bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elimination of Senescent Neutrophils by TNF-Related Apoptosis-Inducing Ligand
Authors: Lum Julian J. , Bren Gary , McClure Rebecca , Badley Andrew D. 
Published: April 2014

AbstractNeutrophils are phagocytic effectors which are produced in the bone marrow and released into the circulation. Thereafter, they are either recruited to sites of inflammation or rapidly become senescent, return to the bone marrow, and undergo apoptosis. Stromal cell-derived factor 1 (SDF-1) coordinates the return of senescent neutrophils to the bone marrow by interacting with CXCR4 that is preferentially expressed on senescent neutrophils. We demonstrate that CXCR4 ligation by SDF-1 or other CXCR4 agonists significantly increases the expression of both TNF-related apoptosis-inducing ligand (TRAIL) and of the death-inducing TRAIL receptors on neutrophils, which confers an acquired sensitivity to TRAIL-mediated death and results in TRAIL-dependent apoptosis. In vivo administration of TRAIL antagonists results in neutrophilic accumulation within the bone marrow and a reduction in neutrophil apoptosis; conversely recombinant TRAIL administration reduced neutrophil number within bone marrow. Thus, SDF-1 ligation of CXCR4 causes the parallel processes of chemotaxis and enhanced TRAIL and TRAIL death receptor expression, resulting in apoptosis of senescent neutrophils upon their return to the bone marrow.
P-Selectin Glycoprotein Ligand 1 Is Not Required for the Development of Experimental Autoimmune Encephalomyelitis in SJL and C57BL/6 Mice
Authors: Engelhardt Britta , Kempe Birgit , Merfeld-Clauss Stephanie , Laschinger Melanie , Furie Bruce , Wild Martin K. , Vestweber Dietmar 
Published: April 2014

Abstract
In multiple sclerosis and in its animal model experimental autoimmune encephalomyelitis (EAE), inflammatory cells migrate across the endothelial blood-brain barrier and gain access to the CNS. The involvement of P-selectin glycoprotein ligand 1 (PSGL-1) and of its major endothelial ligand P-selectin in this process have been controversial. In this study we demonstrate that although encephalitogenic T cells express functional PSGL-1, which can bind to soluble and immobilize P-selectin if presented in high concentrations, PSGL-1 is not involved T cell interaction with P-selectin expressing brain endothelial cells in vitro. Furthermore, neither anti-PSGL-1 Abs nor the lack of PSGL-1 in PSGL-1-deficient mice inhibits the recruitment of inflammatory cells across the blood-brain barrier or the development of clinical EAE. Taken together, our findings demonstrate that PSGL-1 is not required for the pathogenesis of EAE.
Mucosal B Cell Deficiency in IgA−/− Mice Abrogates the Development of Allergic Lung Inflammation
Authors: Arnaboldi Paul M. , Behr Melissa J. , Metzger Dennis W. 
Published: April 2014

AbstractWe have investigated the consequence of lack of IgA on host immunity using a murine model of allergic lung inflammation. Mice with a targeted disruption of the α-switch region and 5′ H chain gene (IgA−/− mice), which lack total IgA, developed significantly reduced pulmonary inflammation with fewer inflammatory cells in lung tissue and bronchoalveolar lavage fluids, as well as reduced levels of total and IgG1 OVA-specific Abs and decreased IL-4 and IL-5 in bronchoalveolar lavage fluids compared with IgA+/+ controls, following allergen sensitization and challenge. This defect was attributable to fewer B cells in the lungs of IgA−/− mice. Polymeric IgR-deficient (pIgR−/−) mice, which lack the receptor that transports polymeric IgA across the mucosal epithelium where it is cleaved to form secretory IgA, were used to assess the contribution of secretory IgA vs total IgA in the induction of allergic lung inflammation. pIgR−/− and pIgR+/+ mice had comparable levels of inflammation, demonstrating that IgA bound to secretory component is not necessary for the development of allergic lung inflammation, although this does not necessarily rule out a role for transudated IgA in lung secretions because of “mucosal leakiness” in these mice. The results indicate that Ag-specific B cells are required at mucosal surfaces for induction of inflammation and likely function as major APCs in the lung for soluble protein Ags.
Contribution of the Lymphotoxin β Receptor to Liver Regeneration
Authors: Anders Robert A. , Subudhi Sumit K. , Wang Jing , Pfeffer Klaus , Fu Yang-Xin 
Published: April 2014

Abstract
The liver has an enormous capacity to regenerate in response to insults, but the cellular events and molecules involved in liver regeneration are not well defined. In this study, we report that ligands expressed on the surface of lymphocytes have a substantial effect on liver homeostasis. We demonstrate that a T cell-restricted ligand, homologous to lymphotoxin, exhibits inducible expression, competes with herpesvirus glycoprotein D for herpesvirus entry mediator on T cells (LIGHT), signaling through the lymphotoxin receptor (LTβR) expressed on mature hepatocytes induces massive hepatomegaly. Using genetic targeting and a receptor fusion protein, we further show that mice deficient in LTβR signaling have a severe defect in their ability to survive partial hepatectomy with marked liver damage and failure to initiate DNA synthesis after partial hepatectomy. We further show that mice deficient in a LTβR ligand, LTα, also show decreased ability to survive partial hepatectomy with similar levels of liver damage and decreased DNA synthesis. Therefore, our study has revealed an unexpected role of lymphocyte-restricted ligands and defined a new pathway in supporting liver regeneration.
Targeting Positive Regulatory Domain I-Binding Factor 1 and X Box-Binding Protein 1 Transcription Factors by Multiple Myeloma-Reactive CTL
Authors: Lotz Carina , Mutallib Sarah Abdel , Oehlrich Nicole , Liewer Ulrike , Ferreira Edite Antunes , Moos Marion , Hundemer Michael , Schneider Sandra , Strand Susanne , Huber Christoph , Goldschmidt Hartmut , Theobald Matthias 
Published: April 2014

Abstract
Growing evidence indicates that multiple myeloma (MM) and other malignancies are susceptible to CTL-based immune interventions. We studied whether transcription factors inherently involved in the terminal differentiation of mature B lymphocytes into malignant and nonmalignant plasma cells provide MM-associated CTL epitopes. HLA-A*0201 (A2.1) transgenic mice were used to identify A2.1-presented peptide Ag derived from the plasma cell-associated transcriptional regulators, positive regulatory domain I-binding factor 1 (PRDI-BF1) and X box-binding protein 1 (XBP-1). A2.1-restricted CTL specific for PRDI-BF1 and XBP-1 epitopes efficiently killed a variety of MM targets. PRDI-BF1- and XBP-1-reactive CTL were able to recognize primary MM cells from A2.1+ patients. Consistent with the expression pattern of both transcription factors beyond malignant and nonmalignant plasma cells, PRDI-BF1- and XBP-1-specific CTL activity was not entirely limited to MM targets, but was also associated with lysis of certain other malignancies and, in defined instances, with low-to-intermediate level recognition of a few types of normal cells. Our results also indicate that the A2.1-restricted, PRDI-BF1- and XBP-1-specific human CD8+ T cell repertoire is affected by partial self tolerance and may thus require the transfer of high-affinity TCR to break tolerance. We conclude that transcription factors governing terminal cellular differentiation may provide MM- and tumor-associated CTL epitopes.
IL-1β Induces IL-6 Expression in Human Orbital Fibroblasts: Identification of an Anatomic-Site Specific Phenotypic Attribute Relevant to Thyroid-Associated Ophthalmopathy
Authors: Chen Beiling , Tsui Shanli , Smith Terry J. 
Published: April 2014

Abstract
Human orbital fibroblasts exhibit a unique inflammatory phenotype. In the present study, we report that these fibroblasts, when treated with IL-1β, express high levels of IL-6, a cytokine involved in B cell activation and the regulation of adipocyte metabolism. The magnitude of this induction is considerably greater than that in dermal fibroblasts and involves up-regulation of IL-6 mRNA levels. IL-1β activates both p38 and ERK 1/2 components of the MAPK pathways. Disrupting these could attenuate the IL-6 induction. The up-regulation involves enhanced IL-6 gene promoter activity and retardation of IL-6 mRNA decay by IL-1β. Dexamethasone completely blocked the effect of IL-1β on IL-6 expression. Orbital fibroblasts also express higher levels of IL-6R than do skin-derived cells. When treated with rIL-6 (10 ng/ml), STAT3 is transiently phosphorylated. Thus, the exaggerated capacity of orbital fibroblasts to express high levels of both IL-6 and its receptor in an anatomic site-selective manner could represent an important basis for immune responses localized to the orbit in Graves’ disease.
Genotype-Proteotype Linkage in the Wiskott-Aldrich Syndrome
Authors: Lutskiy Maxim I. , Rosen Fred S. , Remold-O’Donnell Eileen 
Published: April 2014

AbstractWiskott-Aldrich syndrome (WAS) is a platelet/immunodeficiency disease arising from mutations of WAS protein (WASP), a hemopoietic cytoskeletal protein. Clinical symptoms vary widely from mild (X-linked thrombocytopenia) to life threatening. In this study, we examined the molecular effects of individual mutations by quantifying WASP in peripheral lymphocytes of 44 patients and identifying the molecular variant (collectively called proteotype). Nonpredicted proteotypes were found for 14 genotypes. These include WASP-negative lymphocytes found for five missense genotypes and WASP-positive lymphocytes for two nonsense, five frameshift, and two splice site genotypes. Missense mutations in the Ena/VASP homology 1 (EVH1) domain lead to decreased/absent WASP but normal mRNA levels, indicating that proteolysis causes the protein deficit. Because several of the EVH1 missense mutations alter WIP binding sites, the findings suggest that abrogation of WIP binding induces proteolysis. Whereas platelets of most patients were previously shown to lack WASP, WASP-positive platelets were found for two atypical patients, both of whom have mutations outside the EVH1 domain. WASP variants with alternative splicing and intact C-terminal domains were characterized for eight nonsense and frameshift genotypes. One of these, a nonsense genotype in a mild patient, supports expression of WASP lacking half of the proline-rich region. With one notable exception, genotype and proteotype were linked, indicating that a genotype-proteotype registry could be assembled to aid in predicting disease course and planning therapy for newly diagnosed infants. Knowledge of the molecular effect of mutations would aid also in identifying disease-modifying genes.
Cutting Edge: IL-12 Induces CD4+CD25− T Cell Activation in the Presence of T Regulatory Cells
Authors: King Irah L. , Segal Benjamin M. 
Published: April 2014

Abstract
IL-12p40 cytokines have been implicated in the development of organ-specific autoimmune diseases as well as pathogen-specific adaptive immunity. In addition to inducing IFN-γ, IL-12 stimulates effector CD4+ T cells to express adhesion molecules and homing receptors that facilitate their migration to sites of inflammation. In this study, we expand upon those observations by demonstrating an alternative pathway by which IL-12 could promote Th1 inflammatory responses in mice, namely, by restoring proliferation and cytokine expression by effector T cells in the presence of CD4+CD25+ regulatory T cells (Treg). This effect of IL-12 was not replicated by IL-23 or IFN-γ and was dependent on signaling through the IL-12R expressed on CD25− responder cells, but not on Treg. Our studies suggest that IL-12 could act in concert with other proinflammatory factors to stimulate CD4+CD25− T cell activation in the presence of Treg.
Active Ca2+/Calmodulin-Dependent Protein Kinase IIγB Impairs Positive Selection of T Cells by Modulating TCR Signaling
Authors: McGargill Maureen A. , Sharp Leslie L. , Bui Jack D. , Hedrick Stephen M. , Calbo Sébastien 
Published: April 2014

Abstract
T cell development is regulated at two critical checkpoints that involve signaling events through the TCR. These signals are propagated by kinases of the Src and Syk families, which activate several adaptor molecules to trigger Ca2+ release and, in turn, Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation. In this study, we show that a constitutively active form of CaMKII antagonizes TCR signaling and impairs positive selection of thymocytes in mice. Following TCR engagement, active CaMKII decreases TCR-mediated CD3ζ chain phosphorylation and ZAP70 recruitment, preventing further downstream events. Therefore, we propose that CaMKII belongs to a negative-feedback loop that modulates the strength of the TCR signal through the tyrosine phosphatase Src homology 2 domain-containing phosphatase 2 (SHP-2).
Mechanisms of the Antitumor Responses and Host-versus-Graft Reactions Induced by Recipient Leukocyte Infusions in Mixed Chimeras Prepared with Nonmyeloablative Conditioning: A Critical Role for Recipient CD4+ T Cells and Recipient Leukocyte Infusion-Derived IFN-γ-Producing CD8+ T Cells
Authors: Rubio Marie-Therese , Saito Toshiki I. , Kattleman Kristin , Zhao Guiling , Buchli Jennifer , Sykes Megan 
Published: April 2014

AbstractSurprisingly, antitumor responses can occur in patients who reject donor grafts following nonmyeloablative hemopoietic cell transplantation. In murine mixed chimeras prepared with nonmyeloablative conditioning, we previously showed that recipient leukocyte infusions (RLI) induced loss of donor chimerism, IFN-γ production, and antitumor responses against host-type tumors. However, the mechanisms behind this phenomenon remain to be determined. We now demonstrate that the effects of RLI are mediated by distinct and complex mechanisms. Donor marrow rejection is induced by RLI-derived alloactivated T cells, which activate non-RLI-derived, recipient IFN-γ-producing cells. RLI-derived CD8 T cells induce the production of IFN-γ by both RLI and non-RLI-derived recipient cells. The antitumor responses of RLI involve mainly RLI-derived IFN-γ-producing CD8 T cells and recipient-derived CD4 T cells and do not involve donor T cells. The pathways of donor marrow and tumor rejection lead to the development of tumor-specific cell-mediated cytotoxic responses that are not due to bystander killing by alloreactive T cells.
The Synthetic Peptide Trp-Lys-Tyr-Met-Val-D-Met Inhibits Human Monocyte-Derived Dendritic Cell Maturation via Formyl Peptide Receptor and Formyl Peptide Receptor-Like 2
Authors: Kang Hyun Kyu , Lee Ha-Young , Kim Mi-Kyoung , Park Kyoung Sun , Park Yeong Min , Kwak Jong-Young , Bae Yoe-Sik 
Published: April 2014

AbstractTrp-Lys-Tyr-Met-Val-D-Met (WKYMVm) has been reported to stimulate monocytes, neutrophils, and dendritic cells (DCs). However, although WKYMVm has been reported to function as a DC chemoattractant, its role on DC maturation has not been examined. In this study, we investigated the effects of WKYMVm on human DC maturation. The costimulation of DCs with WKYMVm and LPS dramatically inhibited LPS-induced IL-12 production, CD86 and HLA-DR surface expression, and DC-mediated T cell proliferation. However, DC phagocytic activity was increased by WKYMVm stimulation. These findings demonstrate that WKYMVm inhibits DC maturation by LPS. In terms of the mechanism underlying DC maturation inhibition by WKYMVm, we found that LPS-induced DC maturation was negatively regulated by WKYMVm-stimulated ERK activity. Moreover, the costimulation of DCs with WKYMVm and LPS dramatically inhibited the LPS-induced accumulations of IL-12 mRNA, thus suggesting that WKYMVm inhibits LPS-induced IL-12 production at the transcriptional level. We also found that DCs express two WKYMVm receptors, formyl peptide receptor (FPR) and FPR-like 2 (FPRL2). In addition, formyl-Met-Leu-Phe (a FPR ligand), Trp-Lys-Tyr-Met-Val-Met, Hp(2–20) peptide, and F2L (three FPRL2 ligands) inhibited LPS-induced IL-12 production in DCs. Taken together, our findings indicate that the activations of FPR and FPRL2 inhibit LPS-induced DC maturation, and suggest that these two receptors should be regarded as important potential therapeutic targets for the modulation of DC maturation.
In Vivo Hydrodynamic Delivery of cDNA Encoding IL-2: Rapid, Sustained Redistribution, Activation of Mouse NK Cells, and Therapeutic Potential in the Absence of NKT Cells
Authors: Ortaldo John R. , Winkler-Pickett Robin T. , Bere Earl W. , Watanabe Morihiro , Murphy William J. , Wiltrout Robert H. 
Published: April 2014

AbstractIn the present study, we have tested the ability of hydrodynamically delivered IL-2 cDNA to modulate the number and function of murine leukocyte subsets in different organs and in mice of different genetic backgrounds, and we have evaluated effects of this mode of gene delivery on established murine tumor metastases. Hydrodynamic administration of the IL-2 gene resulted in the rapid and transient production of up to 160 ng/ml IL-2 in the serum. The appearance of IL-2 was followed by transient production of IFN-γ and a dramatic and sustained increase in NK cell numbers and NK-mediated cytolytic activity in liver and spleen leukocytes. In addition, significant increases in other lymphocyte subpopulations (e.g., NKT, T, and B cells) that are known to be responsive to IL-2 were observed following IL-2 cDNA plasmid delivery. Finally, hydrodynamic delivery of only 4 μg of the IL-2 plasmid to mice bearing established lung and liver metastases was as effective in inhibiting progression of metastases as was the administration of large amounts (100,000 IU/twice daily) of IL-2 protein. Studies performed in mice bearing metastatic renal cell tumors demonstrated that the IL-2 cDNA plasmid was an effective treatment against liver metastasis and moderately effective against lung metastasis. Collectively, these results demonstrate that hydrodynamic delivery of relatively small amounts of IL-2 cDNA provides a simple and inexpensive method to increase the numbers of NK and NKT cells, to induce the biological effects of IL-2 in vivo for use in combination with other biological agents, and for studies of its antitumor activity.
Bordetella pertussis Adenylate Cyclase Toxin Modulates Innate and Adaptive Immune Responses: Distinct Roles for Acylation and Enzymatic Activity in Immunomodulation and Cell Death
Authors: Boyd Aoife P. , Ross Pádraig J. , Conroy Helen , Mahon Nicola , Lavelle Ed C. , Mills Kingston H. G. 
Published: April 2014

Abstract
Adenylate cyclase toxin (CyaA) of Bordetella pertussis belongs to the repeat in toxin family of pore-forming toxins, which require posttranslational acylation to lyse eukaryotic cells. CyaA modulates dendritic cell (DC) and macrophage function upon stimulation with LPS. In this study, we examined the roles of acylation and enzymatic activity in the immunomodulatory and lytic effects of CyaA. The adenylate cyclase activity of CyaA was necessary for its modulatory effects on murine innate immune cells. In contrast, acylation was not essential for the immunomodulatory function of CyaA, but was required for maximal caspase-3 activation and cytotoxic activity. The wild-type acylated toxin (A-CyaA) and nonacylated CyaA (NA-CyaA), but not CyaA with an inactive adenylate cyclase domain (iAC-CyaA), enhanced TLR-ligand-induced IL-10 and inhibited IL-12, TNF-α, and CCL3 production by macrophages and DC. In addition, both A-CyaA and NA-CyaA, but not iAC-CyaA, enhanced surface expression of CD80 and decreased CpG-stimulated CD40 and ICAM-1 expression on immature DC. Furthermore, both A-CyaA and NA-CyaA promoted the induction of murine IgG1 Abs, Th2, and regulatory T cells against coadministered Ags in vivo, whereas iAC-CyaA had more limited adjuvant activity. In contrast, A-CyaA and iAC-CyaA induced caspase-3 activation and cell death in macrophages, but these effects were considerably reduced or absent with NA-CyaA. Our findings demonstrate that the enzymatic activity plays a critical role in the immunomodulatory effects of CyaA, whereas acylation facilitates the induction of apoptosis and cell lysis, and as such, NA-CyaA has considerable potential as a nontoxic therapeutic molecule with potent anti-inflammatory properties.
Phospholipase C-γ2 Is a Critical Signaling Mediator for Murine NK Cell Activating Receptors
Authors: Tassi Ilaria , Presti Rachel , Kim Sungjin , Yokoyama Wayne M. , Gilfillan Susan , Colonna Marco 
Published: April 2014

AbstractPhospholipase C-γ (PLCγ) is a key regulator of intracellular Ca2+ mobilization. Two isoforms of PLCγ have been identified, PLCγ1 and PLCγ2. Previously, in vitro studies indicated that activating NK cell receptors signal through both isoforms. However, PLCγ2 deficiency alone was sufficient to induce a substantial impairment of NK cell-mediated cytotoxicity in vitro. Why PLCγ2 is more important than PLCγ1 for NK cell activation and whether PLCγ2 is also critical for NK cell development, secretion of IFN-γ, and clearance of viral infections in vivo is not known. In this study, we report that PLCγ2 is the predominant isoform expressed in murine NK cells. PLCγ2 deficiency did not affect NK cell numbers in bone marrow and spleen, but acquisition of Ly49 receptors by NK cells was partially impaired. PLCγ2-deficient NK cells exhibited a dramatic impairment of cytolytic function and IFN-γ production upon ligation of activating receptors, whereas they did secrete IFN-γ in response to cytokines. Consequently, mice lacking PLCγ2 controlled murine CMV infection substantially less effectively than did wild-type animals, and this defect was most evident in the spleen, where viral clearance mostly depends on NK cell lytic function. These results demonstrate that PLCγ2 is crucial for development of the NK cell receptor repertoire and signaling of activating NK cell receptors, mediating optimal NK cell function in vivo.
IL-21 Sustains CD28 Expression on IL-15-Activated Human Naive CD8+ T Cells
Authors: Alves Nuno L. , Arosa Fernando A. , van Lier René A. W. 
Published: April 2014

Abstract
Human naive CD8+ T cells are able to respond in an Ag-independent manner to IL-7 and IL-15. Whereas IL-7 largely maintains CD8+ T cells in a naive phenotype, IL-15 drives these cells to an effector phenotype characterized, among other features, by down-regulation of the costimulatory molecule CD28. We evaluated the influence of the CD4+ Th cell-derived common γ-chain cytokine IL-21 on cytokine-induced naive CD8+ T cell activation. Stimulation with IL-21 did not induce division and only slightly increased IL-15-induced proliferation of naive CD8+ T cells. Strikingly, however, IL-15-induced down-modulation of CD28 was completely prevented by IL-21 at the protein and transcriptional level. Subsequent stimulation via combined TCR/CD3 and CD28 triggering led to a markedly higher production of IL-2 and IFN-γ in IL-15/IL-21-stimulated cells compared with IL-15-stimulated T cells. Our data show that IL-21 modulates the phenotype of naive CD8+ T cells that have undergone IL-15 induced homeostatic proliferation and preserves their responsiveness to CD28 ligands.