bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lipoxin A4 and Aspirin-Triggered 15-epi-Lipoxin A4 Inhibit Human Neutrophil Migration: Comparisons Between Synthetic 15 Epimers in Chemotaxis and Transmigration with Microvessel Endothelial Cells and Epithelial Cells
Authors: Fierro Iolanda M. , Colgan Sean P. , Bernasconi Giovanni , Petasis Nicos A. , Clish Clary B. , Arita Makoto , Serhan Charles N. 
Published: April 2014

Abstract
Lipoxins (LX) are bioactive eicosanoids that can be formed during cell to cell interactions in human tissues to self limit key responses in host defense and promote resolution. Aspirin treatment initiates biosynthesis of carbon 15 epimeric LXs, and both series of epimers (LX and aspirin-triggered 15-epi-LX) display counter-regulatory actions with neutrophils. In this study, we report that synthetic lipoxin A4 (LXA4) and 15-epi-LXA4 (i.e., 15(R)-LXA4 or aspirin-triggered LXA4) are essentially equipotent in inhibiting human polymorphonuclear leukocytes (PMN) in vitro chemotaxis in response to leukotriene B4, with the maximum inhibition (∼50% reduction) obtained at 1 nM LXA4. At higher concentrations, 15-epi-LXA4 proved more potent than LXA4 as its corresponding carboxyl methyl ester. Also, exposure of PMN to LXA4 and 15-epi-LXA4 markedly decreased PMN transmigration across both human microvessel endothelial and epithelial cells, where 15-epi-LXA4 was more active than LXA4 at “stopping” migration across epithelial cells. Differences in potency existed between LXA4 and 15-epi-LXA4 as their carboxyl methyl esters appear to arise from cell type-specific conversion of their respective carboxyl methyl esters to their corresponding carboxylates as monitored by liquid chromatography tandem mass spectrometry. Both synthetic LXA4 and 15-epi-LXA4 as free acids activate recombinant human LXA4 receptor (ALXR) to regulate gene expression, whereas the corresponding methyl ester of LXA4 proved to be a partial ALXR antagonist and did not effectively regulate gene expression. These results demonstrate the potent stereospecific actions shared by LXA4 and 15-epi-LXA4 for activating human ALXR-regulated gene expression and their ability to inhibit human PMN migration during PMN vascular as well as mucosal cell to cell interactions.
Studies Investigating Pretransplant Donor-Specific Blood Transfusion, Rapamycin, and the CD154-Specific Antibody IDEC-131 in a Nonhuman Primate Model of Skin Allotransplantation
Authors: Xu He , Montgomery Sean P. , Preston Edwin H. , Tadaki Douglas K. , Hale Douglas A. , Harlan David M. , Kirk Allan D. 
Published: April 2014

Abstract
Anti-CD154 variably prolongs allograft survival in nonhuman primates. Rodent studies suggest that adding pretransplant donor-specific transfusion (DST) and/or rapamycin to anti-CD154 improves survival. The CD154-specific Ab IDEC-131 was tested alone and in combination with rapamycin for its ability to inhibit rhesus MLRs. The ability of the Ab to block endothelial activation was also assessed. IDEC-131 was then tested alone and in combination with DST and/or rapamycin for its ability to prevent rejection of full-thickness, MHC-mismatched rhesus skin allografts. Animals were monitored for donor-specific hyporesponsiveness by MLR and alloantibody determination. IDEC-131 modestly inhibited rhesus MLRs and inhibited CD154-dependent endothelial cell activation. Rapamycin combined with IDEC-131 additively inhibited MLRs. IDEC-131 modestly prolonged allograft survival when compared with no treatment, rapamycin alone, or DST plus rapamycin. Adding DST to IDEC-131 did not prolong survival beyond IDEC-131 alone. IDEC-131 plus rapamycin was effective in prolonging graft survival, although animals had episodes of acute rejection before graft demise. Therapy with IDEC-131, rapamycin, and DST induced long-term allograft survival without intermittent acute rejection. However, no evidence for MLR inhibition was seen, and most animals eventually developed alloantibody. All animals ultimately rejected their grafts after drug withdrawal. IDEC-131 modestly prolongs rhesus skin allograft survival. Rapamycin and rapamycin plus DST improves the efficacy of IDEC-131 in prolonging allograft survival. IDEC-131, rapamycin, and DST are a promising combination for clinical evaluation in allotransplantation.
Cutting Edge: Impairment of Dendritic Cells and Adaptive Immunity by Ebola and Lassa Viruses
Authors: Mahanty Siddhartha , Hutchinson Karen , Agarwal Sudhanshu , Mcrae Michael , Rollin Pierre E. , Pulendran Bali 
Published: April 2014

Abstract
Acute infection of humans with Ebola and Lassa viruses, two principal etiologic agents of hemorrhagic fevers, often results in a paradoxical pattern of immune responses: early infection, characterized by an outpouring of inflammatory mediators such as TNF-α, IL-1β, and IL-6, vs late stage infections, which are associated with poor immune responses. The mechanisms underlying these diverse outcomes are poorly understood. In particular, the role played by cells of the innate immune system, such as dendritic cells (DC), is not known. In this study, we show that Ebola and Lassa viruses infect human monocyte-derived DC and impair their function. Monocyte-derived DC exposed to either virus fail to secrete proinflammatory cytokines, do not up-regulate costimulatory molecules, and are poor stimulators of T cells. These data represent the first evidence for a mechanism by which Ebola and Lassa viruses target DC to impair adaptive immunity.
Unresponsiveness to Lymphoid-Mediated Signals at the Neonatal Follicular Dendritic Cell Precursor Level Contributes to Delayed Germinal Center Induction and Limitations of Neonatal Antibody Responses to T-Dependent Antigens
Authors: Pihlgren Maria , Tougne Chantal , Bozzotti Paola , Fulurija Alma , Duchosal Michel A. , Lambert Paul-Henri , Siegrist Claire-Anne 
Published: April 2014

Abstract
The factors limiting neonatal and infant IgG Ab responses to T-dependent Ags are only partly known. In this study, we assess how these B cell responses are influenced by the postnatal development of the spleen and lymph node microarchitecture. When BALB/c mice were immunized with alum-adsorbed tetanus toxoid at various stages of their immune development, a major functional maturation step for induction of serum IgG, Ab-secreting cells, and germinal center (GC) responses was identified between the second and the third week of life. This correlated with the development of the follicular dendritic cell (FDC) network, as mature FDC clusters only appeared at 2 wk of age. Adoptive transfer of neonatal splenocytes into adult SCID mice rapidly induced B cell follicles and FDC precursor differentiation into mature FDC, indicating effective recruitment and signaling capacity of neonatal B cells. In contrast, adoptive transfer of adult splenocytes into neonatal SCID mice induced primary B cell follicles without any differentiation of mature FDC and failed to correct limitations of tetanus toxoid-induced GC. Thus, unresponsiveness to lymphoid-mediated signals at the level of neonatal FDC precursors delays FDC maturation and GC induction, thus limiting primary Ab-secreting cell responses to T-dependent Ags in early postnatal life.
The Size of the Synaptic Cleft and Distinct Distributions of Filamentous Actin, Ezrin, CD43, and CD45 at Activating and Inhibitory Human NK Cell Immune Synapses
Authors: McCann Fiona E. , Vanherberghen Bruno , Eleme Konstantina , Carlin Leo M. , Newsam Ray J. , Goulding David , Davis Daniel M. 
Published: April 2014

Abstract
In this study, we report the organization of cytoskeletal and large transmembrane proteins at the inhibitory and activating NK cell immunological or immune synapse (IS). Filamentous actin accumulates at the activating, but not the inhibitory, NK cell IS. However, surprisingly, ezrin and the associated protein CD43 are excluded from the inhibitory, but not the activating, NK cell IS. This distribution of ezrin and CD43 at the inhibitory NK cell IS is similar to that previously seen at the activating T cell IS. CD45 is also excluded from the inhibitory, but not activating, NK cell IS. In addition, electron microscopy reveals wide and narrow domains across the synaptic cleft. Target cell HLA-C, located by immunogold labeling, clusters where the synaptic cleft spans the size of HLA-C bound to the inhibitory killer Ig-like receptor. These data are consistent with assembly of the NK cell IS involving a combination of cytoskeletal-driven mechanisms and thermodynamics favoring the organization of receptor/ligand pairs according to the size of their extracellular domains.
Vav-1 and the IKKα Subunit of IκB Kinase Functionally Associate to Induce NF-κB Activation in Response to CD28 Engagement
Authors: Piccolella Enza , Spadaro Francesca , Ramoni Carlo , Marinari Barbara , Costanzo Antonio , Levrero Massimo , Thomson Lesley , Abraham Robert T. , Tuosto Loretta 
Published: April 2014

AbstractWe have recently observed that CD28 engagement initiates a signaling pathway leading to the activation of IκB kinase (IKK) complex and, consequently, to NF-κB activation, and we identified Vav-1 as an important mediator of this function. Here we report for the first time that Vav-1 constitutively associates with IKKα in both Jurkat and primary CD4+ T cells. Vav-1/IKKα association is mediated by their helix-loop-helix domains, does not involve IKKβ, and is functionally relevant in that Vav-1-associated IKKα kinase activity is increased following CD28 engagement by B7. Moreover, we demonstrate that CD28-induced NF-κB activation is augmented by both IKKα and Vav-1, but not IKKβ. Confocal microscopy showed that endogenous Vav-1 and IKKα, but not IKKβ, were recruited to the membrane and colocalized in response to CD28 stimulation. Taken together, these data evidence that Vav-1 plays a key role in the control of NF-κB pathway by targeting IKKα in the T cell membrane and favoring its activation in response to CD28 stimulation.
Glucocorticoids Alter the Lipid and Protein Composition of Membrane Rafts of a Murine T Cell Hybridoma
Authors: Laethem François Van , Liang Xiquan , Andris Fabienne , Urbain Jacques , Vandenbranden Michel , Ruysschaert Jean-Marie , Resh Marilyn D. , Stulnig Thomas M. , Leo Oberdan 
Published: April 2014

Abstract
Glucocorticoids (GC) are widely used anti-inflammatory agents known to suppress T cell activation by interfering with the TCR activation cascade. The attenuation of early TCR signaling events by these compounds has been recently attributed to a selective displacement of key signaling proteins from membrane lipid rafts. In this study, we demonstrate that GC displace the acyl-bound adaptor proteins linker for activation of T cells and phosphoprotein associated with glycosphingolipid-enriched microdomains from lipid rafts of murine T cell hybridomas, possibly by inhibiting their palmitoylation status. Analysis of the lipid content of the membrane rafts revealed that GC treatment led to a significant decrease in palmitic acid content. Moreover, we found an overall decrease in the proportion of raft-associated saturated fatty acids. These changes were consistent with a decrease in fluorescence anisotropy of isolated lipid rafts, indicating an increase in their fluidity. These findings identify the mechanisms underlying the complex inhibitory effects of glucocorticoids on early TCR signaling and suggest that some of the inhibitory properties of GC on T cell responses may be related to their ability to affect the membrane lipid composition and the palmitoylation status of important signaling molecules.
The Cyclic Adenosine 5′-Monophosphate Response Element Modulator Suppresses IL-2 Production in Stimulated T Cells by a Chromatin-Dependent Mechanism
Authors: Tenbrock Klaus , Juang Yuang-Taung , Tolnay Mate , Tsokos George C. 
Published: April 2014

Abstract
The production of IL-2 is tightly controlled by several transcription factors that bind to the IL-2 promoter. The cAMP response element modulator (CREM) is known to form complexes with CREB and bind to the −180 site of the IL-2 promoter in anergic and in systemic lupus erythematosus T cells. In this study we show that CREM is transcriptionally induced in T cells following stimulation through CD3 and CD28, binds to the IL-2 promoter in vivo, and suppresses IL-2 production. Transfection of an antisense CREM plasmid into T cells blocked the expression and binding of CREM to the IL-2 promoter and the decrease of IL-2 production, which follows the early increase after T cell stimulation with CD3 and CD28. In addition, as assessed by chromatin immunoprecipitation experiments, antisense CREM prevented the binding of protein 300 and cAMP response element binding protein and promoted the acetylation of histones. Antisense CREM also enhanced the accessibility of the IL-2 promoter to endonucleases and prevented the condensation of chromatin in vivo. Our data suggest that upon T cell activation, CREM gradually replaces phosphorylated CREB at the −180 site of the IL-2 promoter. CREM, in turn, binds protein 300 and cAMP response element binding protein, but CREM is unable to activate its histone acetyltransferase activity, which results in condensation of chromatin and down-regulation of IL-2 production.
Quantifying Recruitment of Cytosolic Peptides for HLA Class I Presentation: Impact of TAP Transport
Authors: Fruci Doriana , Lauvau Grégoire , Saveanu Loredana , Amicosante Massimo , Butler Richard H. , Polack Axel , Ginhoux Florent , Lemonnier François , Firat Hüseyin , van Endert Peter M. 
Published: April 2014

AbstractMHC class I ligands are recruited from the cytosolic peptide pool, whose size is likely to depend on the balance between peptide generation by the proteasome and peptide degradation by downstream peptidases. We asked what fraction of this pool is available for presentation, and how the size of this fraction is modulated by peptide affinity for the TAP transporters. A model epitope restricted by HLA-A2 and a series of epitope precursors with N-terminal extensions by single residues modifying TAP affinity were expressed in a system that allowed us to monitor and modulate cytosolic peptide copy numbers. We show that presentation varies strongly according to TAP affinities of the epitope precursors. The fraction of cytosolic peptides recruited for MHC presentation does not exceed 1% and is more than two logs lower for peptides with very low TAP affinities. Therefore, TAP affinity has a substantial impact on MHC class I Ag presentation.
Regulatory T Cells Control Autoimmunity In Vivo by Inducing Apoptotic Depletion of Activated Pathogenic Lymphocytes
Authors: Madakamutil Loui Thomas , Maricic Igor , Sercarz Eli , Kumar Vipin 
Published: April 2014

Abstract
Clinical autoimmunity requires both activation of self-reactive T cells as well as a failure of peripheral tolerance mechanisms. We previously identified one such mechanism that involves regulatory T cells recognizing TCR Vβ8.2 chain-derived peptides in the context of MHC. How this regulation affects the fate of target Vβ8.2+ T lymphocytes in vivo that mediate experimental autoimmune encephalomyelitis has remained unknown. The present study using immunoscope and CFSE-labeling analysis demonstrates that the expansion of regulatory CD4 and CD8 T cells in vivo results in apoptotic depletion of the dominant, myelin basic protein-reactive Vβ8.2+ T cells, but not subdominant Vβ13+ T cells. The elimination of only activated T cells by this negative feedback mechanism preserves the remainder of the naive Vβ8.2+ T cell repertoire and at the same time results in protection from disease. These studies are the first in clearly elucidating the fate of myelin basic protein-specific encephalitogenic T cells in vivo following regulation.
Cu/Zn Superoxide Dismutase Plays Important Role in Immune Response
Authors: Marikovsky Moshe , Ziv Vered , Nevo Nava , Harris-Cerruti Catherine , Mahler Ori 
Published: April 2014

Abstract
Activation of macrophages leads to the secretion of cytokines and enzymes that shape the inflammatory response and increase metabolic processes. This, in turn, results in increased production of reactive oxygen species. The role of Cu/Zn superoxide dismutase (SOD-1), an important enzyme in cellular oxygen metabolism, was examined in activated peritoneal elicited macrophages (PEM) and in several inflammatory processes in vivo. LPS and TNF-α induced SOD-1 in PEM. SOD-1 induction by LPS was mainly via extracellular signal-regulated kinase-1 activation. Transgenic mice overexpressing SOD-1 demonstrated a significant increase in the release of TNF-α and of the metalloproteinases MMP-2 and MMP-9 from PEM. Disulfiram (DSF), an inhibitor of SOD-1, strongly inhibited the release of TNF-α, vascular endothelial growth factor, and MMP-2 and MMP-9 from cultured activated PEM. These effects were prevented by addition of antioxidants, further indicating involvement of reactive oxygen species. In vivo, transgenic mice overexpressing SOD-1 demonstrated a 4-fold increase in serum TNF-α levels and 2-fold stronger delayed-type hypersensitivity reaction as compared with control nontransgenic mice. Conversely, oral administration of DSF lowered TNF-α serum level by 4-fold, lowered the delayed-type hypersensitivity response in a dose-dependent manner, and significantly inhibited adjuvant arthritis in Lewis rats. The data suggest an important role for SOD-1 in inflammation, establish DSF as a potential inhibitor of inflammation, and raise the possibility that regulation of SOD-1 activity may be important in the treatment of immune-dependent pathologies.
CD28 Signal Enhances Apoptosis of CD8 T Cells After Strong TCR Ligation
Authors: Yu Xue-Zhong , Martin Paul J. , Anasetti Claudio 
Published: April 2014

AbstractHigh avidity ligation of the TCR induces negative selection in the thymus and can also induce apoptosis of peripheral T cells. Costimulation through CD28 enhances T cell activation and facilitates negative selection in the thymus, but the role of CD28 in peripheral T cell deletional tolerance has not been investigated. We used 2C CD28 wild-type and 2C CD28-deficient strains to assess the effects of CD28 and TCR avidity on peripheral T cell expansion and apoptosis. We compared the activation, division, expansion, and apoptosis of CD28+/+ and CD28−/− 2C cells in response to self-Ag (Kb), alloantigens with intermediate (Kbm3), high (Ld), or very high (Ld + QL9 peptide) avidity. With intermediate avidity alloantigen, the CD28 signal enhanced T cell activation and expansion. However, when T cells encountered high avidity alloantigen, the CD28 signal reduced T cell expansion and increased apoptosis. These results indicate that the CD28 signal can down-regulate peripheral T cell responses by increasing apoptosis when TCR ligation exceeds a critical threshold.
Activation of Alloreactive CD8+ T Cells Operates Via CD4-Dependent and CD4-Independent Mechanisms and Is CD154 Blockade Sensitive
Authors: Zhai Yuan , Meng Lingzhong , Busuttil Ronald W. , Sayegh Mohamed H. , Kupiec-Weglinski Jerzy W. 
Published: April 2014

Abstract
CD154, one of the most extensively studied T cell costimulation molecules, represents a promising therapeutic target in organ transplantation. However, the immunological mechanisms of CD154 blockade that result in allograft protection, particularly in the context of alloreactive CD4/CD8 T cell activation, remain to be elucidated. We now report on the profound inhibition of alloreactive CD8+ T cells by CD154 blockade via both CD4-dependent and CD4-independent activation pathways. Using CD154 KO recipients that are defective in alloreactive CD8+ T cell activation and unable to reject cardiac allografts, we were able to restore CD8 activation and graft rejection by adoptively transferring CD4+ or CD8+ T cells from wild-type syngeneic donor mice. CD4-independent activation of alloreactive CD8+ T cells was confirmed following treatment of wild-type recipients with CD4-depleting mAb, and by using CD4 KO mice. Comparable levels of alloreactive CD8+ T cell activation was induced by allogenic skin engraftment in both animal groups. CD154 blockade inhibited CD4-independent alloreactive CD8+ T cell activation. Furthermore, we analyzed whether disruption of CD154 signaling affects cardiac allograft survival in skin-sensitized CD4 KO and CD8 KO recipients. A better survival rate was observed consistently in CD4 KO, as compared with CD8 KO recipients. Our results document CD4-dependent and CD4-independent activation pathways for alloreactive CD8+ T cells that are both sensitive to CD154 blockade. Indeed, CD154 blockade was effective in preventing CD8+ T cell-mediated cardiac allograft rejection.
Ca2+ Stores and Ca2+ Entry Differentially Contribute to the Release of IL-1β and IL-1α from Murine Macrophages
Authors: Brough David , Le Feuvre Rosalind A. , Wheeler Rachel D. , Solovyova Natasha , Hilfiker Sabine , Rothwell Nancy J. , Verkhratsky Alex 
Published: April 2014

Abstract
Interleukin-1 is a primary mediator of immune responses to injury and infection, but the mechanism of its cellular release is unknown. IL-1 exists as two agonist forms (IL-1α and IL-1β) present in the cytosol of activated monocytes/macrophages. IL-1β is synthesized as an inactive precursor that lacks a signal sequence, and its trafficking does not use the classical endoplasmic reticulum-Golgi route of secretion. Using primary cultured murine peritoneal macrophages, we demonstrate that P2X7 receptor activation causes release of IL-1β and IL-1α via a common pathway, dependent upon the release of Ca2+ from endoplasmic reticulum stores and caspase-1 activity. Increases in intracellular Ca2+ alone do not promote IL-1 secretion because a concomitant efflux of K+ through the plasmalemma is required. In addition, we demonstrate the existence of an alternative pathway for the secretion of IL-1α, independent of P2X7 receptor activation, but dependent upon Ca2+ influx. The identification of these mechanisms provides insight into the mechanism of IL-1 secretion, and may lead to the identification of targets for the therapeutic modulation of IL-1 action in inflammation.
Mast Cell-Derived Exosomes Induce Phenotypic and Functional Maturation of Dendritic Cells and Elicit Specific Immune Responses In Vivo
Authors: Skokos Dimitris , Botros Hany Goubran , Demeure Christian , Morin Joelle , Peronet Roger , Birkenmeier Gerd , Boudaly Sarah , Mécheri Salaheddine 
Published: April 2014

AbstractMast cells (MCs) are considered major players in IgE-mediated allergic responses, but have also recently been recognized as active participants in innate as well as specific immune responses. Recent work provided evidence that MCs are able to activate B and T lymphocytes through the release of vesicles called exosomes. Here we demonstrate that exosomes, which are located in the endocytic pathway, harbor exogenous Ags that associate with other molecules endowed with immunomodulatory functions, including 60- and 70-kDa heat shock proteins. Administration to naive mice of Ag-containing exosomes in the absence of conventional adjuvants elicits specific Ab responses across the MHC II haplotype barrier. We demonstrate that MC-exosomes induce immature dendritic cells (DCs) to up-regulate MHC class II, CD80, CD86, and CD40 molecules and to acquire potent Ag-presenting capacity to T cells. Uptake and processing of Ag-associated exosomes by endogenous DCs were also demonstrated. Finally, exosome-associated heat shock proteins are critical for the acquisition by DCs of the Ag-presenting function. This work demonstrates a heretofore unrecognized collaborative interaction between MCs and DCs leading to the elicitation of specific immune responses.