bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of a Soluble TGF-β Receptor by Tumor Cells Enhances Dendritic Cell/Tumor Fusion Vaccine Efficacy
Authors: Zhang Min , Berndt Bradford E. , Chen Jian-Jun , Kao John Y. 
Published: April 2014

Abstract
Dendritic cell (DC)-based antitumor immunotherapy is a promising cancer therapy. We have previously shown that tumor-derived TGF-β limits the efficacy of the DC/tumor fusion vaccine in mice. In the current study we investigated the effect of neutralizing tumor-derived TGF-β on the efficacy of the DC/tumor fusion vaccine. An adenovirus encoding human TGF-β receptor type II fused to the Fc region of human IgM (Adv-TGF-β-R) or a control adenovirus encoding LacZ (Adv-LacZ) was used to express a soluble form of the neutralizing TGF-β receptor (TGF-β-R). Murine breast carcinoma cells, 4T1, but not bone marrow-derived DCs, were successfully transfected with Adv-TGF-β-R (4T1+Adv-TGF-β-R) using a multiplicity of infection of 300. Immunization with irradiated 4T1+Adv-TGF-β-R tumor cells conferred enhanced antitumor immunity compared with immunization with irradiated 4T1+Adv-LacZ tumor cells. The DC/4T1+Adv-TGF-β-R fusion vaccine offered enhanced protective and therapeutic efficacy compared with the DC/4T1-Adv-LacZ fusion vaccine. Because TGF-β is known to induce regulatory T cells (Tregs), we further showed that the DC/4T1+Adv-TGF-β-R fusion vaccine induced fewer CD4+CD25+Foxp3+ Tregs than the DC/4T1+Adv-LacZ fusion vaccine in vitro and in vivo. The suppressive role of splenic CD4+CD25+ Tregs isolated from mice immunized with DC/4T1+Adv-LacZ was demonstrated using a CTL killing assay. Similar enhanced therapeutic efficacy was observed in murine renal cell carcinoma, RenCa, which expresses a high level of TGF-β. We conclude that the blockade of tumor-derived TGF-β reduces Treg induction by the DC/tumor fusion vaccine and enhances antitumor immunity. This may be an effective strategy to enhance human DC-based antitumor vaccines.
Inhalation of Staphylococcus aureus Enterotoxin A Induces IFN-γ and CD8 T Cell-Dependent Airway and Interstitial Lung Pathology in Mice
Authors: Muralimohan Guruprasaadh , Rossi Robert J. , Guernsey Linda A. , Thrall Roger S. , Vella Anthony T. 
Published: April 2014

Abstract
Staphylococcus aureus, a primary source of bacterial superantigen (SAg), is known to colonize the human respiratory tract and has been implicated in airway inflammation. Studies have documented a role for SAgs in respiratory disorders, such as nasal polyps, chronic obstructive pulmonary disease, chronic rhinosinusitis, and asthma. However, cellular and molecular mediators involved in SAg-mediated pulmonary disease have not been clearly identified. In this study, we investigated the effect of intranasal staphylococcal enterotoxin A (SEA) exposure on murine lung. The pathological features in the lung resulting from SEA exposure had characteristics of both obstructive and restrictive pulmonary disorders. There was also an increase in bronchoalveolar lavage protein concentration and cellularity following SEA challenge. Massive CD8+Vβ3+ T cell accumulation observed in the lung was dependent on CD4 T cell help, both for recruitment and for IFN-γ synthesis. The primary source of IFN-γ synthesis was CD8 T cells, and depletion of these cells abrogated disease. IFN-γ deficiency also prevented SEA-mediated disease, and this was by enhancing early recruitment of neutrophils as detected in the bronchoalveolar lavage. Thus, IFN-γ appeared to selectively aid the recruitment of T cells to the lungs while preventing the neutrophil accumulation. Therefore, our results show that IFN-γ-producing CD8 T cells mediated pulmonary alveolitis and inflammation, which were dependent upon CD4 T cells for their recruitment to the lung.
The Src Kinase Lck Facilitates Assembly of HIV-1 at the Plasma Membrane
Authors: Strasner Amy B. , Natarajan Malini , Doman Tom , Key Douglas , August Avery , Henderson Andrew J. 
Published: April 2014

Abstract
HIV type 1 (HIV-1) assembly and egress are driven by the viral protein Gag and occur at the plasma membrane in T cells. Recent evidence indicates that secretory vesicles and machinery are essential components of virus packaging in both T cells and macrophages. However, the pathways and cellular mediators of Gag targeting to the plasma membrane are not well characterized. Lck, a lymphoid specific Src kinase critical for T cell activation, is found in the plasma membrane as well as various intracellular compartments and it has been suggested to influence HIV-1 replication. To investigate Lck as a potential regulator of Gag targeting, we assessed HIV-1 replication and Gag-induced virus-like particle release in the presence and absence of Lck. Release of HIV-1 and virus-like particles was reduced in the absence of Lck. This decrease in replication was not due to altered HIV-1 infection, transcription or protein translation. However, in T cells lacking Lck, HIV-1 accumulated intracellularly. In addition, expressing Lck in HeLa cells promoted HIV-1 Gag plasma membrane localization. Palmitoylation of the Lck unique domain, which is essential for directing Lck to the plasma membrane, was critical for its effect on HIV-1 replication. Furthermore, HIV-1 Gag directly interacted with the Lck unique domain in the context of infected cells. These results indicate that Lck plays a key role in targeting HIV-1 Gag to the plasma membrane in T cells.
Macrophage Polarization in Bacterial Infections
Authors: Benoit Marie , Desnues Benoît , Mege Jean-Louis 
Published: April 2014

AbstractConverging studies have shown that M1 and M2 macrophages are functionally polarized in response to microorganisms and host mediators. Gene expression profiling of macrophages reveals that various Gram-negative and Gram-positive bacteria induce the transcriptional activity of a “common host response,” which includes genes belonging to the M1 program. However, excessive or prolonged M1 polarization can lead to tissue injury and contribute to pathogenesis. The so-called M2 macrophages play a critical role in the resolution of inflammation by producing anti-inflammatory mediators. These M2 cells cover a continuum of cells with different phenotypic and functional properties. In addition, some bacterial pathogens induce specific M2 programs in macrophages. In this review, we discuss the relevance of macrophage polarization in three domains of infectious diseases: resistance to infection, infectious pathogenesis, and chronic evolution of infectious diseases.
Cutting Edge: Programmed Death-1 Up-Regulation Is Involved in the Attrition of Cytomegalovirus-Specific CD8+ T Cells in Acute Self-Limited Hepatitis B Virus Infection
Authors: Zhang Ji-Yuan , Zhang Zheng , Jin Bo , Zhang Shu-Ye , Zhou Chun-Bao , Fu Jun-Liang , Wang Fu-Sheng 
Published: April 2014

Abstract
Attrition of heterologous virus-specific CD8+ T cells has been demonstrated in murine viral infection; however, little is known regarding this phenomenon in human viral infections. In this study, we observed that CMV-specific CD8+ T cells displayed numerical decline and functional impairment in the early phase of acute infection, whereas programmed death-1 (PD-1) expression was significantly up-regulated by these CMV-specific CD8+ T cells. This early PD-1 up-regulation was found to be closely associated with the increased apoptotic sensitivity of CMV-specific CD8+ T cells. The in vitro addition of anti-PD-1 further enhanced the spontaneous apoptosis of CMV-specific CD8+ T cells; however, blockade of the PD-1-mediated pathway with anti-PD-L1 significantly restored the CMV-specific CD8+ T cell proliferation and IFN-γ production. Thus, PD-1 plays a crucial role in the attrition of CMV-specific CD8+ T cells in acute hepatitis B virus infection, which in turn, influences the preexisting homeostatic virus-specific CD8+ T cell pool.
Cutting Edge: Instructive Role of Peripheral Tissue Cells in the Imprinting of T Cell Homing Receptor Patterns
Authors: Edele Fanny , Molenaar Rosalie , Gütle Dominique , Dudda Jan C. , Jakob Thilo , Homey Bernhard , Mebius Reina , Hornef Mathias , Martin Stefan F. 
Published: April 2014

Abstract
Tissue-specific homing of effector and memory T cells to skin and small intestine requires the imprinting of specific combinations of adhesion molecules and chemokine receptors by dendritic cells in the draining lymph nodes. In this study, we demonstrate that CD8+ T cells activated by Ag-pulsed bone marrow-derived dendritic cells were induced to express the small intestine homing receptors α4β7 integrin and chemokine receptor CCR9 in coculture with small intestinal epithelial cells. In contrast, in coculture with dermal fibroblasts the skin-homing receptor E-selectin ligand was induced. Interestingly, the imprinting of gut homing receptors on anti-CD3/anti-CD28 stimulated T cells was induced by soluble factors produced by small intestinal epithelial cells. Retinoic acid was identified as a crucial factor. These findings show that peripheral tissue cells directly produce homing receptor imprinting factors and suggest that dendritic cells can acquire their imprinting potential already in the peripheral tissue of origin.
Resistin Inhibits Essential Functions of Polymorphonuclear Leukocytes
Authors: Cohen Gerald , Ilic Dalibor , Raupachova Jana , Hörl Walter H. 
Published: April 2014

Abstract
The serum levels of resistin, a 12-kDa protein primarily expressed in inflammatory cells in humans, are increased in patients with chronic kidney disease and in those with diabetes mellitus. Both groups of patients have an increased risk of infections mainly as a result of disturbed polymorphonuclear leukocyte (PMNL) functions. Therefore, we investigated the influence of resistin on human PMNLs. Serum resistin concentrations were determined with a sandwich enzyme immunoassay. Using PMNLs from healthy subjects, chemotaxis was tested by the under-agarose method. Flow cytometric assays to measure oxidative burst and phagocytosis were conducted in whole blood. The uptake of deoxyglucose was determined as measure of the PMNL activation state. The activity of intracellular kinases was assessed by Western blotting and by in vitro kinase assays. Resistin inhibited PMNL chemotaxis and decreased the oxidative burst stimulated by Escherichia coli and by PMA, but did not influence PMNL phagocytosis of opsonized E. coli and PMNL glucose uptake. The inhibition of PMNLs by resistin was observed at concentrations found in serum samples of uremic patients, but not in concentrations measured in healthy subjects. Experiments with specific signal transduction inhibitors and measurements of intracellular kinases suggest that PI3K is a major target of resistin. In conclusion, resistin interferes with the chemotactic movement and the stimulation of the oxidative burst of PMNL, and therefore may contribute to the disturbed immune response in patients with increased resistin serum levels such as uremic and diabetic subjects.
Characterization of a Novel Nonclassical T Cell Clone with Broad Reactivity against Human Renal Cell Carcinomas
Authors: Wang Qiong J. , Hanada Ken-ichi , Yang James C. 
Published: April 2014

Abstract
A CD4+ T cell clone (HC/2G-1) was established by stimulating peripheral blood T cells from a patient with renal cell carcinoma (RCC) with dendritic cells preincubated with the autologous apoptotic renal tumor line in the presence of IFN-α. It recognizes the autologous RCC and most allogeneic RCC lines by IFN-γ release (10 of 11 lines) and lysis (9 of 10 lines), but does not recognize multiple EBV B cells or fibroblasts. It shows little or no recognition of a panel of melanomas, breast cancers and non-small–cell lung cancers. Phenotypically, HC/2G-1 is CD3+CD4+ TCR αβ+, but CD161−CD16−NKG2D−. Tumor recognition by clone HC/2G-1 was not blocked by Abs to HLA class I or class II, but was significantly reduced by anti-TCR αβ Ab. Furthermore, tumor recognition was β2-microglobulin-independent. HC/2G-1 does not use a Vα or Vβ described for classical NKT cells, but rather Vα14 and Vβ2.1. Allogeneic T cells cotransfected with mRNAs encoding the α and β chains of the HC/2G-1 TCR recognized renal tumor lines, demonstrating that tumor recognition is TCR-mediated. Interestingly, TRAIL appears to play a role in tumor recognition by HC/2G-1 in that reactivity was blocked by anti-TRAIL Ab, and soluble TRAIL could enhance IFN-γ secretion by HC/2G-1 in response to renal tumors. Our findings suggest that clone HC/2G-1 represents a novel type of CD4+ cell that has broad TCR-mediated recognition of a determinant widely expressed by RCC.
Rab27a Regulates Exocytosis of Tertiary and Specific Granules in Human Neutrophils
Authors: Herrero-Turrión M. Javier , Calafat Jero , Janssen Hans , Fukuda Mitsunori , Mollinedo Faustino 
Published: April 2014

Abstract
The correct mobilization of cytoplasmic granules is essential for the proper functioning of human neutrophils in host defense and inflammation. In this study, we have found that human peripheral blood neutrophils expressed high levels of Rab27a, whereas Rab27b expression was much lower. This indicates that Rab27a is the predominant Rab27 isoform present in human neutrophils. Rab27a was up-regulated during neutrophil differentiation of HL-60 cells. Subcellular fractionation and immunoelectron microscopy studies of resting human neutrophils showed that Rab27a was mainly located in the membranes of specific and gelatinase-enriched tertiary granules, with a minor localization in azurophil granules. Rab27a was largely absent from CD35-enriched secretory vesicles. Tertiary and specific granule-located Rab27a population was translocated to the cell surface upon neutrophil activation with PMA that induced exocytosis of both tertiary and specific granules. Specific Abs against Rab27a inhibited Ca2+ and GTP-γ-S activation and PMA-induced exocytosis of CD66b-enriched tertiary and specific granules in electropermeabilized neutrophils, whereas secretion of CD63-enriched azurophil granules was scarcely affected. Human neutrophils lacked or expressed low levels of most Slp/Slac2 proteins, putative Rab27 effectors, suggesting that additional proteins should act as Rab27a effectors in human neutrophils. Our data indicate that Rab27a is a major component of the exocytic machinery of human neutrophils, modulating the secretion of tertiary and specific granules that are readily mobilized upon neutrophil activation.
MyD88 Plays a Critical T Cell-Intrinsic Role in Supporting CD8 T Cell Expansion during Acute Lymphocytic Choriomeningitis Virus Infection
Authors: Rahman Adeeb H. , Cui Weiguo , LaRosa David F. , Taylor Devon K. , Zhang Jidong , Goldstein Daniel R. , Wherry E. John , Kaech Susan M. , Turka Laurence A. 
Published: April 2014

Abstract
During acute lymphocytic choriomeningitis virus (LCMV) infection, CD8 T cells rapidly expand and differentiate into effectors that are required for viral clearance. The accumulation of activated T cells is greatly reduced in mice lacking the adaptor molecule MyD88. Although MyD88 has generally been considered to indirectly regulate adaptive immune responses by controlling inflammatory cytokine production and Ag presentation in innate immune cells, in this study, we identify an unappreciated cell-intrinsic role for MyD88 in LCMV-specific CD8 T cells. Using reciprocal adoptive transfer models and bone marrow chimeras, we show that Myd88−/− CD8 T cells are defective in their clonal expansion in response to LCMV infection, independent of their environment. Furthermore, we show that while MyD88 is dispensable for initial activation and division of LCMV-specific CD8 T cells during the early stages of viral infection, MyD88-dependent signals are critical for supporting their survival and sustained accumulation.
Cell Cycle-Related Acquisition of Cytotoxic Mediators Defines the Progressive Differentiation to Effector Status for Virus-Specific CD8+ T Cells
Authors: Jenkins Misty R. , Mintern Justine , La Gruta Nicole L. , Kedzierska Katherine , Doherty Peter C. , Turner Stephen J. 
Published: April 2014

Abstract
Although analysis of virus-specific CTL function at the peak of infection suggests that granzyme (grz) and perforin (pfp) gene expression is not coregulated, early differentiation events leading to acquisition of function are poorly understood. Using a combination of CFSE dilutions and single-cell RT-PCR, effector gene expression was determined early after CTL activation. There were low levels of pfp and grz expression at division 3, with increased expression by divisions 6–8. The increase in effector mRNA expression with division correlated with increasing ex vivo cytotoxicity. Of the mRNA transcripts detected at division 3, there was an increased frequency of grzB and grzK (compared with grzA or pfp), and this pattern was also observed at later divisions. The prevalence of OT-I CTL expressing grz/pfp mRNA was equivalent for the divided CD62Lhigh and CD62Llow sets, but the concentrations of grzB protein, levels of CTL activity, and the absolute amounts of grzB transcript were substantially greater for the CD62Llow population. Thus, while effector gene expression can be acquired early, maturation of cytotoxic capacity requires extended differentiation.
B Cell Receptor Affinity and B Cell Subset Identity Integrate to Define the Effectiveness, Affinity Threshold, and Mechanism of Anergy
Authors: Diz Ramiro , McCray Suzanne K. , Clarke Stephen H. 
Published: April 2014

Abstract
In this study we show that BCR affinity and subset identity make unique contributions to anergy. Analysis of anti-Smith (Sm) B cells of different affinities indicates that increasing affinity improves anergy’s effectiveness while paradoxically increasing the likelihood of marginal zone (MZ) and B-1 B cell differentiation rather than just follicular (FO) B cell differentiation. Subset identity in turn determines the affinity threshold and mechanism of anergy. Subset-specific affinity thresholds for anergy induction allow discordant regulation of low-affinity anti-Sm FO and MZ B cells and could account for the higher frequency of autoreactive MZ B cells than that of FO B cells in normal mice. The mechanism of anergy changes during differentiation and differs between subsets. This is strikingly illustrated by the observation that blockade of BCR-mediated activation of FO and MZ B cells occurs at different levels in the signaling cascade. Thus, attributes unique to B cells of each subset integrate with signals from the BCR to determine the effectiveness, affinity threshold, and mechanism of anergy.
IgE-Induced Mast Cell Survival Requires the Prolonged Generation of Reactive Oxygen Species
Authors: Sly Laura M. , Kalesnikoff Janet , Lam Vivian , Wong Dana , Song Christine , Omeis Stephanie , Chan Karen , Lee Corinna W. K. , Siraganian Reuben P. , Rivera Juan , Krystal Gerald 
Published: April 2014

Abstract
We show in this study that the ability of five different monomeric IgEs to enhance murine bone marrow-derived mast cell (BMMC) survival correlates with their ability to stimulate extracellular calcium (Ca2+) entry. However, whereas IgE+Ag more potently stimulates Ca2+ entry, it does not enhance survival under our conditions. Exploring this further, we found that whereas all five monomeric IgEs stimulate a less robust Ca2+ entry than IgE+Ag initially, they all trigger a more prolonged Ca2+ influx, generation of reactive oxygen species (ROS), and ERK phosphorylation. These prolonged signaling events correlate with their survival-enhancing ability and positively feedback on each other to generate the prosurvival cytokine, IL-3. Interestingly, the prolonged ERK phosphorylation induced by IgE appears to be regulated by a MAPK phosphatase rather than MEK. IgE-induced ROS generation, unlike that triggered by IgE+Ag, is not mediated by 5-lipoxygenase. Moreover, ROS inhibitors, which block both IgE-induced ROS production and Ca2+ influx, convert the prolonged ERK phosphorylation induced by IgE into the abbreviated phosphorylation pattern observed with IgE+Ag and prevent IL-3 generation. In support of the essential role that IgE-induced ROS plays in IgE-enhanced BMMC survival, we found the addition of H2O2 to IgE+Ag-stimulated BMMCs leads to IL-3 secretion.
Cytokine-Mediated Inhibition of Fibrillar Amyloid-β Peptide Degradation by Human Mononuclear Phagocytes
Authors: Yamamoto Masaru , Kiyota Tomomi , Walsh Shannon M. , Liu Jianuo , Kipnis Jonathan , Ikezu Tsuneya 
Published: April 2014

Abstract
Vaccination therapy of AD animal models and patients strongly suggests an active role of brain mononuclear phagocytes in immune-mediated clearance of amyloid-β peptides (Aβ) in brain. Although Aβ uptake by macrophages can be regulated by pro- and anti-inflammatory cytokines, their effects on macrophage-mediated Aβ degradation are poorly understood. To better understand this mechanism of degradation, we examined whether pro- and anti-inflammatory cytokines affect the degradation of Aβ using primary cultured human monocyte-derived macrophages (MDM) and microglia using pulse-chase analysis of fibrillar and oligomer 125I-Aβ40 and Aβ42. Initial uptake of fibrillar Aβ40 and Aβ42 was 40% and its degradation was saturated by 120 h in both MDM and microglia, compared with an initial uptake of oligomeric Aβ less than 0.5% and saturation of degradation within 24 h. IFN-γ increased the intracellular retention of fibrillar Aβ40 and Aβ42 by inhibiting degradation, whereas IL-4, IL-10, and TGF-β1, but not IL-13 and IL-27, enhanced degradation. Fibrillar Aβ degradation in MDM is sensitive to lysosomal and insulin degrading enzyme inhibitors but insensitive to proteasomal and neprilysin inhibitors. IFN-γ and TNF-α directly reduced the expression of insulin degrading enzyme and chaperone molecules (heat shock protein 70 and heat shock cognate protein 70), which are involved in refolding of aggregated proteins. Coculture of MDM with activated, but not naive T cells, suppressed Aβ degradation in MDM, which was partially blocked by a combination of neutralizing Abs against proinflammatory cytokines. These data suggest that proinflammatory cytokines suppress Aβ degradation in MDM, whereas select anti-inflammatory and regulatory cytokines antagonize these effects.
Fibroblast-Type Reticular Stromal Cells Regulate the Lymph Node Vasculature
Authors: Chyou Susan , Ekland Eric H. , Carpenter April C. , Tzeng Te-Chen Jenny , Tian Sha , Michaud Michael , Madri Joseph A. , Lu Theresa T. 
Published: April 2014

Abstract
The lymph node vasculature is essential to immune function, but mechanisms regulating lymph node vascular maintenance and growth are not well understood. Vascular endothelial growth factor (VEGF) is an important mediator of lymph node endothelial cell proliferation in stimulated lymph nodes. It is expressed basally in lymph nodes and up-regulated upon lymph node stimulation, but the identity of VEGF-expressing cells in lymph nodes is not known. We show that, at homeostasis, fibroblast-type reticular stromal cells (FRC) in the T zone and medullary cords are the principal VEGF-expressing cells in lymph nodes and that VEGF plays a role in maintaining endothelial cell proliferation, although peripheral node addressin (PNAd)+ endothelial cells are less sensitive than PNAd− endothelial cells to VEGF blockade. Lymphotoxin β receptor (LTβR) blockade reduces homeostatic VEGF levels and endothelial cell proliferation, and LTβR stimulation of murine fibroblast-type cells up-regulates VEGF expression, suggesting that LTβR signals on FRC regulate lymph node VEGF levels and, thereby, lymph node endothelial cell proliferation. At the initiation of immune responses, FRC remain the principal VEGF mRNA-expressing cells in lymph nodes, suggesting that FRC may play an important role in regulating vascular growth in stimulated nodes. In stimulated nodes, VEGF regulates the proliferation and expansion of both PNAd+ and PNAd− endothelial cells. Taken together, these data suggest a role for FRC as paracrine regulators of lymph node endothelial cells and suggest that modulation of FRC VEGF expression may be a means to regulate lymph node vascularity and, potentially, immune function.