bluuebunny/crossref_metadata_2025_split huggingface dataset:
New Insights into the Molecular Basis of T Cell Anergy: Anergy Factors, Avoidance Sensors, and Epigenetic Imprinting
Authors: Wells Andrew D. 
Published: June 2009

Abstract
The vertebrate immune system has evolved to deal with invasive pathogens, but this adaptation comes at the expense of immunopathology. Among a number of mechanisms that coevolved to control adaptive immunity is anergy, the functional inactivation of T lymphocytes that respond to Ag in the absence of inflammation. In this review, I highlight a series of intracellular proteins in quiescent T cells that function to integrate signals from Ag, costimulatory, and growth factor receptors. These factors ensure that cells that fail to engage all three pathways are shunted into an alternative transcriptional program designed to dissuade them from participating in subsequent immune responses. Recent studies indicate that anergy is the combined result of factors that negatively regulate proximal TCR-coupled signal transduction, together with a program of active transcriptional silencing that is reinforced through epigenetic mechanisms.
Heterogeneity in HIV Suppression by CD8 T Cells from HIV Controllers: Association with Gag-Specific CD8 T Cell Responses
Authors: Sáez-Cirión Asier , Sinet Martine , Shin So Youn , Urrutia Alejandra , Versmisse Pierre , Lacabaratz Christine , Boufassa Faroudy , Avettand-Fènoël Véronique , Rouzioux Christine , Delfraissy Jean-François , Barré-Sinoussi Françoise , Lambotte Olivier , Venet Alain , Pancino Gianfranco ,   for the ANRS EP36 HIV Controllers Study Group
Published: June 2009

Abstract
“HIV controllers” (HICs) are rare individuals in whom HIV-1 plasma viral load remains undetectable without antiretroviral treatment. This spontaneous viral control in HICs is usually associated to strong functional HIV-specific CD8+ T cell responses. Accordingly, we have recently shown that CD8+ T cells from HICs strongly suppress ex vivo HIV-1 infection of autologous CD4+ T cells, suggesting a crucial role of this response in vivo. Knowledge of the mechanisms underlying the CD8+ T cell antiviral activity might help to develop effective T cell-based vaccines. In the present work, we further characterized the HIV-suppressive capacity of CD8+ T cells in 19 HICs. CD8+ T cells from 14 of the 19 HICs showed strong HIV-suppressive capacity ex vivo. This capacity was stable over time and was partially effective even on other primate lentiviruses. HIV-suppressive capacity of CD8+ T cells correlated strongly with the frequency of HIV-specific CD8+ T cells, and in particular of Gag-specific CD8+ T cells. We also identified five HICs who had weak HIV-suppressive CD8+ T cell capacities and HIV-specific CD8+ T cell responses. Among these five HICs, at least three had highly in vitro replicative viruses, suggesting that the control of viremia in these patients is not due to replication-defective viruses. These results, on the one hand, suggest the importance of Gag responses in the antiviral potency of CD8+ T cells from HICs and, on the other hand, propose that other host mechanisms may contribute to restraining HIV infection in HICs.
Crucial Role of TNF Receptors 1 and 2 in the Control of Polymicrobial Sepsis
Authors: Secher Thomas , Vasseur Virginie , Poisson Didier Marc , Mitchell Jane A. , Cunha Fernando Q. , Alves-Filho José Carlos , Ryffel Bernhard 
Published: June 2009

Abstract
Sepsis is still a major cause of mortality in the intensive critical care unit and results from an overwhelming immune response to the infection. TNF signaling pathway plays a central role in the activation of innate immunity in response to pathogens. Using a model of polymicrobial sepsis by i.p. injection of cecal microflora, we demonstrate a critical role of TNFR1 and R2 activation in the deregulated immune responses and death associated with sepsis. A large and persistent production of TNF was found in wild-type (B6) mice. TNFR1/R2-deficient mice, compared with B6 mice, survive lethal polymicrobial infection with enhanced neutrophil recruitment and bacterial clearance in the peritoneal cavity. Absence of TNFR signaling leads to a decreased local and systemic inflammatory response with diminished organ injury. Furthermore, using TNFR1/R2-deficient mice, TNF was found to be responsible for a decrease in CXCR2 expression, explaining reduced neutrophil extravasation and migration to the infectious site, and in neutrophil apoptosis. In line with the clinical experience, administration of Enbrel, a TNF-neutralizing protein, induced however only a partial protection in B6 mice, with no improvement of clinical settings, suggesting that future TNF immunomodulatory strategies should target TNFR1 and R2. In conclusion, the present data suggest that the endogenous TNFR1/R2 signaling pathway in polymicrobial sepsis reduces neutrophil recruitment contributing to mortality and as opposed to pan-TNF blockade is an important therapeutic target for the treatment of polymicrobial sepsis.
Cross-Presentation of Male Seminal Fluid Antigens Elicits T Cell Activation to Initiate the Female Immune Response to Pregnancy
Authors: Moldenhauer Lachlan M. , Diener Kerrilyn R. , Thring Dougal M. , Brown Michael P. , Hayball John D. , Robertson Sarah A. 
Published: June 2009

Abstract
The events that generate T cell-mediated immune tolerance in early pregnancy are ill-defined. To investigate the significance of seminal fluid Ags in activating maternal T cells, and define the underlying Ag presentation pathways, OVA-specific T cells were adoptively transferred to female mice inseminated by males ubiquitously expressing membrane-bound OVA. OVA-reactive CD8+ OT-I and CD4+ OT-II T cells transferred to mated recipients expressed activation markers CD25 and CD69 and proliferated vigorously in the para-aortic lymph nodes, but not in distal lymph nodes or spleen, and OT-I T cells expressed IFN-γ and IL-2. In contrast, OT-I T cells transferred later in pregnancy or up to 10 days postpartum expressed CD25 and CD69 and proliferated in all peripheral lymphoid tissues examined. OVA Ag was present predominantly in the plasma fraction of seminal fluid, and seminal plasma, but not sperm, was necessary for T cell proliferation. Female H-2Kb bone marrow-derived cells expressing TAP were essential for OT-I T cell proliferation, but responses were not elicited by OVA Ag presented by paternal MHC in seminal fluid or associated with placental cells. This study shows that at conception, seminal fluid drives activation and expansion of paternal Ag-reactive CD4+ and CD8+ T cell populations, and female APCs have an essential role in cross-presenting Ag to CD8+ T cells via a TAP-dependent pathway. Delivery of paternal Ags and immune-deviating cytokines by seminal fluid at conception may activate Ag-dependent CD4+ and CD8+ regulatory T cells mediating tolerance of pregnancy.
Novel Function of CRTH2 in Preventing Apoptosis of Human Th2 Cells through Activation of the Phosphatidylinositol 3-Kinase Pathway
Authors: Xue Luzheng , Barrow Anna , Pettipher Roy 
Published: June 2009

Abstract
It is now well established that interaction of PGD2 with chemoattractant receptor- homologous molecule expressed on Th2 cells (CRTH2) promotes chemotaxis and proinflammatory cytokine production by Th2 lymphocytes. In this study we show a novel function of CRTH2 in mediating an inhibitory effect of PGD2 on the apoptosis of human Th2 cells induced by cytokine deprivation. This effect was mimicked by the selective CRTH2 agonist 13,14-dihydro-15-keto-PGD2, inhibited by the CRTH2 antagonists ramatroban and TM30089, and not observed in CRTH2-negative T cells. D prostanoid receptor 1 (DP1) or the thromboxane-like prostanoid (TP) receptor did not play a role in mediating the effects of PGD2 on the apoptosis of Th2 cells because neither the DP1 antagonist BW868C nor the TP antagonist SQ29548 had any effect on the antiapoptotic effect of PGD2. Apoptosis of Th2 cells induced by Fas ligation was not suppressed by treatment with PGD2, illustrating that activation of CRTH2 only inhibits apoptosis induced by cytokine deprivation. Treatment with PGD2 induced phosphorylation of Akt and BAD, prevented release of cytochrome c from mitochondria, and suppressed cleavage of caspase-3 and poly(ADP-ribose) polymerase in Th2 cells deprived of IL-2. The PI3K inhibitor LY294002 blocked the effect of PGD2 both on the signaling events and on the apoptotic death of Th2 cells. These data suggest that in addition to promoting the recruitment and activation of Th2 cells, PGD2 may also impede the resolution of allergic inflammation through inhibiting apoptosis of Th2 cells.
Atherogenic Lipids Induce High-Density Lipoprotein Uptake and Cholesterol Efflux in Human Macrophages by Up-Regulating Transmembrane Chemokine CXCL16 without Engaging CXCL16-Dependent Cell Adhesion
Authors: Barlic Jana , Zhu Wenjia , Murphy Philip M. 
Published: June 2009

AbstractAtherosclerosis is a complex pathologic process in which chemokine-mediated leukocyte accumulation in arterial walls is thought to be an important mechanism of pathogenesis. An interesting exception to this paradigm is the chemokine CXCL16, also known as the scavenger receptor for phosphatidylserine and oxidized low density lipoprotein, which is highly expressed in mouse and human atherosclerotic lesions, yet appears to be atheroprotective. In this study, we address potential mechanisms responsible for this activity. Consistent with its presence in atherosclerotic plaque, we found that atherogenic lipids up-regulated CXCL16 in primary human monocyte-derived macrophages. However, the same lipids down-regulated the CXCL16-targeted protease ADAM10, resulting in preferential expression of CXCL16 as the transmembrane form, not the shed form. Although transmembrane CXCL16 is known to mediate cell-cell adhesion by binding its receptor CXCR6, and atherogenic lipids are known to stimulate macrophage adhesion to coronary artery smooth muscle cells, we found that heterotypic adhesion of these cell types occurred in a CXCL16-independent manner. Instead we found that in macrophages, CXCL16 promoted internalization of both oxidized low density lipoprotein and high density lipoprotein, as well as release of cholesterol. Moreover, CXCL16 deficiency in macrophages interfered with oxidized low density lipoprotein-induced up-regulation of atheroprotective genes: adenosine triphosphate-binding cassette transporter A1 and G1 as well as apolipoprotein E. Thus, our findings support the hypothesis that CXCL16 mediates atheroprotection through its scavenger role in macrophages and not by cell-cell adhesion.
Modulation of p38 MAPK Activity in Regulatory T Cells after Tolerance with Anti-DNA Ig Peptide in (NZB × NZW)F1 Lupus Mice
Authors: Lourenço Elaine V. , Procaccini Claudio , Ferrera Francesca , Iikuni Noriko , Singh Ram P. , Filaci Gilberto , Matarese Giuseppe , Shi Fu-Dong , Brahn Ernest , Hahn Bevra H. , La Cava Antonio 
Published: June 2009

Abstract
Treatment of (NZB × NZW)F1 (NZB/W) lupus-prone mice with the anti-DNA Ig-based peptide pConsensus prolongs the survival of treated animals and effectively delays the appearance of autoantibodies and glomerulonephritis. We have previously shown that part of these protective effects associated with the induction of CD4+CD25+Foxp3+ regulatory T cells (Tregs) that suppressed autoantibody responses. Because the effects of pConsensus appeared secondary to qualitative rather than quantitative changes in Tregs, we investigated the molecular events induced by tolerance in Tregs and found that signaling pathways including ZAP70, p27, STAT1, STAT3, STAT6, SAPK, ERK, and JNK were not significantly affected. However, peptide tolerization affected in Tregs the activity of the MAPK p38, whose phosphorylation was reduced by tolerance. The pharmacologic inhibition of p38 with the pyridinyl imidazole inhibitor SB203580 in naive NZB/W mice reproduced in vivo the effects of peptide-induced tolerance and protected mice from lupus-like disease. Transfer experiments confirmed the role of p38 in Tregs on disease activity in the NZB/W mice. These data indicate that the modulation of p38 activity in lupus Tregs can significantly influence the disease activity.
Direct Stimulation of tlr5+/+ CD11c+ Cells Is Necessary for the Adjuvant Activity of Flagellin
Authors: Bates John T. , Uematsu Satoshi , Akira Shizuo , Mizel Steven B. 
Published: June 2009

Abstract
Flagellin is a highly effective adjuvant, but the cellular mechanism underlying this activity remains uncertain. More specifically, no consensus exists as to whether flagellin activates dendritic cells (DC) directly or indirectly. Intramuscular immunization with flagellin-OVA fusion protein resulted in enhanced in vivo T cell clustering in draining lymph nodes and IL-2 production by OVA-specific CD4+ T cells. Immunization with flagellin-OVA also triggered greater levels of Ag-specific CD4+ T cell proliferation than immunization with flagellin and OVA as separate proteins. To determine whether flagellin, in the context of a fusion protein with OVA, was acting directly on DC, we used a combination of CD4+ T cell adoptive transfers and bone marrow chimera mice in which the presence or absence of potential tlr5+/+ CD11c+ cells was controlled by injection of diphtheria toxin. The Ag-specific CD4+ T cell response in mice with CD11c+ cells from a tlr5−/− background and mixed populations of all other hematopoietic cells was dramatically reduced in comparison to mice that had DC from tlr5−/− and wild-type backgrounds. Immunization of MyD88−/−tlr5+/+ mice revealed that the enhanced response following immunization with flagellin-OVA is dependent on signaling via the TLR5-MyD88 pathway as well as enhanced Ag uptake and processing resulting from Ag targeting via TLR5. In summary, our data are consistent with the conclusion that direct stimulation of tlr5+/+ CD11c+ cells is necessary for the adjuvant activity of a flagellin fusion protein and that this adjuvant effect requires signaling through TLR5.
Wiskott-Aldrich Syndrome Protein Is Required for Homeostasis and Function of Invariant NKT Cells
Authors: Astrakhan Alexander , Ochs Hans D. , Rawlings David J. 
Published: June 2009

Abstract
NKT cells comprise a separate T lineage expressing semi-invariant T cell receptors. Canonical invariant NKT (iNKT) cells specifically recognize lipid Ags presented by CD1d, a MHC class I-like molecule. iNKT cells function, in part, as initial responders to bacterial infection and play a role in immune surveillance and tumor rejection. The Wiskott-Aldrich Syndrome protein (WASp) serves as a crucial link between cellular stimuli and cytoskeletal rearrangements. Although we and others have identified a key role for WASp in homeostasis of T-regulatory and marginal zone B cells, little data exist regarding the role for WASp within the iNKT lineage. Analysis of WASp-expressing cell populations in heterozygous female WASp mice revealed a substantial selective advantage for WASp+ vs WASp− iNKT cells. Although adult WASp-deficient (WASp−/−) mice had normal thymic and bone marrow iNKT numbers, we observed 2- to 3-fold reduction in the numbers of iNKT cells in the spleen and liver. This peripheral iNKT deficit is manifested, in part, due to defective iNKT homeostasis. WASp−/− iNKT cells exhibited reduced levels of integrin surface expression and decreased homing and/or retention within peripheral tissues in a competitive repopulation model. In addition, analysis of young mice showed that WASp is important for both maturation and egress of thymic iNKT cells. WASp−/− iNKT cells also exhibited a marked reduction in Ag-induced proliferation and cytokine production. Our findings highlight the crucial role for WASp in iNKT development, homeostasis, and activation, and identify iNKT dysfunction as an additional factor likely to contribute to the clinical features observed in WAS patients.
HSP90α and HSP90β Isoforms Selectively Modulate MHC Class II Antigen Presentation in B Cells
Authors: Houlihan Josetta L. , Metzler Jennifer J. , Blum Janice S. 
Published: June 2009

Abstract
Two isoforms of heat shock protein (HSP) 90, α and β, are abundantly expressed in the cytoplasm of cells, yet only HSP90α serves as a chaperone to potentiate epitope presentation in the context of MHC class I molecules. By contrast, the role of HSP90 isoforms in MHC class II presentation of exogenous and endogenous Ags remains less clear. Studies here using human B lymphoblasts demonstrate the importance of HSP90α and HSP90β isoforms in selectively regulating class II presentation of the diabetes autoantigen glutamic acid decarboxylase (GAD). Inactivation of HSP90 function using geldanamycin or radicicol inhibited MHC class II presentation of exogenous and endogenous GAD, but did not perturb the presentation of several other intra- and extracellular Ags. Treatment of human B cells with geldanamycin and radicicol did not alter cellular MHC class II expression, but did induce a stress response in these APCs. Yet, cell stress alone failed to perturb MHC class II presentation of GAD. HSP90 was found to associate with select Ags such as GAD in cells and ex vivo. Knockdown of HSP90α or HSP90β expression using small interfering RNA decreased the abundance of each isoform, respectively, but did not affect MHC class II expression or induce a stress response. Notably, disruption of HSP90α or HSP90β expression specifically inhibited class II presentation of the exogenous and endogenous GAD Ag. Precomplexing HSP90 with GAD Ag enhanced exogenous GAD Ag presentation. These results demonstrate a requirement for HSP90α and HSP90β in regulating class II presentation of select Ags.
Regulation of T Cell Activation by Notch Ligand, DLL4, Promotes IL-17 Production and Rorc Activation
Authors: Mukherjee Sumanta , Schaller Matthew A. , Neupane Rupak , Kunkel Steven L. , Lukacs Nicholas W. 
Published: June 2009

AbstractThe activation and differentiation of T cells are dependent upon numerous initiating events that are influenced by the immune environment, nature of the Ag, as well as the activation state of APCs. In the present studies we have investigated the role of a specific notch ligand, delta-like 4 (Dll4). In particular, our data have indicated that Dll4 is inducible by pathogen-associated signals through TLR activation on dendritic cells but not early response inflammatory cytokines, IL-1 and IL-18 that also activate cells via MyD88 adapter pathway. Our observations from in vitro cultures confirmed earlier reports demonstrating that Dll4 inhibits Th2 cytokine production. Furthermore, Dll4 influences the generation of IL-17-producing T cells in the presence of additional skewing cytokines, IL-6 and TGF-β. In the absence of notch signals, IL-17 production was significantly inhibited even under specific skewing conditions. These studies further demonstrate that Dll4 up-regulates Rorc expression in T cells and that both Rorc and Il17 gene promoters are direct transcriptional notch targets that further enhance the differentiation of Th17 cell populations. Thus, facilitation of efficient T cell differentiation may depend upon the activation of T cells via specific notch ligand stimulation.
The Immunoregulatory Enzyme IDO Paradoxically Drives B Cell-Mediated Autoimmunity
Authors: Scott Grant N. , DuHadaway James , Pigott Elizabeth , Ridge Natalie , Prendergast George C. , Muller Alexander J. , Mandik-Nayak Laura 
Published: June 2009

AbstractRheumatoid arthritis (RA) is a chronic and debilitating inflammatory autoimmune disease of unknown etiology. As with a variety of autoimmune disorders, evidence of elevated tryptophan catabolism has been detected in RA patients indicative of activation of the immunomodulatory enzyme IDO. However, the role that IDO plays in the disease process is not well understood. The conceptualization that IDO acts solely to suppress effector T cell activation has led to the general assumption that inhibition of IDO activity should exacerbate autoimmune disorders. Recent results in cancer models, however, suggest a more complex role for IDO as an integral component of the inflammatory microenvironment necessary for supporting tumor outgrowth. This has led us to investigate the involvement of IDO in the pathological inflammation associated with RA. Using the K/BxN murine RA model and IDO inhibitor 1-methyl-tryptophan, we found that inhibiting IDO activity had the unexpected consequence of ameliorating, rather than exacerbating arthritis symptoms. 1-Methyl tryptophan treatment led to decreased autoantibody titers, reduced levels of inflammatory cytokines, and an attenuated disease course. This alleviation of arthritis was not due to an altered T cell response, but rather resulted from a diminished autoreactive B cell response, thus demonstrating a previously unappreciated role for IDO in stimulating B cell responses. Our findings raise the question of how an immunosuppressive enzyme can paradoxically drive autoimmunity. We suggest that IDO is not simply immunosuppressive, but rather plays a more complex role in modulating inflammatory responses, in particular those that are driven by autoreactive B cells.
CD154-CD40 Interactions Are Essential for Thymus-Dependent Antibody Production in Zebrafish: Insights into the Origin of Costimulatory Pathway in Helper T Cell-Regulated Adaptive Immunity in Early Vertebrates
Authors: Gong Yong-Feng , Xiang Li-Xin , Shao Jian-Zhong 
Published: June 2009

Abstract
The CD154-CD40-mediated costimulatory pathway is critical for T-B cell cooperation in thymus-dependent (TD) immune response in mammals. However, little is known about its existence and occurrence in lower vertebrates. Here, we report on the identification and functional characterization of CD154 and CD40 homologs from the zebrafish (Danio rerio) model. Zebrafish CD154 is a type II membrane-bound protein with a TNF homology domain in its extracellular C-terminal region, whose tertiary structure is a sandwich containing two stacked sheets with “jelly roll” topology, just as the human TNF members do. The zebrafish CD40 is a type I membrane-bound protein with a sequence pattern of four cysteine-rich domains in its extracellular N-terminal region. The consensus TNFR-associated factor (TRAF)2- and TRAF6-binding motifs in mammalian CD40 are found in the cytoplasmic tail of zebrafish CD40, which indicates similar signal transduction mechanisms to higher vertebrates. Zebrafish CD154 and CD40 are widely distributed and can be up-regulated by thymus-dependent Ag. The production of IgM was dramatically decreased by anti-CD154 or soluble CD40, and it was enhanced by soluble CD154 or CD154-encoding plasmid in vivo. Thymus-dependent Ag-induced CD154 expression was inhibited by cyclosporin A, suggesting that CD154 functionally associates with T cells. Double immunofluorescence staining showed that CD40 and membrane IgM colocalized in B cells. CD154-CD40 binding assays showed that CD154 specifically binds to CD40 at homodimeric form. Our results provide the first evidence for the existence of the functional CD154-CD40-mediated costimulatory pathway and helper T cell regulatory mechanism underlying adaptive immunity in a fish species.