bluuebunny/crossref_metadata_2025_split huggingface dataset:
Respiratory Syncytial Virus Decreases p53 Protein to Prolong Survival of Airway Epithelial Cells
Authors: Groskreutz Dayna J. , Monick Martha M. , Yarovinsky Timur O. , Powers Linda S. , Quelle Dawn E. , Varga Steven M. , Look Dwight C. , Hunninghake Gary W. 
Published: April 2014

Abstract
Respiratory syncytial virus (RSV) is a clinically important pathogen. It preferentially infects airway epithelial cells causing bronchiolitis in infants, exacerbations in patients with obstructive lung disease, and life-threatening pneumonia in the immunosuppressed. The p53 protein is a tumor suppressor protein that promotes apoptosis and is tightly regulated for optimal cell growth and survival. A critical negative regulator of p53 is murine double minute 2 (Mdm2), an E3 ubiquitin ligase that targets p53 for proteasome degradation. Mdm2 is activated by phospho-Akt, and we previously showed that RSV activates Akt and delays apoptosis in primary human airway epithelial cells. In this study, we explore further the mechanism by which RSV regulates p53 to delay apoptosis but paradoxically enhance inflammation. We found that RSV activates Mdm2 1–6 h after infection resulting in a decrease in p53 6–24 h after infection. The p53 down-regulation correlates with increased airway epithelial cell longevity. Importantly, inhibition of the PI3K/Akt pathway blocks the activation of Mdm2 by RSV and preserves the p53 response. The effects of RSV infection are antagonized by Nutlin-3, a specific chemical inhibitor that prevents the Mdm2/p53 association. Nutlin-3 treatment increases endogenous p53 expression in RSV infected cells, causing earlier cell death. This same increase in p53 enhances viral replication and limits the inflammatory response as measured by IL-6 protein. These findings reveal that RSV decreases p53 by enhancing Akt/Mdm2-mediated p53 degradation, thereby delaying apoptosis and prolonging survival of airway epithelial cells.
CD4+ T Cell-Specific Deletion of IL-4 Receptor α Prevents Ovalbumin-Induced Anaphylaxis by an IFN-γ-Dependent Mechanism
Authors: Nieuwenhuizen Natalie , Herbert De'Broski R. , Lopata Andreas L. , Brombacher Frank 
Published: April 2014

Abstract
IL-4Rα-mediated STAT6 activation serves an essential role in various animal models of allergy and asthma at both the sensitization and effector phases. IL-4 and IL-13 signaling via the IL-4Rα chain exacerbates murine anaphylaxis, but the cell-specific requirements for IL-4Rα expression are unclear. The purpose of this study was to elucidate the mechanisms of systemic anaphylaxis to OVA in gene-targeted mice with a deletion of the IL-4Rα chain in the macrophage/neutrophil or CD4+ T lymphocyte population. Results demonstrated that anaphylaxis in this model was entirely dependent upon the FcγRII/III and was associated with mast cell degranulation. Expression of the IL-4Rα on CD4+ T cells, but not macrophages or neutrophils, was critical for severe anaphylaxis, characterized by diarrhea, hypothermia, and death. Ab depletion experiments demonstrated that IFN-γ protected against mortality and severe intestinal pathology despite the presence of Ag and specific Ab. This protection was associated with reduced levels of mast cell protease, a marker of mast cell degranulation, suggesting that IFN-γ may inhibit mast cell degranulation in vivo. These data suggest that it may be possible to limit the severity of anaphylaxis using rational therapies designed to increase numbers of IFN-γ-producing cells by targeting IL-4Rα signaling in CD4+ T lymphocytes.
Prostaglandin D2 Suppresses Human NK Cell Function via Signaling through D Prostanoid Receptor
Authors: Chen Yingying , Perussia Bice , Campbell Kerry S. 
Published: April 2014

Abstract
NK cells play critical roles in immune responses against tumors or virus infections by generating type 1 cytokine and cytotoxicity responses. In contrast, during type 2 dominant immune responses, such as allergic diseases, activities of NK cells are often impaired. These type 2 immune-mediated diseases have been reported to be closely associated with local production of PGD2. PGD2 is an eicosanoid primarily synthesized by mast cells and alveolar macrophages, and it functions through two major receptors, D prostanoid receptor (DP) and chemoattractant receptor-like molecule on the Th2 cell. Within the immune system, PGD2 binding to DP generally leads to suppression of cellular functions. In the current study, we show that: 1) DP is expressed in human NK cells as detected by mRNA analysis and Western blot; 2) PGD2 inhibits cytotoxicity, chemotaxis, and type 1 cytokine production of human NK cells via signaling through DP; 3) PGD2 signaling via DP elevates intracellular cAMP levels and the inhibitory effects on NK cells are cAMP dependent; 4) PGD2 binding to DP suppresses Ca2+ mobilization triggered by the cross-linking of the activating receptor, CD16. Together, these data uncover a novel mechanism by which PGD2 functions through DP to suppress type 1 and cytolytic functions of human NK cells, thus contributing to the promotion of a type 2 immune response.
CXCR3 Signaling Reduces the Severity of Experimental Autoimmune Encephalomyelitis by Controlling the Parenchymal Distribution of Effector and Regulatory T Cells in the Central Nervous System
Authors: Müller Marcus , Carter Sally L. , Hofer Markus J. , Manders Peter , Getts Daniel R. , Getts Meghan T. , Dreykluft Angela , Lu Bao , Gerard Craig , King Nicholas J. C. , Campbell Iain L. 
Published: April 2014

Abstract
The chemokine receptor CXCR3 promotes the trafficking of activated T and NK cells in response to three ligands, CXCL9, CXCL10, and CXCL11. Although these chemokines are produced in the CNS in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), their role in the pathogenesis of CNS autoimmunity is unresolved. We examined the function of CXCR3 signaling in EAE using mice that were deficient for CXCR3 (CXCR3−/−). The time to onset and peak disease severity were similar for CXCR3−/− and wild-type (WT) animals; however, CXCR3−/− mice had more severe chronic disease with increased demyelination and axonal damage. The inflammatory lesions in WT mice consisted of well-demarcated perivascular mononuclear cell infiltrates, mainly in the spinal cord and cerebellum. In CXCR3−/− mice, these lesions were more widespread throughout the CNS and were diffused and poorly organized, with T cells and highly activated microglia/macrophages scattered throughout the white matter. Although the number of CD4+ and CD8+ T cells infiltrating the CNS were similar in CXCR3−/− and WT mice, Foxp3+ regulatory T cells were significantly reduced in number and dispersed in CXCR3−/− mice. The expression of various chemokine and cytokine genes in the CNS was similar in CXCR3−/− and WT mice. The genes for the CXCR3 ligands were expressed predominantly in and/or immediately surrounding the mononuclear cell infiltrates. We conclude that in EAE, CXCR3 signaling constrains T cells to the perivascular space in the CNS and augments regulatory T cell recruitment and effector T cell interaction, thus limiting autoimmune-mediated tissue damage.
CD101 Surface Expression Discriminates Potency Among Murine FoxP3+ Regulatory T Cells
Authors: Fernandez Irina , Zeiser Robert , Karsunky Holger , Kambham Neeraja , Beilhack Andreas , Soderstrom Kalle , Negrin Robert S. , Engleman Edgar 
Published: April 2014

Abstract
CD4+CD25+FoxP3+ regulatory T cells (Treg) have been shown to be protective in animal models of autoimmunity and acute graft-vs-host disease. However, owing to the functional heterogeneity among CD4+CD25+ T cells, surface markers expressed selectively on functionally active Treg would be useful for purposes of identifying and isolating such cells. We generated a rabbit mAb against murine CD101, a transmembrane glycoprotein involved in T cell activation. Among freshly isolated T cells, CD101 was detected on 25–30% of CD4+CD25+ Treg and ∼20% of conventional memory T cells. CD101high Treg displayed greater in vitro suppression of alloantigen-driven T cell proliferation as compared with CD101low Treg. In a model of graft-vs-host disease induced by allogeneic bone marrow transplantation in vivo bioluminescence imaging demonstrated reduced expansion of donor-derived luciferase-labeled conventional T cells in mice treated with CD101high Treg, compared with CD101low Treg. Moreover, treatment with CD101high Treg resulted in improved survival, reduced proinflammatory cytokine levels and reduced end organ damage. Among the CD101high Treg all of the in vivo suppressor activity was contained within the CD62Lhigh subpopulation. We conclude that CD101 expression distinguishes murine Treg with potent suppressor activity.
The Antiproliferative Effect of Mesenchymal Stem Cells Is a Fundamental Property Shared by All Stromal Cells
Authors: Jones Simon , Horwood Nicole , Cope Andrew , Dazzi Francesco 
Published: April 2014

Abstract
Although it has been widely demonstrated that human mesenchymal stem cells exert potent immunosuppressive effects, there is little information as to whether more mature mesenchymal stromal cells (SC) share the same property. Accordingly, we set out to test the ability of SC from different human tissues to inhibit the proliferation of PBMC following polyclonal stimuli. Chondrocytes, as well as fibroblasts from synovial joints, lung, and skin, were used as a source of SC. Irrespective of their differentiation potential and/or content of progenitor cells, SC from all tissues exhibited antiproliferative functions. This was in marked contrast to parenchymal cells. Although SC did not interfere with early T lymphocyte activation, they arrested stimulated T cells in the G0/G1 phase of the cell cycle and rescued them from apoptosis. In addition, IFN-γ and TNF-α production were reduced. We observed that the inhibitory effect is ultimately mediated by soluble factors, the production of which requires SC to be licensed in an inflammatory environment by cell contact. We conclude that the immunosuppressive effect of mesenchymal cells is not confined to multipotent stem cells, but is a fundamental characteristic of all stroma. Our data suggest that SC, appropriately licensed, regulate T cell homeostasis.
Targeting T Cell-Specific Costimulators and Growth Factors in a Model of Autoimmune Hemolytic Anemia
Authors: Hoyer Katrina K. , Wolslegel Kristen , Dooms Hans , Abbas Abul K. 
Published: April 2014

Abstract
Although it is established that failure of regulatory mechanisms underlies many autoimmune diseases, the stimuli that activate autoreactive lymphocytes remain poorly understood. Defining these stimuli will lead to therapeutic strategies for autoimmune diseases. IL-2-deficient mice develop spontaneous autoimmunity, because of a deficiency of regulatory T cells, and on the BALB/c background, they rapidly die from autoimmune hemolytic anemia. To define the importance of costimulatory pathways in various components of this autoimmune disorder, we first intercrossed IL-2-deficient mice with mice lacking CD28 or CD40L. Elimination of CD28 reduced the activation of autoreactive T cells and lymphoproliferation as well as production of autoantibodies, whereas elimination of CD40L reduced autoantibody production without affecting T cell expansion and accumulation. To examine the role of IL-7, we blocked IL-7R signaling with neutralizing Abs. This treatment inhibited the production of autoantibodies and the development of autoimmune hemolytic anemia. Together, these data indicate that specific costimulatory and cytokine signals are critical for the spontaneous autoantibody-mediated disease that develops in IL-2-deficient mice.
Dynamic Control of Self-Specific CD8+ T Cell Responses via a Combination of Signals Mediated by Dendritic Cells
Authors: Raveney Ben J. E. , Morgan David J. 
Published: April 2014

Abstract
It is acknowledged that T cell interactions with mature dendritic cells (DC) lead to immunity, whereas interactions with immature DC lead to tolerance induction. Using a transgenic murine system, we have examined how DC expressing self-peptides control naive, self-reactive CD8+ T cell responses in vitro and in vivo. We have shown, for the first time, that immature DC can also stimulate productive activation of naive self-specific CD8+ T cells, which results in extensive proliferation, the expression of a highly activated cell surface phenotype, and differentiation into autoimmune CTL. Conversely, mature DC can induce abortive activation of naive CD8+ T cells, which is characterized by low-level proliferation, the expression of a partially activated cell surface phenotype which does not result in autoimmune CTL. Critically, both CD8+ T cell responses are determined by a combination of signals mediated by the DC, and that altering any one of these signals dramatically shifts the balance between autoimmunity and self-tolerance induction. We hypothesize that DC maintain the steady state of self-tolerance among self-specific CD8+ T cells in an active and dynamic manner, licensing productive immune responses against self-tissues only when required.
CCL19 and CXCL13 Synergistically Regulate Interaction between B Cell Acute Lymphocytic Leukemia CD23+CD5+ B Cells and CD8+ T Cells
Authors: Wang Xingbing , Yuling He , Yanping Jiang , Xinti Tan , Yaofang Yang , Feng Yu , Ruijin Xiao , Li Wang , Lang Chen , Jingyi Liu , Zhiqing Tang , Jingping Ouyang , Bing Xia , Li Qiao , Chang Alfred E. , Sun Zimin , Youxin Jin , Jinquan Tan 
Published: April 2014

Abstract
Interacting with T cells, cytokine-producing B cells play a critical protective role in autoimmune diseases. However, the interaction between malignant B and T cells remains to be fully elucidated. In a previous study, we have reported that ligation of CCL19-CCR7 and CXCL13-CXCR5 activates paternally expressed gene 10 (PEG10), resulting in an enhancement of apoptotic resistance in B-cell acute lymphocytic leukemia (B-ALL) CD23+CD5+ B cells. Here, we report that B-ALL CD23+CD5+ B cells produce IL-10 at high level, which can be further elevated by costimulation with CCL19 and CXCL13. CCL19/CXCL13-activated B-ALL CD23+CD5+ B cells, in turn, increase IL-10 expression in syngeneic CD8+ T cells in a B cell-derived IL-10-dependent manner and requiring a cell-cell contact. IL-10 secreted from B-ALL CD23+CD5+ B cells in vitro impairs tumor-specific CTL responses of syngeneic CD8+ T cells. The impairment of cytotoxicity of syngeneic CD8+ T cells is escalated by means of CCL19/CXCL13-induced up-regulation of IL-10 from B-ALL CD23+CD5+ B cells. Moreover, using a short hairpin RNA to knockdown PEG10, we provide direct evidence that increased expression of PEG10 in B-ALL CD23+CD5+ B cells is involved in malignant B-T cell interaction, contributing to the up-regulation of IL-10 expression, as well as to the impairment of cytotoxicity of syngeneic CD8+ T cells. Thus, malignant B-ALL CD23+CD5+ B cells play an immunoregulatory role in controlling different inflammatory cytokine expressions. IL-10 may be one of the critical cellular factors conferring B-ALL CD23+CD5+ B cells to escape from host immune surveillance.
FcR γ-Chain Dependent Signaling in Immature Neutrophils Is Mediated by FcαRI, but Not by FcγRI
Authors: Otten Marielle A. , Leusen Jeanette H. W. , Rudolph Esther , van der Linden Joke A. , Beelen Robert H. J. , van de Winkel Jan G. J. , van Egmond Marjolein 
Published: April 2014

Abstract
Neutrophil-mediated tumor cell lysis is more efficiently triggered by FcαRI (CD89), than by FcγRI (CD64). This difference is most evident in immature neutrophils in which FcγRI-mediated tumor cell lysis is absent. In this study, we show that FcR γ-chain-dependent functions (such as Ab-dependent cellular cytotoxicity and respiratory burst), as well as signaling (calcium mobilization and MAPK phosphorylation), were potently triggered via FcαRI, but not via FcγRI, in immature neutrophils. Internalization, an FcR γ-chain-independent function, was, however, effectively initiated via both receptors. These data suggest an impaired functional association between FcγRI and the FcR γ-chain, which prompted us to perform coimmunoprecipitation experiments. As a weaker association was observed between FcγRI and FcR γ-chain, compared with FcαRI and FcR γ-chain, our data support that differences between FcαRI- and FcγRI-mediated functions are attributable to dissimilarities in association with the FcR γ-chain.
Effector Mechanisms of Recombinant IgA Antibodies against Epidermal Growth Factor Receptor
Authors: Dechant Michael , Beyer Thomas , Schneider-Merck Tanja , Weisner Wencke , Peipp Matthias , van de Winkel Jan G. J. , Valerius Thomas 
Published: April 2014

Abstract
IgA is the most abundantly produced Ab isotype in humans, but its potential as immunotherapeutic reagent has hardly been explored. In this study, we describe anti-tumor mechanisms of mouse/human chimeric IgA Abs against the epidermal growth factor receptor (EGF-R). EGF-R Abs of IgG isotype are currently approved for the treatment of colon or head and neck cancers. As expected, the human IgG1, IgA1, and IgA2 variants of the 225 Ab demonstrated similar binding to EGF-R. Furthermore, IgA Abs were as effective as IgG in mediating direct effector mechanisms such as blockade of EGF binding, inhibition of EGF-R phosphorylation, and induction of growth inhibition. None of the three variants induced complement-mediated lysis. Human IgG1 effectively recruited MNC for ADCC, but activated PMN only weakly, whereas both IgA isoforms proved to be effective in triggering neutrophils. Interestingly, the IgA2 isoform was significantly superior to its IgA1 counterpart in recruiting PMN as effector cells. Because neutrophils constitute the most abundant effector cell population in human blood, this enhanced neutrophil recruitment lead to increased killing of EGF-R expressing tumor cells in whole blood assays. This killing was further enhanced when blood from G-CSF-primed donors was compared with healthy donor blood. Together, these data suggest EGF-R Abs of human IgA isotype to bear promise for therapeutic use in cancer.
Dynamics of CD8+ T Cell Responses during Acute and Chronic Lymphocytic Choriomeningitis Virus Infection
Authors: Althaus Christian L. , Ganusov Vitaly V. , De Boer Rob J. 
Published: April 2014

Abstract
Infection of mice with lymphocytic choriomeningitis virus (LCMV) is frequently used to study the underlying principles of viral infections and immune responses. We fit a mathematical model to recently published data characterizing Ag-specific CD8+ T cell responses during acute (Armstrong) and chronic (clone 13) LCMV infection. This allows us to analyze the differences in the dynamics of CD8+ T cell responses against different types of LCMV infections. For the four CD8+ T cell responses studied, we find that, compared with the responses against acute infection, responses against chronic infection are generally characterized by an earlier peak and a faster contraction phase thereafter. Furthermore, the model allows us to give a new interpretation of the effect of thymectomy on the dynamics of CD8+ T cell responses during chronic LCMV infection: a smaller number of naive precursor cells is sufficient to account for the observed differences in the responses in thymectomized mice. Finally, we compare data characterizing LCMV-specific CD8+ T cell responses from different laboratories. Although the data were derived from the same experimental model, we find quantitative differences that can be solved by introducing a scaling factor. Also, we find kinetic differences that are at least partly due to the infrequent measurements of CD8+ T cells in the different laboratories.
CD8+ T Cell Activation Is Governed by TCR-Peptide/MHC Affinity, Not Dissociation Rate
Authors: Tian Shaomin , Maile Robert , Collins Edward J. , Frelinger Jeffrey A. 
Published: April 2014

Abstract
Binding of peptide/MHC (pMHC) complexes by TCR initiates T cell activation. Despite long interest, the exact relationship between the biochemistry of TCR/pMHC interaction (particularly TCR affinity or ligand off-rate) and T cell responses remains unresolved, because the number of complexes examined in each independent system has been too small to draw a definitive conclusion. To test the current models of T cell activation, we have analyzed the interactions between the mouse P14 TCR and a set of altered peptides based on the lymphocytic choriomeningitis virus epitope gp33–41 sequence bound to mouse class I MHC Db. pMHC binding, TCR-binding characteristics, CD8+ T cell cytotoxicity, and IFN-γ production were measured for the peptides. We found affinity correlated well with both cytotoxicity and IFN-γ production. In contrast, no correlation was observed between any kinetic parameter of TCR-pMHC interaction and cytotoxicity or IFN-γ production. This study strongly argues for an affinity threshold model of T cell activation.
Airway Hyperresponsiveness through Synergy of γδ T Cells and NKT Cells
Authors: Jin Niyun , Miyahara Nobuaki , Roark Christina L. , French Jena D. , Aydintug M. Kemal , Matsuda Jennifer L. , Gapin Laurent , O’Brien Rebecca L. , Gelfand Erwin W. , Born Willi K. 
Published: April 2014

Abstract
Mice sensitized and challenged with OVA were used to investigate the role of innate T cells in the development of allergic airway hyperresponsiveness (AHR). AHR, but not eosinophilic airway inflammation, was induced in T cell-deficient mice by small numbers of cotransferred γδ T cells and invariant NKT cells, whereas either cell type alone was not effective. Only Vγ1+Vδ5+ γδ T cells enhanced AHR. Surprisingly, OVA-specific αβ T cells were not required, revealing a pathway of AHR development mediated entirely by innate T cells. The data suggest that lymphocytic synergism, which is key to the Ag-specific adaptive immune response, is also intrinsic to T cell-dependent innate responses.
Identification of ERdj3 and OBF-1/BOB-1/OCA-B as Direct Targets of XBP-1 during Plasma Cell Differentiation
Authors: Shen Ying , Hendershot Linda M. 
Published: April 2014

Abstract
Plasma cell differentiation is accompanied by a modified unfolded protein response (UPR), which involves activation of the Ire1 and activating transcription factor 6 branches, but not the PKR-like endoplasmic reticulum kinase branch. Ire1-mediated splicing of XBP-1 (XBP-1(S)) is required for terminal differentiation, although the direct targets of XBP-1(S) in this process have not been identified. We demonstrate that XBP-1(S) binds to the promoter of ERdj3 in plasmacytoma cells and in LPS-stimulated primary splenic B cells, which corresponds to increased expression of ERdj3 transcripts in both cases. When small hairpin RNA was used to decrease XBP-1 expression in plasmacytoma lines, ERdj3 transcripts were concomitantly reduced. The accumulation of Ig γ H chain protein was also diminished, but unexpectedly this occurred at the transcriptional level as opposed to effects on H chain stability. The decrease in H chain transcripts correlated with a reduction in mRNA encoding the H chain transcription factor, OBF-1/BOB-1/OCA-B. Chromatin immunoprecipitation experiments revealed that XBP-1(S) binds to the OBF-1/BOB-1/OCA-B promoter in the plasmacytoma line and in primary B cells not only during plasma cell differentiation, but also in response to classical UPR activation. Gel shift assays suggest that XBP-1(S) binding occurs through a UPR element conserved in both murine and human OBF-1/BOB-1/OCA-B promoters as opposed to endoplasmic reticulum stress response elements. Our studies are the first to identify direct downstream targets of XBP-1(S) during either plasma cell differentiation or the UPR. In addition, our data further define the XBP-1(S)-binding sequence and provide yet another role for this protein as a master regulator of plasma cell differentiation.