bluuebunny/crossref_metadata_2025_split huggingface dataset:
Platelet Factor 4 Inhibits Proliferation and Cytokine Release of Activated Human T Cells
Authors: Fleischer Jens , Grage-Griebenow Evelin , Kasper Brigitte , Heine Holger , Ernst Martin , Brandt Ernst , Flad Hans-Dieter , Petersen Frank 
Published: April 2014

AbstractPlatelet factor 4 (PF-4), a platelet-derived CXC chemokine, has been shown to induce the differentiation of monocytes into a subset of macrophages that lack the expression of HLA-DR Ag. This suggests a potential role for PF-4 in the modulation of monocyte-dependent T cell activation. Using an Ag-specific stimulation model in which T cells were cocultured with monocytes in the presence of recall Ags, we could show that under these conditions PF-4-treatment caused a strong decrease of T cell proliferation as well as of IFN-γ release. However, inhibition of T cell functions such as proliferation, IL-2 release, and IL-2 mRNA production did also occur when isolated T cells were activated in the absence of monocytes with immobilized Abs directed against CD3 in combination with cross-linked anti-CD28 Abs. The effect could be reversed when low concentrations of exogenous IL-2 instead of anti-CD28 were used as a costimulus in combination with anti-CD3 Abs. Further evidence for direct modulation of T cell function by PF-4 was obtained by the detection of specific binding sites for the chemokine on the surface of these cells. Taken together, our results show that specific binding of PF-4, resulting in the down-regulation of the IL-2-release correlates with the inhibition of functions in activated T cells.
Inhibition of Antigen-Specific T Cell Proliferation and Cytokine Production by Protein Kinase A Type I
Authors: Aandahl Einar Martin , Moretto Walter J. , Haslett Patrick A. , Vang Torkel , Bryn Tone , Tasken Kjetil , Nixon Douglas F. 
Published: April 2014

Abstract
cAMP inhibits biochemical events leading to T cell activation by triggering of an inhibitory protein kinase A (PKA)-C-terminal Src kinase pathway assembled in lipid rafts. In this study, we demonstrate that activation of PKA type I by Sp-8-bromo-cAMPS (a cAMP agonist) has profound inhibitory effects on Ag-specific immune responses in peripheral effector T cells. Activation of PKA type I inhibits both cytokine production and proliferative responses in both CD4+ and CD8+ T cells in a concentration-dependent manner. The observed effects of cAMP appeared to occur endogenously in T cells and were not dependent on APC. The inhibition of responses was not due to apoptosis of specific T cells and was reversible by a PKA type I-selective cAMP antagonist. This supports the notion of PKA type I as a key enzyme in the negative regulation of immune responses and a potential target for inhibiting autoreactive T cells.
Immobilized Lactoferrin Is a Stimulus for Eosinophil Activation
Authors: Thomas Larry L. , Xu Wei , Ardon Tamir T. 
Published: April 2014

Abstract
Eosinophils are strongly implicated in the pathogenesis of asthma, particularly in damage to the airway epithelial lining. We examined the potential for lactoferrin, a multifunctional glycoprotein present in the airway surface liquid, to activate eosinophils. Incubating eosinophils in tissue culture wells pretreated with 1–100 μg/ml human lactoferrin stimulated concentration-dependent superoxide production by eosinophils. The same concentrations of immobilized transferrin were without effect. The potency of immobilized lactoferrin was approximately one-third that of immobilized secretory IgA in the same experiments. In contrast, immobilized lactoferrin did not stimulate neutrophil superoxide production. Eosinophils bound lactoferrin as determined by flow cytometry and by binding of 125I-labeled lactoferrin. Transferrin did not block binding of 125I-labeled lactoferrin. Soluble lactoferrin, however, did not activate the eosinophils and did not block superoxide production stimulated by immobilized lactoferrin. Immobilized lactoferrin also stimulated release of eosinophil-derived neurotoxin and low levels of leukotriene C4 production; the latter was significantly enhanced in the presence of 100 pg/ml GM-CSF. GM-CSF also enhanced superoxide production and eosinophil-derived neurotoxin release stimulated by the lower concentrations of immobilized lactoferrin. Pretreatment of the lactoferrin with peptide N-glycosidase F or addition of heparin or chondroitin sulfate to the incubation contents had no or only a minimal effect on the activity of immobilized lactoferrin. These results demonstrate that lactoferrin adherent to the surface epithelium may contribute to the activation of eosinophils that infiltrate the airway lumen in eosinophil-associated disorders such as asthma.
Cutting Edge: Fyn Is Essential for Tyrosine Phosphorylation of Csk-Binding Protein/Phosphoprotein Associated with Glycolipid-Enriched Microdomains in Lipid Rafts in Resting T Cells
Authors: Yasuda Koubun , Nagafuku Masakazu , Shima Takaki , Okada Masato , Yagi Takeshi , Yamada Takenao , Minaki Yasuko , Kato Akiko , Tani-ichi Shizue , Hamaoka Toshiyuki , Kosugi Atsushi 
Published: April 2014

Abstract
In resting T cells, Csk is constitutively localized in lipid rafts by virtue of interaction with a phosphorylated adaptor protein, Csk-binding protein (Cbp)/phosphoprotein associated with glycolipid-enriched microdomains, and sets an activation threshold in TCR signaling. In this study, we examined a kinase responsible for Cbp phosphorylation in T cell membrane rafts. By analyzing T cells from Fyn−/− mice, we clearly demonstrated that Fyn, but not Lck, has its kinase activity in membrane rafts, and plays a critical role in Cbp phosphorylation, Cbp-Csk interaction, and Csk kinase activity. Naive CD44lowCD62 ligandhigh T cells were substantially reduced in Fyn−/− mice, presumably due to the inhibition of Cbp phosphorylation. Thus, Fyn mediates Cbp-Csk interaction and recruits Csk to rafts by phosphorylating Cbp. Csk recruited to rafts would then be activated and inhibit the kinase activity of Lck to keep resting T cells in a quiescent state. Our results elucidate a negative regulatory role for Fyn in proximal TCR signaling in lipid rafts.
Cutting Edge: Susceptibility to Psoriatic Arthritis: Influence of Activating Killer Ig-Like Receptor Genes in the Absence of Specific HLA-C Alleles
Authors: Martin Maureen P. , Nelson George , Lee Jeong-Hee , Pellett Fawnda , Gao Xiaojiang , Wade Judith , Wilson Michael J. , Trowsdale John , Gladman Dafna , Carrington Mary 
Published: April 2014

Abstract
NK cell activity is partially controlled through interactions between killer Ig-like receptors (KIR) on NK cells and their respective HLA class I ligands. Independent segregation of HLA and KIR genes, along with KIR specificity for particular HLA allotypes, raises the possibility that any given individual may express KIR molecules for which no ligand is present. Inhibitory receptor genes KIR2DL2/3 and KIR2DL1 were present in nearly all subjects sampled in this study, whereas their respective activating homologs, KIR2DS2 and KIR2DS1, are each present in about half of the subjects. In this work we report that subjects with activating KIR2DS1 and/or KIR2DS2 genes are susceptible to developing psoriatic arthritis, but only when HLA ligands for their homologous inhibitory receptors, KIR2DL1 and KIR2DL2/3, are missing. Absence of ligands for inhibitory KIRs could potentially lower the threshold for NK (and/or T) cell activation mediated through activating receptors, thereby contributing to pathogenesis of psoriatic arthritis.
Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Signaling in Activated T Cells Abrogates TRAIL-Induced Apoptosis Upstream of the Mitochondrial Amplification Loop and Caspase-8
Authors: Söderström Thomas S. , Poukkula Minna , Holmström Tim H. , Heiskanen Kaisa M. , Eriksson John E. 
Published: April 2014

AbstractFas ligand and TNF-related apoptosis-inducing ligand (TRAIL) induce apoptosis in many different cell types. Jurkat T cells die rapidly by apoptosis after treatment with either ligand. We have previously shown that mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) can act as a negative regulator of apoptosis mediated by the Fas receptor. In this study we examined whether MAPK/ERK can also act as a negative regulator of apoptosis induced by TRAIL. Activated Jurkat T cells were efficiently protected from TRAIL-induced apoptosis. The protection was shown to be MAPK/ERK dependent and independent of protein synthesis. MAPK/ERK suppressed TRAIL-induced apoptosis upstream of the mitochondrial amplification loop because mitochondrial depolarization and release of cytochrome c were inhibited. Furthermore, caspase-8-mediated relocalization and activation of Bid, a proapoptotic member of the Bcl family, was also inhibited by the MAPK/ERK signaling. The protection occurred at the level of the apoptotic initiator caspase-8, as the cleavage of caspase-8 was inhibited but the assembly of the death-inducing signaling complex was unaffected. Both TRAIL and Fas ligand have been suggested to regulate the clonal size and persistence of different T cell populations. Our previous results indicate that MAPK/ERK protects recently activated T cells from Fas receptor-mediated apoptosis during the initial phase of an immune response before the activation-induced cell death takes place. The results of this study show clearly that MAPK/ERK also participates in the inhibition of TRAIL-induced apoptosis after T cell activation.
Colocalization of the B Cell Receptor and CD20 Followed by Activation-Dependent Dissociation in Distinct Lipid Rafts
Authors: Petrie Ryan J. , Deans Julie P. 
Published: April 2014

Abstract
The B cell Ag receptor (BCR) and CD20, a putative calcium channel, inducibly associate with cholesterol-dependent membrane microdomains known as lipid rafts. A functional association between the BCR and CD20 is suggested by the effects of CD20-specific mAbs, which can modulate cell cycle transitions elicited by BCR signaling. Using immunofluorescence microscopy we show here that the BCR and CD20 colocalize after receptor ligation and then rapidly dissociate at the cell surface before endocytosis of the BCR. After separation, surface BCR and CD20 were detected in distinct lipid rafts isolated as low density, detergent-resistant membrane fragments. Pretreatment with methyl-β-cyclodextrin, which we have previously shown to enhance receptor-mediated calcium mobilization, did not prevent colocalization of the BCR and CD20, but slowed their dissociation. The data demonstrate rapid dynamics of the BCR in relation to CD20 at the cell surface. Activation-dependent dissociation of the BCR from CD20 occurs before receptor endocytosis and appears to require in part the integrity of lipid rafts.
Innate Immune Response to Malaria: Rapid Induction of IFN-γ from Human NK Cells by LivePlasmodium falciparum-Infected Erythrocytes
Authors: Artavanis-Tsakonas Katerina , Riley Eleanor M. 
Published: April 2014

AbstractTo determine the potential contribution of innate immune responses to the early proinflammatory cytokine response to Plasmodium falciparum malaria, we have examined the kinetics and cellular sources of IFN-γ production in response to human PBMC activation by intact, infected RBC (iRBC) or freeze-thaw lysates of P. falciparum schizonts. Infected erythrocytes induce a more rapid and intense IFN-γ response from malaria-naive PBMC than do P. falciparum schizont lysates correlating with rapid iRBC activation of the CD3−CD56+ NK cell population to produce IFN-γ. IFN-γ+ NK cells are detectable within 6 h of coculture with iRBC, their numbers peaking at 24 h in most donors. There is marked heterogeneity between donors in magnitude of the NK-IFN-γ response that does not correlate with mitogen- or cytokine-induced NK activation or prior malaria exposure. The NK cell-mediated IFN-γ response is highly IL-12 dependent and appears to be partially IL-18 dependent. Exogenous rIL-12 or rIL-18 did not augment NK cell IFN-γ responses, indicating that production of IL-12 and IL-18 is not the limiting factor explaining differences in NK cell reactivity between donors or between live and dead parasites. These data indicate that NK cells may represent an important early source of IFN-γ, a cytokine that has been implicated in induction of various antiparasitic effector mechanisms. The heterogeneity of this early IFN-γ response between donors suggests a variation in their ability to mount a rapid proinflammatory cytokine response to malaria infection that may, in turn, influence their innate susceptibility to malaria infection, malaria-related morbidity, or death from malaria.
Peripheral Immature CD2−/low T Cell Development from Type 2 to Type 1 Cytokine Production
Authors: Loza Matthew J. , Perussia Bice 
Published: April 2014

AbstractImmature myeloid and NK cells exist, and undergo cytokine-induced differentiation, in the periphery. In this study, we show that also immature CD2−/low T cells exist in peripheral blood. These cells produce the type 2 cytokines IL-13, IL-4, and IL-5, but not IFN-γ or IL-10, and, upon culture with IL-12- and TCR-mediated stimuli, differentiate to IL-13+IFN-γ+ cells producing high IL-2 levels, and finally IL-13−IFN-γ+ cells. The monokine combination IL-12, IL-18, and IFN-α substitutes for TCR-mediated stimulation to induce the same differentiation process in both immature CD2−/low and primary mature CD2+ IL-13+ Τ cells. IFN-α is needed to maintain high level IL-2 production, which is confined to type 2 cytokine-producing cells and lost in the IFN-γ+ ones. Upon TCR-mediated stimulation, IFN-γ+ cells are then induced to produce IL-10 as they undergo apoptosis. These data indicate that peripheral type 2 cytokine+ T cells are immature cells that can differentiate to effector IFN-γ+ cells following a linear monokine-regulated pathway identical with that previously described for NK cells. They define the cellular bases to support that cell-mediated immune responses are regulated not only via Ag-induced activation of mature effector cells, but also via bystander monokine-induced maturation of immature T cells.
Regulation of IFN Regulatory Factor 4 Expression in Human T Cell Leukemia Virus-I-Transformed T Cells
Authors: Sharma Sonia , Grandvaux Nathalie , Mamane Yael , Genin Pierre , Azimi Nazli , Waldmann Thomas , Hiscott John 
Published: April 2014

AbstractIFN regulatory factor (IRF)-4 is a lymphoid/myeloid-restricted member of the IRF transcription factor family that plays an essential role in the homeostasis and function of mature lymphocytes. IRF-4 expression is tightly regulated in resting primary T cells and is transiently induced at the mRNA and protein levels after activation by Ag-mimetic stimuli such as TCR cross-linking or treatment with phorbol ester and calcium ionophore (PMA/ionomycin). However, IRF-4 is constitutively upregulated in human T cell leukemia virus type I (HTLV-I) infected T cells as a direct gene target for the HTLV-I Tax oncoprotein. In this study we demonstrate that chronic IRF-4 expression in HTLV-I-infected T lymphocytes is associated with a leukemic phenotype, and we examine the mechanisms by which continuous production of IRF-4 is achieved in HTLV-I-transformed T cells. IRF-4 expression in HTLV-1-infected cells is driven through activation of the NF-κB and NF-AT pathways, resulting in the binding of p50, p65, and c-Rel to the κB1 element and p50, c-Rel, and NF-ATp to the CD28RE element within the −617 to −209 region of the IRF-4 promoter. Furthermore, mutation of either the κB1 or CD28RE sites blocks Tax-mediated transactivation of the human IRF-4 promoter in T cells. These experiments constitute the first detailed analysis of human IRF-4 transcriptional regulation within the context of HTLV-I infection and transformation of CD4+ T lymphocytes.
Caspase-9/-3 Activation and Apoptosis Are Induced in Mouse Macrophages upon Ingestion and Digestion ofEscherichia coliBacteria
Authors: Häcker Hans , Fürmann Christine , Wagner Hermann , Häcker Georg 
Published: April 2014

AbstractA number of highly virulent, intracellular bacteria are known to induce cell death by apoptosis in infected host cells. In this work we demonstrate that phagocytosis of bacteria from the Escherichia coli laboratory strain K12 DH5α is a potent cell death stimulus for mouse macrophages. RAW264.7 mouse macrophages took up bacteria and digested them within 2–4 h as investigated with green fluorescent protein-expressing bacteria. No evidence of apoptosis was seen at 8 h postexposure, but at 24 h ∼70% of macrophages displayed an apoptotic phenotype by a series of parameters. Apoptosis was blocked by inhibition of caspases or by forced expression of the apoptosis-inhibiting protein Bcl-2. Processing of caspase-3 and caspase-9 but not caspase-8 was seen suggesting that the mitochondrial branch of the apoptotic pathway was activated. Active effector caspases could be detected in two different assays. Because the adapter molecule myeloid differentiation factor 88 (MyD88) has been implicated in apoptosis, involvement of the Toll-like receptor pathway was investigated. In RAW264.7 cells, heat-treated bacteria were taken up poorly and failed to induce significant apoptosis. However, cell activation was almost identical between live and heat-inactivated bacteria as measured by extracellular signal-regulated kinase activation, generation of free radicals, and TNF secretion. Furthermore, primary bone marrow-derived macrophages from wild-type as well as from MyD88-deficient mice underwent apoptosis upon phagocytosis of bacteria. These results show that uptake and digestion of bacteria leads to MyD88-independent apoptosis in mouse macrophages. This form of cell death might have implications for the generation of the immune response.
CD80+Gr-1+ Myeloid Cells Inhibit Development of Antifungal Th1 Immunity in Mice with Candidiasis
Authors: Mencacci Antonella , Montagnoli Claudia , Bacci Angela , Cenci Elio , Pitzurra Lucia , Spreca Antonio , Kopf Manfred , Sharpe Arlene H. , Romani Luigina 
Published: April 2014

AbstractTo find out whether polymorphonuclear neutrophils (PMN), abundantly recruited in disseminated Candida albicans infection, could directly affect the activation of Th cells we addressed the issues as to whether murine PMN, like their human counterparts, express costimulatory molecules and the functional consequence of this expression in terms of antifungal immune resistance. To this purpose, we assessed 1) the expression of CD80 (B7-1) and CD86 (B7-2) molecules on peripheral, splenic, and inflammatory murine Gr-1+ PMN; 2) its modulation upon interaction with C. albicans in vitro, in vivo, and in human PMN; 3) the effect of Candida exposure on the ability of murine PMN to affect CD4+ Th1 cell proliferation and cytokine production; and 4) the mechanism responsible for this effect. Murine PMN constitutively expressed CD80 molecules on both the surface and intracellularly; however, in both murine and human PMN, CD80 expression was differentially modulated upon interaction with Candida yeasts or hyphae in vitro as well as in infected mice. The expression of the CD86 molecule was neither constitutive nor inducible upon exposure to the fungus. In vitro, Gr-1+ PMN were found to inhibit the activation of IFN-γ-producing CD4+ T cells and to induce apoptosis through a CD80/CD28-dependent mechanism. A population of CD80+Gr-1+ myeloid cells was found to be expanded in conventional as well as in bone marrow-transplanted mice with disseminated candidiasis, but its depletion increased the IFN-γ-mediated antifungal resistance. These data indicate that alternatively activated PMN expressing CD80 may adversely affect Th1-dependent resistance in fungal infections.
Syntaxins 13 and 7 Function at Distinct Steps During Phagocytosis
Authors: Collins Richard F. , Schreiber Alan D. , Grinstein Sergio , Trimble William S. 
Published: April 2014

Abstract
The phagosome is a dynamic organelle that undergoes progressive changes to acquire the machinery required to kill and degrade internalized foreign particles. This maturation process involves sequential interaction of newly formed phagosomes with several components of the endocytic pathway. The proteins that mediate the ordered fusion of endosomes and lysosomes with the phagosome are not known. In this study, we investigated the possible role of syntaxins present in the endo/lysosomal pathway in directing phagosomal maturation. We show that in phagocytic cells syntaxin 13 is localized to the recycling endosome compartment, while syntaxin 7 is found in late endosomes/lysosomes. Both proteins are recruited to the phagosome, but syntaxin 13 is acquired earlier and rapidly recycles off the phagosome, while syntaxin 7 is recruited later and continues to accumulate throughout the maturation process. Overexpression of truncated (cytosolic) forms of syntaxin 13 or 7 had no effect on phagocytosis, but exerted an inhibitory effect on phagosomal maturation. These results indicate that syntaxins 13 and 7 are both required for interaction of endosomes and/or lysosomes with the phagosome, but play distinct roles in the maturation process.
Enhanced Type 1 Immunity After Secondary Viral Challenge in Mice Primed as Neonates
Authors: Fadel Shaza A. , Ozaki Daniel A. , Sarzotti Marcella 
Published: April 2014

AbstractThe goal of infant immunization against viral infection is to develop protective long term memory responses. Priming neonatal mice with a low dose of Cas-Br-E murine leukemia virus (Cas) results in adult-like, type 1 protective responses. However, other studies suggest that Ag priming of neonates leads to an increase in type 2 secondary responses even when primary responses were type 1. We assessed whether type 1 CD8+ T cell-mediated responses developed in murine neonates are maintained after secondary challenge with Cas in adulthood. Despite the induction of significant anti-viral CD8+-mediated cytotoxic T lymphocyte and IFN-γ responses, initial neonatal priming led to a lower frequency of virus-specific T cells compared with adult priming. Adult frequencies were reached in mice primed as neonates only after secondary challenge in adulthood. A nonspecific and transient CD4+-mediated IL-4 response was present in all groups after secondary challenge with Cas or medium, indicating that this rise in type 2 cytokine production was not unique to mice that had been primed as neonates. Rather, type 1 anti-viral memory CD8+ T cell responses developed in neonatal mice are stable, protective, and enhanced after secondary challenge.
Activation of Monocytic Cells Through Fcγ Receptors Induces the Expression of Macrophage-Inflammatory Protein (MIP)-1α, MIP-1β, and RANTES
Authors: Fernández Nieves , Renedo Marta , García-Rodríguez Carmen , Sánchez Crespo Mariano 
Published: April 2014

AbstractMonocytic cells were stimulated with IgG-OVA equivalence immune complexes, mAb reacting with FcγRI, FcγRIIA, and FcγRIII, LPS, TNF-α, and the combination of ionomycin and phorbol ester, to address their effects on the expression of the mRNAs encoding for chemokines. Stimulation of monocytes with immune complexes induced a rapid expression of macrophage-inflammatory protein (MIP)-1α, MIP-1β, and IL-8 mRNAs. In contrast, RANTES mRNA was already detectable in resting cells and only increased after 16 h of stimulation. A similar pattern was observed following homotypic stimulation of FcγR with mAb reacting with FcγRI and FcγRIIA, but not with a mAb reacting with FcγRIII, a subtype of receptor not expressed in THP-1 cells, thus indicating that both FcγRI and FcγRIIA are involved in the response. The pattern of chemokine induction elicited by LPS and the combination of ionomycin and PMA showed some similarities to those produced by FcγR cross-linking, although expression of IFN-γ-inducible protein 10 mRNA was also observed in response to those agonists. The production of MIP-1α, MIP-1β, and RANTES proteins encompassing the induction of their mRNAs was confirmed by specific ELISA. Experiments to address the transcription factors involved in the regulation of MIP-1α using pharmacological agents and EMSA showed the possible involvement of CCAAT/enhancer-binding protein β sites and ruled out the functional significance of both NF-AT and AP-1 sites.