we investigate this issue in detail in mice by using multiple GC B cell markers, two different antigenic systems, primary and secondary GC responses, and by excluding the influence of splenic influx of immature B cells and passive acquisition of FcγRIIB from follicular dendritic cells. Our results are in concordance with previous data indicating that FcγRIIB expression is up-regulated on GC B cells in normal mice. In contrast, we observe comparable levels of FcγRIIB on GC and non-GC B cells in New Zealand White, New Zealand Black, and B6.Sle1 autoimmune-prone strains. Therefore, we suggest that these strains exhibit failed up-regulation of FcγRIIB on GC B cells, rather than down-regulation, as previously suggested. Also, in contrast to previous indications, this perturbed regulation is not uniquely associated with deletion polymorphisms in the promoter region of the FcγRIIB gene but does appear to be independent of genetic background. Finally, we present evidence indicating that FcγRIII, a low-affinity activating IgG FcR, is expressed on the GC B cells of normal but not autoimmune-prone mice.
IgE Enhances Antibody and T Cell Responses In Vivo via CD23+ B Cells
Authors: Getahun Andrew , Hjelm Fredrik , Heyman Birgitta 
Published: April 2014

AbstractIgE Abs, passively administered together with their specific Ag, can enhance the production of Abs recognizing this Ag by &gt;100-fold. IgE-mediated feedback enhancement requires the low affinity receptor for IgE, CD23. One possible mechanism is that B cells take up IgE-Ag via CD23 and efficiently present Ag to Th cells, resulting in better Ab responses. To test whether IgE Abs have an effect on Th cells in vivo, mice were adoptively transferred with CD4+ T cells expressing a transgenic OVA-specific TCR, before immunization with IgE anti-TNP (2,4,6-trinitrophenyl) plus OVA-TNP or with OVA-TNP alone. IgE induced a 6- to 21-fold increase in the number of OVA-specific T cells. These cells acquired an activated phenotype and were visible in splenic T cell zones. The T cell response peaked 3 days after immunization and preceded the OVA-specific Ab response by a few days. Transfer of CD23+ B cells to CD23-deficient mice rescued their ability to respond to IgE-Ag. Interestingly, in this situation also CD23-negative B cells produce enhanced levels of OVA-specific Abs. The data are compatible with the Ag presentation model and suggest that B cells can take up Ag via “unspecific” receptors and activate naive T cells in vivo.
Prostaglandin E2 Induces FOXP3 Gene Expression and T Regulatory Cell Function in Human CD4+ T Cells
Authors: Baratelli Felicita , Lin Ying , Zhu Li , Yang Seok-Chul , Heuzé-Vourc’h Nathalie , Zeng Gang , Reckamp Karen , Dohadwala Mariam , Sharma Sherven , Dubinett Steven M. 
Published: April 2014

Abstract
Naturally occurring CD4+CD25+ regulatory T cells (T reg) are pivotal in suppressing immune responses and maintaining tolerance. The identification of molecules controlling T reg differentiation and function is important in understanding host immune responses in malignancy and autoimmunity. In this study we show that PGE2 enhances the in vitro inhibitory function of human purified CD4+CD25+ T reg cells. Moreover, PGE2 induces a regulatory phenotype in CD4+CD25− T cells. PGE2-treated T cell-mediated inhibition of anti-CD3-stimulated lymphocyte proliferation did not require cell contact. Phenotypic analysis revealed that PGE2 diminished CD25 expression in both CD4+CD25dim T cells and CD4+CD25bright T reg cells. PGE2 exposure induced the T reg cell-specific transcription factor forkhead/winged helix transcription factor gene (FOXP3) in CD4+CD25− T cells and significantly up-regulated its expression in CD4+CD25+ T reg cells. Similarly, 24-h incubation with supernatants from cyclooxygenase-2-overexpressing lung cancer cells that secrete high levels of PGE2 significantly induced FOXP3 in CD4+CD25− T cells. Finally, PGE2 up-regulated FOXP3 at both mRNA and protein levels and enhanced FOXP3 promoter activity. This is the first report indicating that PGE2 can modulate FOXP3 expression and T reg function in human lymphocytes.
CD8α+, but Not CD8α−, Dendritic Cells Tolerize Th2 Responses via Contact-Dependent and -Independent Mechanisms, and Reverse Airway Hyperresponsiveness, Th2, and Eosinophil Responses in a Mouse Model of Asthma
Authors: Gordon John R. , Li Fang , Nayyar Aarti , Xiang Jim , Zhang Xiaobei 
Published: April 2014

Abstract
Splenic CD8α+ dendritic cells reportedly tolerize T cell responses by inducing Fas ligand-mediated apoptosis, suppressing IL-2 expression, or catabolizing T cell tryptophan reserves through expression of IDO. We report in this study that CD8α+, but not CD8α−, dendritic cells purified from the spleens of normal mice can tolerize the Th2 responses of cells from asthma phenotype mice through more than one mechanism. This tolerance could largely be reversed in vitro by anti-IL-10 or anti-TGFβ Ab treatment. However, loss of direct dendritic cell-T cell contact also reduced tolerance, although to a lesser extent, as did adding the IDO inhibitor 1-methyltryptophan or an excess of free tryptophan to the cultures. Within 3 wk of reconstituting asthma phenotype mice with 1 × 105 OVA-pulsed CD8α+, but not CD8α−, dendritic cells, the mice experienced a reversal of airway hyperresponsiveness, eosinophilic airway responses, and pulmonary Th2 cytokine expression. This data indicates that CD8α+ dendritic cells can simultaneously use multiple mechanisms for tolerization of T cells and that, in vivo, they are capable of tolerizing a well-established disease complex such as allergic lung disease/asthma.
Specific Role of Phosphodiesterase 4B in Lipopolysaccharide-Induced Signaling in Mouse Macrophages
Authors: Jin S.-L. Catherine , Lan Linda , Zoudilova Maria , Conti Marco 
Published: April 2014

Abstract
Cyclic nucleotide signaling functions as a negative modulator of inflammatory cell responses, and type 4 phosphodiesterases (PDE4) are important regulators of this pathway. In this study, we provide evidence that only one of the three PDE4 genes expressed in mouse peritoneal macrophages is involved in the control of TLR signaling. In these cells, LPS stimulation of TLR caused a major up-regulation of PDE4B but not the paralogs PDE4A or PDE4D. Only ablation of PDE4B impacted LPS signaling and TNF-α production. TNF-α mRNA and protein were decreased by &gt;50% in PDE4B−/−, but not in PDE4A−/− or PDE4D−/− macrophages. The PDE4 selective inhibitors rolipram and roflumilast had no additional inhibitory effect in macrophages deficient in PDE4B, but suppressed the TNF-α response in the other PDE4 null cells. The inhibition of TNF-α production that follows either genetic ablation or acute inhibition of PDE4B is cAMP-dependent and requires protein kinase A activity. However, no global changes in cAMP concentration were observed in the PDE4B−/− macrophages. Moreover, ablation of PDE4B protected mice from LPS-induced shock, suggesting that altered TLR signaling is retained in vivo. These findings demonstrate the highly specialized function of PDE4B in macrophages and its critical role in LPS signaling. Moreover, they provide proof of concept that a PDE4 inhibitor with subtype selectivity retains useful pharmacological effects.
CD226 Is Specifically Expressed on the Surface of Th1 Cells and Regulates Their Expansion and Effector Functions
Authors: Dardalhon Valerie , Schubart Anna S. , Reddy Jayagopala , Meyers Jennifer Hartt , Monney Laurent , Sabatos Catherine A. , Ahuja Rakesh , Nguyen Khuong , Freeman Gordon J. , Greenfield Edward A. , Sobel Raymond A. , Kuchroo Vijay K. 
Published: April 2014

Abstract
Surface molecules that are differentially expressed on Th1 and Th2 cells may be useful in regulating specific immune responses in vivo. Using a panel of mAbs, we have identified murine CD226 as specifically expressed on the surface of differentiated Th1 cells but not Th2 or Th0 cells. Although CD226 is constitutively expressed on CD8 cells, it is up-regulated on CD4 cells upon activation. Th1 differentiation results in enhanced CD226 expression, whereas expression is down-regulated upon Th2 polarization. We demonstrate that CD226 is involved in the regulation of T cell activation; in vivo treatment with anti-CD226 results in significant reduction of Th1 cell expansion and in the induction of APCs that inhibit T cell activation. Furthermore, anti-CD226 treatment delays the onset and reduces the severity of a Th1-mediated autoimmune disease, experimental autoimmune encephalomyelitis. Our data suggest that CD226 is a costimulatory molecule that plays an important role in activation and effector functions of Th1 cells.
CD25-Expressing CD8+ T Cells Are Potent Memory Cells in Old Age
Authors: Herndler-Brandstetter Dietmar , Schwaiger Susanne , Veel Ellen , Fehrer Christine , Cioca Daniel P. , Almanzar Giovanni , Keller Michael , Pfister Gerald , Parson Walther , Würzner Reinhard , Schönitzer Diether , Henson Sian M. , Aspinall Richard , Lepperdinger Günter , Grubeck-Loebenstein Beatrix 
Published: April 2014

Abstract
We have recently described an IL-2/IL-4-producing CD8+CD25+ nonregulatory memory T cell population that occurs in a subgroup of healthy elderly persons who characteristically still have a good humoral response after vaccination. The present study addresses this specific T cell subset and investigates its origin, clonal composition, Ag specificity, and replicative history. We demonstrate that CD8+CD25+ memory T cells frequently exhibit a CD4+CD8+ double-positive phenotype. The expression of the CD8 αβ molecule and the occurrence of signal-joint TCR rearrangement excision circles suggest a thymic origin of these cells. They also have longer telomeres than their CD8+CD25− memory counterparts, thus indicating a shorter replicative history. CD8+CD25+ memory T cells display a polyclonal TCR repertoire and respond to IL-2 as well as to a panel of different Ags, whereas the CD8+CD25− memory T cell population has a more restricted TCR diversity, responds to fewer Ags, and does not proliferate in response to stimulation with IL-2. Molecular tracking of specific clones with clonotypic primers reveals that the same clones occur in CD8+CD25+ and CD8+CD25− memory T cell populations, demonstrating a lineage relationship between CD25+ and CD25− memory CD8+ T cells. Our results suggest that CD25-expressing memory T cells represent an early stage in the differentiation of CD8+ cells. Accumulation of these cells in elderly persons appears to be a prerequisite of intact immune responsiveness in the absence of naive T cells in old age.
Drug-Induced Expansion and Differentiation of Vγ9Vδ2 T Cells In Vivo: The Role of Exogenous IL-2
Authors: Casetti Rita , Perretta Gemma , Taglioni Alessandra , Mattei Maurizio , Colizzi Vittorio , Dieli Francesco , D’Offizi Gianpiero , Malkovsky Miroslav , Poccia Fabrizio 
Published: April 2014

Abstract
Human Vγ9Vδ2 T cells recognize nonpeptidic Ags generated by the 1-deoxy-d-xylulose 5-phosphate (many eubacteria, algae, plants, and Apicomplexa) and mevalonate (eukaryotes, archaebacteria, and certain eubacteria) pathways of isoprenoid synthesis. The potent Vγ9Vδ2 T cell reactivity 1) against certain cancer cells or 2) induced by infectious agents indicates that therapeutic augmentations of Vγ9Vδ2 T cell activities may be clinically beneficial. The functional characteristics of Vγ9Vδ2 T cells from Macaca fascicularis (cynomolgus monkey) are very similar to those from Homo sapiens. We have found that the i.v. administration of nitrogen-containing bisphosphonate or pyrophosphomonoester drugs into cynomolgus monkeys combined with s.c. low-dose (6 × 105 U/animal) IL-2 induces a large pool of CD27+ and CD27− effector/memory T cells in the peripheral blood of treated animals. The administration of these drugs in the absence of IL-2 is substantially less effective, indicating the importance of additional exogenous costimuli. Shortly after the costimulatory IL-2 treatment, only γδ (but not αβ) T cells expressed the CD69 activation marker, indicating that Vγ9Vδ2 T lymphocytes are more responsive to low-dose IL-2 than αβ T cells. Up to 100-fold increases in the numbers of peripheral blood Vγ9Vδ2 T cells were observed in animals receiving the γδ stimulatory drug plus IL-2. Moreover, the expanded Vγ9Vδ2 T cells were potent Th1 effectors capable of releasing large amounts of IFN-γ. These results may be relevant for designing novel (or modifying current) immunotherapeutic trials with nitrogen-containing bisphosphonate or pyrophosphomonoester drugs.
TLR7/8-Mediated Activation of Human NK Cells Results in Accessory Cell-Dependent IFN-γ Production
Authors: Hart Orla M. , Athie-Morales Veronica , O’Connor Geraldine M. , Gardiner Clair M. 
Published: April 2014

Abstract
NK cells express receptors that allow them to recognize pathogens and activate effector functions such as cytotoxicity and cytokine production. Among these receptors are the recently identified TLRs that recognize conserved pathogen structures and initiate innate immune responses. We demonstrate that human NK cells express TLR3, TLR7, and TLR8 and that these receptors are functional. TLR3 is expressed at the cell surface where it functions as a receptor for polyinosinic acid:cytidylic acid (poly(I:C)) in a lysosomal-independent manner. TLR7/8 signaling is sensitive to chloroquine inhibition, indicating a requirement for lysosomal signaling as for other cell types. Both R848, an agonist of human TLR7 and TLR8, and poly(I:C) activate NK cell cytotoxicity against Daudi target cells. However, IFN-γ production is differentially regulated by these TLR agonists. In contrast to poly(I:C), R848 stimulates significant IFN-γ production by NK cells. This is accessory cell dependent and is inhibited by addition of a neutralizing anti-IL-12 Ab. Moreover, stimulation of purified monocyte populations with R848 results in IL-12 production, and reconstitution of purified NK cells with monocytes results in increased IFN-γ production in response to R848. In addition, we demonstrate that while resting NK cells do not transduce signals directly in response to R848, they can be primed to do so by prior exposure to either IL-2 or IFN-α. Therefore, although NK cells can be directly activated by TLRs, accessory cells play an important and sometimes essential role in the activation of effector functions such as IFN-γ production and cytotoxicity.
TLR-4 Regulates CD8+ T Cell Trapping in the Liver
Authors: John Beena , Crispe Ian Nicholas 
Published: April 2014

Abstract
Mammalian TLRs are understood primarily as an activating system for innate and adaptive immunity, but have also been implicated in sensing cellular damage and in promoting intestinal integrity. In this study we show that TLR-4 also controls the in vivo distribution of activated CD8+ T cells. The liver is a site for trapping and apoptosis of activated CD8+ T cells during systemic immune responses, but the reason for this is unknown. In this study we tested the hypothesis that the liver’s constant exposure to endotoxin, derived from commensal bacteria in the gut, acts via TLR-4 to promote activated T cell adhesion. In the absence of TLR-4, the liver was compromised in its ability to sequester activated CD8+ T cells, and there was an inverse correlation between the frequency of activated CD8+ T cells trapped in the liver and their frequency in the circulating pool. Thus, in the absence of any inflammation, TLR-4 ligands play a significant role in the ability of the liver to trap activated CD8+ T cells. This provides a new perspective on the regulation of immune responses by TLR-4 under basal conditions.
CD8+ T Cell Tolerance in Nonobese Diabetic Mice Is Restored by Insulin-Dependent Diabetes Resistance Alleles
Authors: Martinez Xavier , Kreuwel Huub T. C. , Redmond William L. , Trenney Rebecca , Hunter Kara , Rosen Hugh , Sarvetnick Nora , Wicker Linda S. , Sherman Linda A. 
Published: April 2014

Abstract
Although candidate genes controlling autoimmune disease can now be identified, a major challenge that remains is defining the resulting cellular events mediated by each locus. In the current study we have used NOD-InsHA transgenic mice that express the influenza hemagglutinin (HA) as an islet Ag to compare the fate of HA-specific CD8+ T cells in diabetes susceptible NOD-InsHA mice with that observed in diabetes-resistant congenic mice having protective alleles at insulin-dependent diabetes (Idd) 3, Idd5.1, and Idd5.2 (Idd3/5 strain) or at Idd9.1, Idd9.2, and Idd9.3 (Idd9 strain). We demonstrate that protection from diabetes in each case is correlated with functional tolerance of endogenous islet-specific CD8+ T cells. However, by following the fate of naive, CFSE-labeled, islet Ag-specific CD8+ (HA-specific clone-4) or CD4+ (BDC2.5) T cells, we observed that tolerance is achieved differently in each protected strain. In Idd3/5 mice, tolerance occurs during the initial activation of islet Ag-specific CD8+ and CD4+ T cells in the pancreatic lymph nodes where CD25+ regulatory T cells (Tregs) effectively prevent their accumulation. In contrast, resistance alleles in Idd9 mice do not prevent the accumulation of islet Ag-specific CD8+ and CD4+ T cells in the pancreatic lymph nodes, indicating that tolerance occurs at a later checkpoint. These results underscore the variety of ways that autoimmunity can be prevented and identify the elimination of islet-specific CD8+ T cells as a common indicator of high-level protection.
Investigation of Peptide Involvement in T Cell Allorecognition Using Recombinant HLA Class I Multimers
Authors: Whitelegg Alison M. E. , Oosten Liesbeth E. M. , Jordan Susan , Kester Michel , van Halteren Astrid G. S. , Madrigal J. Alejandro , Goulmy Els , Barber Linda D. 
Published: April 2014

Abstract
Alloreactive T cells are involved in injurious graft rejection and graft-vs-host disease. However, they can also evoke beneficial responses to tumor Ags restricted by foreign MHC molecules. Manipulation of these alloreactivities requires information on the basis of T cell allorecognition. The vigorous T cell response to foreign MHC molecules may arise from peptide-independent recognition of polymorphic residues of foreign MHC molecules or peptide-specific recognition of novel peptides presented by foreign MHC molecules. We investigated CD8+ T cell allorecognition using recombinant HLA class I/peptide complexes. Peptide-specific allorecognition was examined using tetramers of HLA-A*0201 representing five peptides derived from ubiquitously expressed self-proteins that are known to bind endogenously to HLA-A*0201. Distinct subsets of CD8+ T cells specific for each HLA-A*0201/peptide combination were detected within four in vitro-stimulated T cell populations specific for foreign HLA-A*0201. Peptide-independent allorecognition was investigated using artificial Ag-presenting constructs (aAPCs) coated with CD54, CD80, and functional densities of a single HLA-A*0201/peptide combination for four different peptides. None of the four T cell populations specific for foreign HLA-A*0201 were stimulated by the aAPCs, whereas they did produce IFN-γ upon stimulation with cells naturally expressing HLA-A*0201. Thus, aAPCs did not stimulate putative peptide-independent allorestricted T cells. The results show that these alloreactive populations comprise subsets of T cells, each specific for a self-peptide presented by foreign class I molecules, with no evidence of peptide-independent components.
Regulator of Complement Activation (RCA) Locus in Chicken: Identification of Chicken RCA Gene Cluster and Functional RCA Proteins
Authors: Oshiumi Hiroyuki , Shida Kyoko , Goitsuka Ryo , Kimura Yuko , Katoh Jun , Ohba Shinya , Tamaki Yuichiroh , Hattori Takashi , Yamada Nozomi , Inoue Norimitsu , Matsumoto Misako , Mizuno Shigeki , Seya Tsukasa 
Published: April 2014

Abstract
A 150-kb DNA fragment, which contains the gene of the chicken complement regulatory protein CREM (formerly named Cremp), was isolated from a microchromosome by screening bacterial artificial chromosome library. Within 100 kb of the cloned region, three complete genes encoding short consensus repeats (SCRs, motifs with tandemly arranged 60 aa) were identified by exon-trap method and 3′- or 5′-RACE. A chicken orthologue of the human gene 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2, which exists in close proximity to the regulator of complement activation genes in humans and mice, was located near this chicken SCR gene cluster. Moreover, additional genes encoding SCR proteins appeared to be present in this region. Three distinct transcripts were detected in RNA samples from a variety of chicken organs and cell lines. Two novel genes named complement regulatory secretory protein of chicken (CRES) and complement regulatory GPI-anchored protein of chicken (CREG) besides CREM were identified by cloning corresponding cDNA. Based on the predicted primary structures and properties of the expressed molecules, CRES is a secretory protein, whereas CREG is a GPI-anchored membrane protein. CREG and CREM were protected host cells from chicken complement-mediated cytolysis. Likewise, a membrane-bound form of CRES, which was artificially generated, also protected host cells from chicken complement. Taken together, the chicken possesses an regulator of complement activation locus similar to those of the mammals, and the gene products function as complement regulators.