bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overcoming T Cell Tolerance to the Hepatitis B Virus Surface Antigen in Hepatitis B Virus-Transgenic Mice
Authors: Sette Alessandro D. , Oseroff Carla , Sidney John , Alexander Jeff , Chesnut Robert W. , Kakimi Kazuhiro , Guidotti Luca G. , Chisari Francis V. 
Published: April 2014

Abstract
The sequence of the hepatitis B virus (HBV) major envelope (Env) protein (ayw subtype) was scanned for the presence of H-2d,b motifs. Following binding and immunogenicity testing, two new H-2d-restricted epitopes (Env.362 and Env.364) were identified. These epitopes induced CTLs capable of recognizing naturally processed HBV-Env, but were apparently generated with lower efficiency than the previously defined dominant Env.28 epitope. Next, HBV-transgenic mice that express all of the HBV proteins and produce fully infectious particles were immunized with a mixture of lipopeptides encompassing the Env.28, Env.362, and Env.364 epitopes. Significant CTL responses were obtained, but they had no effect on viral replication in the liver, nor did they induce an inflammatory liver disease. However, in adoptive transfer experiments, CTL lines generated from the HBV-transgenic mice following immunization were able to inhibit viral replication in vivo without causing hepatitis. This is in contrast to CTL lines derived from nontransgenic mice that displayed both antiviral and cytopathic effects, presumably because they displayed higher avidity for the viral epitopes than the transgenic CTLs. These results suggest that T cell tolerance to HBV can be broken with appropriate immunization but the magnitude and characteristics of the resultant T cell response are significantly different from the response in HBV-naive individuals since their antiviral potential is stronger than their cytotoxic potential. This has obvious implications for immunotherapy of chronic HBV infection.
Cutting Edge: Differential Sequestration of Plasma Membrane-Associated B Cell Antigen Receptor in Mature and Immature B Cells into Glycosphingolipid-Enriched Domains
Authors: Chung James B. , Baumeister Mark A. , Monroe John G. 
Published: April 2014

Abstract
Glycosphingolipid-enriched domains (GEDs) are believed to act as platforms for transduction of B cell Ag receptor (BCR)-induced signals from the cell surface. We sought to study whether differential sequestration of BCR into GEDs may contribute to the described intrinsic signaling differences between mature and immature B cells. In this study we found that mature B cells copolarize the BCR with GEDs following BCR aggregation, whereas transitional immature B cells do not. Although anti-BCR treatment leads to receptor aggregation by immature stage B cells, the aggregated complexes do not colocalize with GEDs. We found this difference to be independent of the isotype of the receptor, thereby associating this difference in BCR-GED colocalization to the developmental stage of the B cell. These findings suggest a structural basis for the developmentally regulated differences observed in Ag receptor-mediated signal transduction.
Cutting Edge: Detection of Antigen-Specific CD4+ T Cells by HLA-DR1 Oligomers Is Dependent on the T Cell Activation State
Authors: Cameron Thomas O. , Cochran Jennifer R. , Yassine-Diab Bader , Sékaly Rafick-Pierre , Stern Lawrence J. 
Published: April 2014

Abstract
Class I MHC tetramers have proven to be invaluable tools for following and deciphering the CD8+ T cell response, but the development of similar reagents for detection of CD4+ T cells based on class II MHC proteins has been more difficult. We evaluated fluorescent streptavidin-based oligomers of HLA-DR1 for use as reagents to analyze Ag-specific human CD4+ T cells. Staining was blocked at low temperatures and by drugs that disrupt microfilament formation and endocytosis. Cell-associated MHC oligomers were resistant to a surface stripping protocol and were observed by microscopy in intracellular compartments. This behavior indicates that detection of CD4+ T cells using class II MHC oligomers can depend on an active cellular process in which T cells cluster and/or endocytose their Ag receptors. T cells of identical specificity but in different activation states varied greatly in their ability to be detected by class II MHC oligomers.
Gene Expression in Antigen-Specific CD8+ T Cells During Viral Infection
Authors: Grayson Jason M. , Murali-Krishna Kaja , Altman John D. , Ahmed Rafi 
Published: April 2014

AbstractFollowing infection with intracellular pathogens, Ag-specific CD8+ T cells become activated and begin to proliferate. As these cells become activated, they elaborate effector functions including cytokine production and cytolysis. After the infection has been cleared, the immune system returns to homeostasis through apoptosis of the majority of the Ag-specific effector cells. The surviving memory cells can persist for extended periods and provide protection against reinfection. Little is known about the changes in gene expression as Ag-specific cells progress through these stages of development, i.e., naive to effector to memory. Using recombinant MHC class I tetramers, we isolated Ag-specific CD8+ T cells from mice infected with lymphocytic choriomeningitis virus at various time points and performed semiquantitative RT-PCR. We examined expression of: 1) genes involved in cell cycle control, 2) effector and regulatory functions, and 3) susceptibility to apoptosis. We found that Ag-specific CD8+ memory T cells contain high steady-state levels of Bcl-2, Bax, IFN-γ, and lung Kruppel-like factor (LKLF), and decreased levels of p21 and p27 mRNA. Moreover, the pattern of gene expression between naive and memory cells is distinct and suggests that these two cell types control susceptibility to apoptosis through different mechanisms.
Soluble CD14 Mediates Efflux of Phospholipids from Cells
Authors: Sugiyama Tsuyoshi , Wright Samuel D. 
Published: April 2014

AbstractSoluble CD14 (sCD14), a 55-kDa glycoprotein found in plasma, has been shown to act as a shuttle for bacterial LPS and phospholipids, transporting LPS and phospholipid monomers from LPS aggregates or liposomes to high density lipoprotein particles. sCD14 has also been shown to mediate the transport of LPS and phosphatidylinositol into cells. Here we show that sCD14 mediates not only the influx but also the efflux of cellular phospholipids. Addition of sCD14 enhanced efflux of cellular phospholipids labeled with [3H]palmitic acid, [3H]oleic acid, or [3H]choline chloride from differentiated THP-1 monocytic cells. Efflux was dependent on the concentration of sCD14 added and was essentially complete in 30 min. The role of membrane-bound CD14 (mCD14) in lipid efflux was assessed using matched pairs of cell lines that express or fail to express this protein. While efflux was very dependent on mCD14 in U373 cells, it was not dependent on mCD14 in Chinese hamster ovary cells, suggesting a role for additional cellular proteins in determining the pathway of phospholipid efflux. A deletion mutant of sCD14 lacking the LPS binding site had less ability to efflux phospholipids than intact sCD14, suggesting that this site is needed for CD14 to serve in phospholipid transport. [3H]Palmitate-labeled lipids released by sCD14 were precipitated with anti-CD14 then analyzed by HPLC. Phosphatidylcholine was the dominant phospholipid exported and bound to sCD14. These results demonstrate that sCD14 mediates efflux of phospholipids from cells and suggest that sCD14 contributes to phospholipid transport in blood.
CD11b Expression Identifies CD8+CD28+ T Lymphocytes with Phenotype and Function of Both Naive/Memory and Effector Cells
Authors: Fiorentini Simona , Licenziati Stefano , Alessandri Giulio , Castelli Francesco , Caligaris Silvio , Bonafede Monica , Grassi Manuela , Garrafa Emirena , Balsari Andrea , Turano Adolfo , Caruso Arnaldo 
Published: April 2014

Abstract
A previously unreported CD8+CD28+CD11b+ T cell subset occurs in healthy individuals and expands in patients suffering from primary viral infections. In functional terms, these cells share the features of naive/memory CD8+CD28+CD11b− and terminally differentiated effector CD8+CD28−CD11b+ subpopulations. Like CD28− cells, CD28+CD11b+ lymphocytes have the ability to produce IFN-γ, to express perforin granules in vivo, and to exert a potent cytolytic activity. Moreover, these cells can respond to chemotactic stimuli and can efficiently cross the endothelial barrier. In contrast, like their CD11b− counterpart, they still produce IL-2 and retain the ability to proliferate following mitogenic stimuli. The same CD28+CD11b+ subpopulation detected in vivo could be generated by culturing naive CD28+CD11b− cells in the presence of mitogenic stimuli following the acquisition of a CD45RO+ memory phenotype. Considering both phenotypic and functional properties, we argue that this subset may therefore constitute an intermediate phenotype in the process of CD8+ T cell differentiation and that the CD11b marker expression can distinguish between memory- and effector-type T cells in the human CD8+CD28+ T cell subset.
Heterogeneity of the Memory CD4 T Cell Response: Persisting Effectors and Resting Memory T Cells
Authors: Ahmadzadeh Mojgan , Hussain S. Farzana , Farber Donna L. 
Published: April 2014

AbstractDefining the cellular composition of the memory T cell pool has been complicated by an inability to distinguish effector and memory T cells. We present here an activation profile assay, using anti-CD3 and antigenic stimuli, that clearly distinguishes effector and memory CD4 T cells and defines subsets of long-lived memory CD4 T cells based on CD62 ligand (CD62L) expression. The CD62Llow memory subset functionally resembles effector cells, exhibiting hyper-responsiveness to antigenic and anti-CD3 mediated stimuli, high proliferative capacity, and rapid activation kinetics. The CD62Lhigh memory subset functionally resembles resting memory cells, exhibiting hyporesponsiveness to anti-CD3 stimuli, lower proliferative capacity, and slower activation kinetics. Our results indicate that the memory CD4 T cell pool is heterogeneous, consisting of persisting effectors and resting memory T cells.
Selective Blocking of Voltage-Gated K+ Channels Improves Experimental Autoimmune Encephalomyelitis and Inhibits T Cell Activation
Authors: Beeton Christine , Barbaria Jocelyne , Giraud Pierre , Devaux Jerome , Benoliel Anne-Marie , Gola Maurice , Sabatier Jean Marc , Bernard Dominique , Crest Marcel , Béraud Evelyne 
Published: April 2014

Abstract
Kaliotoxin (KTX), a blocker of voltage-gated potassium channels (Kv), is highly selective for Kv1.1 and Kv1.3. First, Kv1.3 is expressed by T lymphocytes. Blockers of Kv1.3 inhibit T lymphocyte activation. Second, Kv1.1 is found in paranodal regions of axons in the central nervous system. Kv blockers improve the impaired neuronal conduction of demyelinated axons in vitro and potentiate the synaptic transmission. Therefore, we investigated the therapeutic properties of KTX via its immunosuppressive and symptomatic neurological effects, using experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. The T line cells used to induce adoptive EAE were myelin basic protein (MBP)-specific, constitutively contained mRNA for Kv1.3. and expressed Kv1.3. These channels were shown to be blocked by KTX. Activation is a crucial step for MBP T cells to become encephalitogenic. The addition of KTX during Ag-T cell activation led to a great reduction in the MBP T cell proliferative response, in the production of IL-2 and TNF, and in Ca2+ influx. Furthermore, the addition of KTX during T cell activation in vitro led a decreased encephalitogenicity of MBP T cells. Moreover, KTX injected into Lewis rats impaired T cell function such as the delayed-type hypersensitivity. Lastly, the administration of this blocker of neuronal and lymphocyte channels to Lewis rats improved the symptoms of EAE. We conclude that KTX is a potent immunosuppressive agent with beneficial effects on the neurological symptoms of EAE.
Induction of Anergy in Th1 Cells Associated with Increased Levels of Cyclin-Dependent Kinase Inhibitors p21Cip1 and p27Kip1 1
Authors: Jackson Stephanie K. , DeLoose Annick , Gilbert Kathleen M. 
Published: April 2014

Abstract
Th1 cells exposed to Ag and the G1 blocker n-butyrate in primary cultures lose their ability to proliferate in Ag-stimulated secondary cultures. The ability of n-butyrate to induce anergy in Ag-stimulated, but not resting, Th1 cells was shown here to be blocked by cycloheximide. Subsequent experiments to delineate the nature of the protein apparently required for n-butyrate-induced Th1 cell anergy focused on the role of cyclin-dependent kinase (cdk) inhibitors p21Cip1 and p27Kip1. Normally, entry into S phase by Th1 cells occurs around 24 h after Ag stimulation and corresponds with relatively low levels of both p21Cip1 and p27Kip1. However, unlike control Th1 cells, anergic Th1 cells contained high levels of both p21Cip1 and p27Kip1 when examined 24 h after Ag stimulation. The increase in p21Cip1 observed in Ag-stimulated anergic Th1 cells appeared to be initiated in primary cultures. In contrast, the increase in p27Kip1 observed in these anergic Th1 cells appears to represent a re-expression of the protein much earlier than control cells following Ag stimulation in secondary cultures. The anergic Th1 cells contained functionally active cdk inhibitors capable of inhibiting the activity of both endogenous and exogenous cdks. Consequently, it appears that n-butyrate-induced anergy in Th1 cells correlated with the up-regulation of p21Cip1 and perhaps the downstream failure to maintain low levels of p27Kip1. Increased levels of both p21Cip1 and p27Kip1 at the end of G1 could prevent cdk-mediated entry into S phase, and thus help maintain the proliferative unresponsiveness found in the anergic Th1 cells.
Viral Infection Causes Rapid Sensitization to Lipopolysaccharide: Central Role of IFN-αβ
Authors: Nansen Anneline , Randrup Thomsen Allan 
Published: April 2014

Abstract
LPS is the major active agent in the pathogenesis of Gram-negative septic shock. In this report we have studied the influence of concurrent viral infection on the outcome of LPS-induced shock. We find that infection with vesicular stomatitis virus sensitizes mice to LPS at an early time point following infection. Treatment of mice with the chemical IFN inducer, polyinosinic:polycytidylic acid, has a similar effect. This hypersensitivity to LPS correlated with hyperproduction of TNF-α in vivo. The cellular and molecular mechanisms underlying this phenomenon were investigated using Ab-depleted and gene-targeted mice. Our results revealed that while NK cell depletion and elimination of IFN-γ partially protected against the sensitizing effects of vesicular stomatitis virus and polyinosinic:polycytidylic acid, the most striking effect was observed in IFN-αβR-deficient mice. Thus hyperproduction of TNF-α was completely abrogated in IFN-αβR-deficient mice, indicating that the principal mechanism underlying rapid virus-induced sensitization to LPS is an IFN-αβ-mediated priming of mice for an augmented production of TNF-α in response to LPS. This conclusion was further supported by the finding that pretreatment of mice with rIFN-αβ mimicked the effect of viral infection. In conclusion, our results reveal a previously unrecognized proinflammatory effect of IFN-αβ and point to a new pathway through which viral infection may influence the outcome of concurrent bacterial infection.
Cutting Edge: The Neurotoxic Prion Peptide Fragment PrP106–126 Is a Chemotactic Agonist for the G Protein-Coupled Receptor Formyl Peptide Receptor-Like 1
Authors: Le Yingying , Yazawa Hiroshi , Gong Wanghua , Yu Zuxi , Ferrans Victor J. , Murphy Philip M. , Wang Ji Ming 
Published: April 2014

Abstract
Prion diseases are transmissible and fatal neurodegenerative disorders which involve infiltration and activation of mononuclear phagocytes at the brain lesions. A 20-aa acid fragment of the human cellular prion protein, PrP106–126, was reported to mimic the biological activity of the pathologic isoform of prion and activates mononuclear phagocytes. The cell surface receptor(s) mediating the activity of PrP106–126 is unknown. In this study, we show that PrP106–126 is chemotactic for human monocytes through the use of a G protein-coupled receptor formyl peptide receptor-like 1 (FPRL1), which has been reported to interact with a diverse array of exogenous or endogenous ligands. Upon stimulation by PrP106–126, FPRL1 underwent a rapid internalization and, furthermore, PrP106–126 enhanced monocyte production of proinflammatory cytokines, which was inhibited by pertussis toxin. Thus, FPRL1 may act as a “pattern recognition” receptor that interacts with multiple pathologic agents and may be involved in the proinflammatory process of prion diseases.
Cutting Edge: The Dendritic Cell Cytoskeleton Is Critical for the Formation of the Immunological Synapse
Authors: Al-Alwan Monther M. , Rowden Geoffrey , Lee Timothy D. G. , West Kenneth A. 
Published: April 2014

Abstract
The binding of a T cell to an APC results in T cell actin cytoskeletal rearrangement leading to the formation of an immunological synapse. The APC cytoskeleton has been thought to play a passive role in this process. In this study, we demonstrate that dendritic cells (DC), unlike other APC, actively polarize their actin cytoskeleton during interaction with T cells. DC cytoskeletal rearrangement was critical for both the clustering and the activation of resting T cells. This study provides compelling evidence that the APC cytoskeleton plays an active role in the immunological synapse and may explain the unique ability of DC to activate resting T cells.
Cutting Edge: Expression of the C-C Chemokine Receptor CCR3 in Human Airway Epithelial Cells
Authors: Stellato Cristiana , Brummet Mary E. , Plitt James R. , Shahabuddin Syed , Baroody Fuad M. , Liu Mark C. , Ponath Paul D. , Beck Lisa A. 
Published: April 2014

Abstract
Chemokine-induced eosinophil chemotaxis is mediated primarily through the C-C chemokine receptor, CCR3. We have now detected CCR3 immunoreactivity on epithelial cells in biopsies of patients with asthma and other respiratory diseases. CCR3 mRNA was detected by Northern blot analysis after TNF-α stimulation of the human primary bronchial epithelial cells as well as the epithelial cell line, BEAS-2B; IFN-γ potentiated the TNF-α-induced expression. Western blots and flow cytometry confirmed the expression of CCR3 protein. This receptor is functional based on studies demonstrating eotaxin-induced intracellular Ca2+ flux and tyrosine phosphorylation of cellular proteins. The specificity of this functional response was confirmed by blocking these signaling events with anti-CCR3 mAb (7B11) or pertussis toxin. Furthermore, 125I-eotaxin binding assay confirmed that CCR3 expressed on epithelial cells have the expected ligand specificity. These studies indicate that airway epithelial cells express CCR3 and suggest that CCR3 ligands may influence epithelial cell functions.
Natural Autoreactive B Cells in Transgenic Mice Reproduce an Apparent Paradox to the Clonal Tolerance Theory
Authors: Koenig-Marrony Severine , Soulas Pauline , Julien Sylvie , Knapp Anne-Marie , Garaud Jean-Claude , Martin Thierry , Pasquali Jean-Louis 
Published: April 2014

Abstract
Naturally occurring autoreactive B cells are thought to be physically eliminated or rendered functionally silent through different mechanisms of tolerance. However, multireactive low affinity natural autoantibody-producing B cells seem to escape these mechanisms in normal adults and could constitute the B cell pool from which pathological autoantibodies can emerge. To analyze this apparent paradox to the clonal tolerance theory, we have made two transgenic mouse lines (μk, μ∂k) producing a natural low affinity multireactive human autoantibody. These models enable us to test both the central tolerance mechanisms (reactivity with single-stranded DNA) and the peripheral tolerance mechanisms after Ag administration. Not only are the multireactive B cells not deleted in the bone marrow, they circulate and remain in the periphery even after the prolonged administration of Ag, the presence of membrane IgD increasing the number of mature autoreactive B cells. Self-reactive B cells are shown to be autoantigen ignorant both in vivo and in vitro, but they are not anergic because they can be easily activated through both B cell receptor-dependent and -independent pathways. Thus, these mouse lines reproduce an apparent paradox to the clonal tolerance theory meriting further investigation of the biological significance of this phenomenon.
Th Type 1-Stimulating Activity of Lung Macrophages Inhibits Th2-Mediated Allergic Airway Inflammation by an IFN-γ-Dependent Mechanism
Authors: Tang Chibing , Inman Mark D. , van Rooijen Nico , Yang Pingchang , Shen Huahao , Matsumoto Koichiro , O’Byrne Paul M. 
Published: April 2014

Abstract
In the mucosal immune system, resident dendritic cells are specialized for priming Th2-polarized immunity, whereas the Ag-presenting activity of macrophages has been linked with the development of Th1 phenotype. As an immune switch toward Th1 can protect against Th2-mediated allergic response, this study investigated the capacity of lung macrophages to stimulate Th1 responses during the secondary exposure to inhaled allergen, thereby suppressing Th2-mediated allergic airway inflammation in a murine model of allergic asthma. Following airway macrophage depletion in OVA-sensitized mice, lung T cells defaulted to a phenotype that produced less Th1 (IFN-γ) and more Th2 (IL-4 and IL-5) cytokines, leading to more severe airway hyperreactivity and inflammation after intranasal Ag challenge. After OVA pulsing and adoptive transfer, lung macrophages selectively promoted a Th1 response in Ag-sensitized recipients and did not induce pulmonary eosinophilia. By contrast, OVA pulsing and adoptive transfer of a lung cell preparation, consisting of dendritic cells, B cells, and macrophages, promoted a Th2 response with an associated inflammatory response that was suppressed when macrophages were present and pretreated with IFN-γ, but exacerbated when macrophages were depleted before IFN-γ treatment. In addition, Th1-promoting activity of lung macrophages was not related to the autocrine production of IL-12p40. These results suggest that the Th1-promoting APC activity may be an inherent property of the lung macrophage population, and may play an important role, upon stimulation by IFN-γ, in antagonizing an ongoing Th2 immunity and Th2-dependent allergic responses.
Osteoprotegerin, a Crucial Regulator of Bone Metabolism, Also Regulates B Cell Development and Function
Authors: Yun Theodore J. , Tallquist Michelle D. , Aicher Alexandra , Rafferty Katherine L. , Marshall Aaron J. , Moon James J. , Ewings Maria K. , Mohaupt Mariette , Herring Susan W. , Clark Edward A. 
Published: April 2014

Abstract
Osteoprotegerin (OPG) is a CD40-regulated gene in B cells and dendritic cells (DCs). We investigated the role of OPG in the immune system by generating opg−/− mice. Like its role as a regulator of bone metabolism, OPG also influences processes in the immune system, notably in B cell development. Ex vivo, opg−/− pro-B cells have enhanced proliferation to IL-7, and in opg−/− spleen, there is an accumulation of type 1 transitional B cells. Furthermore, opg−/− bone marrow-derived DCs are more effective in stimulating allogeneic T cells than control DCs. When challenged with a T-dependent Ag, opg−/− mice had a compromised ability to sustain an IgG3 Ag-specific response. Thus, in the immune system, OPG regulates B cell maturation and development of efficient Ab responses.