bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cross-Regulation between Type I and Type II NKT Cells in Regulating Tumor Immunity: A New Immunoregulatory Axis
Authors: Ambrosino Elena , Terabe Masaki , Halder Ramesh C. , Peng Judy , Takaku Shun , Miyake Sachiko , Yamamura Takashi , Kumar Vipin , Berzofsky Jay A. 
Published: April 2014

Abstract
Negative immunoregulation is a major barrier to successful cancer immunotherapy. The NKT cell is known to be one such regulator. In this study we explored the roles of and interaction between the classical type I NKT cell and the poorly understood type II NKT cell in the regulation of tumor immunity. Selective stimulation of type II NKT cells suppressed immunosurveillance, whereas stimulation of type I NKT cells protected against tumor growth even when responses were relatively skewed toward Th2 cytokines. When both were stimulated simultaneously, type II NKT cells appeared to suppress the activation in vitro and protective effect in vivo of type I NKT cells. In the absence of type I, suppression by type II NKT cells increased, suggesting that type I cells reduce the suppressive effect of type II NKT cells. Thus, in tumor immunity type I and type II NKT cells have opposite and counteractive roles and define a new immunoregulatory axis. Alteration of the balance between the protective type I and the suppressive type II NKT cell may be exploited for therapeutic intervention in cancer.
Regulation of Ca2+ Signaling in Mast Cells by Tyrosine-Phosphorylated and Unphosphorylated Non-T Cell Activation Linker
Authors: Dráberová Lubica , Shaik Gouse Mohiddin , Volná Petra , Heneberg Petr , Tůmová Magda , Lebduška Pavel , Korb Jan , Dráber Petr 
Published: April 2014

Abstract
Engagement of the FcεRI in mast cells and basophils leads to a rapid tyrosine phosphorylation of the transmembrane adaptors LAT (linker for activation of T cells) and NTAL (non-T cell activation linker, also called LAB or LAT2). NTAL regulates activation of mast cells by a mechanism, which is incompletely understood. Here we report properties of rat basophilic leukemia cells with enhanced or reduced NTAL expression. Overexpression of NTAL led to changes in cell morphology, enhanced formation of actin filaments and inhibition of the FcεRI-induced tyrosine phosphorylation of the FcεRI subunits, Syk kinase and LAT and all downstream activation events, including calcium and secretory responses. In contrast, reduced expression of NTAL had little effect on early FcεRI-induced signaling events but inhibited calcium mobilization and secretory response. Calcium response was also repressed in Ag-activated cells defective in Grb2, a major target of phosphorylated NTAL. Unexpectedly, in cells stimulated with thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+ ATPase, the amount of cellular NTAL directly correlated with the uptake of extracellular calcium even though no enhanced tyrosine phosphorylation of NTAL was observed. The combined data indicate that NTAL regulates FcεRI-mediated signaling at multiple steps and by different mechanisms. At early stages NTAL interferes with tyrosine phosphorylation of several substrates and formation of signaling assemblies, whereas at later stages it regulates the activity of store-operated calcium channels through a distinct mechanism independent of enhanced NTAL tyrosine phosphorylation.
A Link between PDL1 and T Regulatory Cells in Fetomaternal Tolerance
Authors: Habicht Antje , Dada Shirine , Jurewicz Mollie , Fife Brian T. , Yagita Hideo , Azuma Miyuki , Sayegh Mohamed H. , Guleria Indira 
Published: April 2014

Abstract
Acceptance of the fetus expressing allogeneic paternal Ags by the mother is a physiologic model of transplantation tolerance. Various mechanisms contribute to fetal evasion from immune attack by maternal leukocytes. We have recently demonstrated that the inhibitory costimulatory molecule PDL1 plays a critical role in fetomaternal tolerance in that PDL1 blockade or deficiency resulted in decreased allogeneic fetal survival rates. CD4+CD25+ T regulatory cells (Tregs) have also been demonstrated to play an important role in fetomaternal tolerance. Since PDL1 is expressed on Tregs, we explored the interactions between PDL1 and Tregs in vivo in a mouse model of fetomaternal tolerance. Depletion of CD25+ T cells abrogated the effect of anti-PDL1 Ab indicating that the effect of PDL1 is possibly mediated by CD25+ Tregs. Adoptive transfer of Tregs from wild-type but not PDL1-deficient mice into PDL1-deficient recipients significantly improved fetal survival. The frequency, phenotype and placental trafficking of Tregs from PDL1-deficient mice were similar to those of wild-type controls, but were defective in inhibiting alloreactive Th1 cells in vitro. This is the first report providing evidence for a link between PDL1 and T regulatory cells in mediating fetomaternal tolerance.
Lymphotoxin αβ2 (Membrane Lymphotoxin) Is Critically Important for Resistance to Leishmania major Infection in Mice
Authors: Xu Guilian , Liu Dong , Fan Yijun , Yang Xi , Korner Heinrich , Fu Yang-Xin , Uzonna Jude E. 
Published: April 2014

Abstract
Although the essential role of TNF-α in the control of intracellular pathogens including Leishmania major is well established, it is uncertain whether the related cytokine lymphotoxin αβ2 (LTα1β2, membrane lymphotoxin) plays any role in this process. In this study, we investigated the contribution of membrane lymphotoxin in host response to L. major infection by using LTβ-deficient (LTβ−/−) mice on the resistant C57BL/6 background. Despite mounting early immune responses comparable to those of wild-type (WT) mice, LTβ−/− mice developed chronic nonhealing cutaneous lesions due to progressive and unresolving inflammation that is accompanied by uncontrolled parasite proliferation. This chronic disease was associated with striking reduction in IL-12 and Ag-specific IFN-γ production by splenocytes from infected mice. Consistent with defective cellular immune response, infected LTβ−/− mice had significantly low Ag-specific serum IgG1 and IgG2a levels compared with WT mice. Although administration of rIL-12 to L. major-infected LTβ−/− mice caused complete resolution of chronic lesions, it only partially (but significantly) reduced parasite proliferation. In contrast, blockade of LIGHT signaling in infected LTβ−/− mice resulted in acute and progressive lesion development, massive parasite proliferation, and dissemination to the visceral organs. Although infected LTβ−/− WT bone marrow chimeric mice were more resistant than LTβ−/− mice, they still had reduced ability to control parasites and showed defective IL-12 and IFN-γ production compared with infected WT mice. These results suggest that membrane lymphotoxin plays critical role in resistance to L. major by promoting effective T cell-mediated anti-Leishmania immunity.
IL-13 Induces Disease-Promoting Type 2 Cytokines, Alternatively Activated Macrophages and Allergic Inflammation during Pulmonary Infection of Mice with Cryptococcus neoformans
Authors: Müller Uwe , Stenzel Werner , Köhler Gabriele , Werner Christoph , Polte Tobias , Hansen Gesine , Schütze Nicole , Straubinger Reinhard K. , Blessing Manfred , McKenzie Andrew N. J. , Brombacher Frank , Alber Gottfried 
Published: April 2014

Abstract
In the murine model of Cryptococcus neoformans infection Th1 (IL-12/IFN-γ) and Th17 (IL-23/IL-17) responses are associated with protection, whereas an IL-4-dependent Th2 response exacerbates disease. To investigate the role of the Th2 cytokine IL-13 during pulmonary infection with C. neoformans, IL-13-overexpressing transgenic (IL-13Tg+), IL-13-deficient (IL-13−/−), and wild-type (WT) mice were infected intranasally. Susceptibility to C. neoformans infection was found when IL-13 was induced in WT mice or overproduced in IL-13Tg+ mice. Infected IL-13Tg+ mice had a reduced survival time and higher pulmonary fungal load as compared with WT mice. In contrast, infected IL-13−/− mice were resistant and 89% of these mice survived the entire period of the experiment. Ag-specific production of IL-13 by susceptible WT and IL-13Tg+ mice was associated with a significant type 2 cytokine shift but only minor changes in IFN-γ production. Consistent with enhanced type 2 cytokine production, high levels of serum IgE and low ratios of serum IgG2a/IgG1 were detected in susceptible WT and IL-13Tg+ mice. Interestingly, expression of IL-13 by susceptible WT and IL-13Tg+ mice was associated with reduced IL-17 production. IL-13 was found to induce formation of alternatively activated macrophages expressing arginase-1, macrophage mannose receptor (CD206), and YM1. In addition, IL-13 production led to lung eosinophilia, goblet cell metaplasia and elevated mucus production, and enhanced airway hyperreactivity. This indicates that IL-13 contributes to fatal allergic inflammation during C. neoformans infection.
Adiponectin Enhances IL-6 Production in Human Synovial Fibroblast via an AdipoR1 Receptor, AMPK, p38, and NF-κB Pathway
Authors: Tang Chih-Hsin , Chiu Yung-Cheng , Tan Tzu-Wei , Yang Rong-Sen , Fu Wen-Mei 
Published: April 2014

Abstract
Articular adipose tissue is a ubiquitous component of human joints, and adiponectin is a protein hormone secreted predominantly by differentiated adipocytes and involved in energy homeostasis. We investigated the signaling pathway involved in IL-6 production caused by adiponectin in both rheumatoid arthritis synovial fibroblasts and osteoarthritis synovial fibroblasts. Rheumatoid arthritis synovial fibroblasts and osteoarthritis synovial fibroblasts expressed the AdipoR1 and AdipoR2 isoforms of the adiponectin receptor. Adiponectin caused concentration- and time-dependent increases in IL-6 production. Adiponectin-mediated IL-6 production was attenuated by AdipoR1 and 5′-AMP-activated protein kinase (AMPK)α1 small interference RNA. Pretreatment with AMPK inhibitor (araA and compound C), p38 inhibitor (SB203580), NF-κB inhibitor, IκB protease inhibitor, and NF-κB inhibitor peptide also inhibited the potentiating action of adiponectin. Adiponectin increased the kinase activity and phosphorylation of AMPK and p38. Stimulation of synovial fibroblasts with adiponectin activated IκB kinase α/β (IKK α/β), IκBα phosphorylation, IκBα degradation, p65 phosphorylation at Ser (276), p65 and p50 translocation from the cytosol to the nucleus, and κB-luciferase activity. Adiponectin-mediated an increase of IKK α/β activity, κB-luciferase activity, and p65 and p50 binding to the NF-κB element and was inhibited by compound C, SB203580 and AdipoR1 small interference RNA. Our results suggest that adiponectin increased IL-6 production in synovial fibroblasts via the AdipoR1 receptor/AMPK/p38/IKKαβ and NF-κB signaling pathway.
Mature B Cells Preferentially Lose Tolerance in the Chronic Graft-versus-Host Disease Model of Systemic Lupus Erythematosus
Authors: Choudhury Arpita , Cohen Philip L. , Eisenberg Robert A. 
Published: April 2014

Abstract
Chronic graft-vs-host (cGVH) disease is a well-characterized systemic lupus erythematosus (SLE) model. Induction of cGVH in anti-DNA H chain knockin (3H9KI) transgenic mice results in specific activation of anti-dsDNA B cells. In this study, we show that B cells from 3H9KI mice were activated by cGVH even when adoptively transferred into irradiated JHT−/− recipients that lack endogenous B cells. This process of activation was reflected by high autoantibody titers and changes in phenotypic markers. We have used this system to characterize the particular B cell subsets that were responsible for secreting autoantibodies during cGVH response. We isolated splenic B cell subsets based on their expression of specific cell surface markers and used them in our adoptive transfer studies. We found that mature B cells were the most vulnerable to the allostimulus and were the major source of autoantibodies compared with immature B cells. The greater susceptibility of mature B cells to become activated and thereby lose tolerance was unanticipated and has implications for maintenance of peripheral tolerance and for the development of autoimmunity. Furthermore, of the mature B cells, marginal zone B cells were particularly responsible for mounting the initial response to the cGVH stimulus. This observation underscores the critical role of marginal zone B cells in activation and production of autoantibodies.
How Regulatory CD25+CD4+ T Cells Impinge on Tumor Immunobiology: The Differential Response of Tumors to Therapies
Authors: Leon Kalet , Garcia Karina , Carneiro Jorge , Lage Agustin 
Published: April 2014

Abstract
Aiming to get a better insight on the impact of regulatory CD25+CD4+ T cells in tumor-immunobiology, a simple mathematical model was previously formulated and studied. This model predicts the existence of two alternative modes of uncontrolled tumor growth, which differ on their coupling with the immune system, providing a plausible explanation to the observation that the development of some tumors expand regulatory T cells whereas others do not. We report now the study of how these two tumor classes respond to different therapies, namely vaccination, immune suppression, surgery, and their different combinations. We show 1) how the timing and the dose applied in each particular treatment determine whether the tumor will be rejected, with or without concomitant autoimmunity, or whether it will continue progressing with slower or faster pace; 2) that both regulatory T cell-dependent and independent tumors are equally sensitive to vaccination, although the former are more sensitive to T cell depletion treatments and are unresponsive to partial surgery alone; 3) that surgery, suppression, and vaccination treatments, can synergistically improve their individual effects, when properly combined. Particularly, we predict rational combinations helping to overcome the limitation of these individual treatments on the late stage of tumor development.
Extent of Stimulation Controls the Formation of Memory CD8 T Cells
Authors: Quigley Michael , Huang Xiaopei , Yang Yiping 
Published: April 2014

Abstract
Only a small fraction of effector CD8 T cells survives to become long-lived memory cells, whereas the majority of them die after an acute infection. What controls the formation of memory CD8 T cells remains mostly unknown. In this study, we showed CD8 T cells primed earlier during vaccinia viral infection received stronger stimulation, divided more extensively, and survived better than those primed later, leading to generation of a larger memory pool. Despite differentiation into effectors, the late-primed CD8 T cells lacked full cell division, displayed increased apoptosis, and failed to develop into memory cells, suggesting that the extent of stimulation influences the survival of effector CD8 T cells. We further demonstrated that the extent of stimulation, which included both the duration and the levels of antigenic stimulation/costimulation, during priming determined the formation of memory CD8 T cells via controlling the extent of Akt activation, and functional suppression of Akt led to defective CD8 memory formation in vivo. Collectively, our data suggest that the extent of stimulation controls CD8 memory formation via activation of Akt and may provide important insights into the design of effective vaccines.
Autoimmunity Stimulated by Adoptively Transferred Dendritic Cells Is Initiated by Both αβ and γδ T Cells but Does Not Require MyD88 Signaling
Authors: Martin David A. , Zhang Kang , Kenkel Justin , Hughes Grant , Clark Edward , Davidson Anne , Elkon Keith B. 
Published: April 2014

Abstract
Vaccination of nonautoimmune prone mice with syngeneic dendritic cells (DC) readily induces anti-DNA autoantibodies but does not trigger systemic disease. We observed that anti-DNA autoantibody generation absolutely required αβ T cells and that γδ T cells also contributed to the response, but that regulatory T cells restrained autoantibody production. Although both NZB/W F1 mice and DC vaccinated C57/BL6 mice produced autoantibodies against dsDNA, vaccinated mice had higher levels of Abs against H1 histone and lower levels of antinucleosome Abs than NZB/W F1 mice. Despite a 100-fold increase in IL-12 and Th1 skewing to a foreign Ag, OVA, synergistic TLR activation of DC in vitro failed to augment anti-DNA Abs or promote class switching beyond that induced by LPS alone. TLR stimulation was not absolutely required for the initial loss of B cell tolerance because anti-DNA levels were similar when wild-type (WT) or MyD88-deficient DC were used for vaccination or WT and MyD88-deficient recipients were vaccinated with WT DC. In contrast, systemic administration of LPS, augmented anti-DNA Ab levels and promoted class switching, and this response was dependent on donor DC signaling via MyD88. LPS also augmented responses in the MyD88-deficient recipients, suggesting that LPS likely exerts its effects on both transferred DC and host B cells in vivo. These results indicate that both the αβ and γδ subsets are necessary for promoting autoantibody production by DC vaccination, and that although TLR/MyD88 signaling is not absolutely required for initiation, this pathway does promote augmentation, and Th1-mediated skewing, of anti-DNA autoantibodies.
A Functionally Coupled μ3-Like Opiate Receptor/Nitric Oxide Regulatory Pathway in Human Multi-Lineage Progenitor Cells
Authors: Cadet Patrick , Mantione Kirk J. , Zhu Wei , Kream Richard M. , Sheehan Melinda , Stefano George B. 
Published: April 2014

AbstractOngoing studies from our group support the existence and biological importance of a distinct cellular signaling pathway involving endogenously synthesized, chemically authentic, l-morphine, its cognate μ3 opiate receptor subtype, and constitutive NO synthase. Based on prior studies indicating evolutionary conservation and adaptation of morphinergic/NO-coupled signaling to mediate autocrine/paracrine control of cellular functions, our goal was to determine whether a functionally competent μ3 opiate receptor/NO-coupled regulatory pathway exists in human multilineage progenitor cells (MLPC) prepared from umbilical cord blood. Real-time PCR analysis indicated significant expression of μ3 opiate receptor-encoding RNA by undifferentiated human MLPC, in the absence of traditional μ1 opioid receptor-encoding RNA expression. Unpredictably, confirmatory RT-PCR analyses indicated cellular expression of a splice variant of the previously characterized μ3 opiate receptor-encoding mRNA. Pharmacological analyses provided critical validating evidence of functional μ3-like opiate receptor/NO-coupled signaling within primary cultures of undifferentiated human MLPC via morphine-evoke real-time release of NO. Control analyses indicated that morphine-stimulated NO release was markedly inhibited by prior treatment with the opiate antagonist l-naloxone or the constitutive NO synthase inhibitor N(G)-nitro-l-arginine methyl ester and unresponsive to stimulation by the opioid peptide methionine enkephalin. Complementary microarray analysis demonstrated that traditional μ1, δ, and κ opioid receptor gene expression is not detected in both undifferentiated and differentiated MLPC. Chemical differentiation of MLPC into neuronal progenitor cells effected significant phenotypic expression of a variety of neurally-associated genes. Our data provide compelling evidence in support of both the evolutionary primacy and primordial regulatory role of μ3-like opiate receptor/NO signaling in embryogenesis.
B Cell Activation State-Governed Formation of Germinal Centers following Viral Infection
Authors: Fink Katja , Manjarrez-Orduño Nataly , Schildknecht Anita , Weber Jacqueline , Senn Beatrice M. , Zinkernagel Rolf M. , Hengartner Hans 
Published: April 2014

AbstractGerminal centers are structures that promote humoral memory cell formation and affinity maturation, but the triggers for their development are not entirely clear. Activated extrafollicular B cells can form IgM-producing plasmablasts or enter a germinal center reaction and differentiate into memory or plasma cells, mostly of the IgG isotype. Vesicular stomatitis virus (VSV) induces both types of response, allowing events that promote each of these pathways to be studied. In this work, extrafollicular vs germinal center responses were examined at a cellular level, analyzing VSV-specific B cells in infected mice. We show that VSV-specific germinal centers are transiently formed when insufficient proportions of specific T cell help is available and that strong B cell activation in cells expressing high levels of the VSV-specific BCR promoted their differentiation into early blasts, whereas moderate stimulation of B cells or interaction with Th cells restricted extrafollicular responses and promoted germinal center formation.
Regulatory Role of Lymphoid Chemokine CCL19 and CCL21 in the Control of Allergic Rhinitis
Authors: Takamura Kaoru , Fukuyama Satoshi , Nagatake Takahiro , Kim Dong-Young , Kawamura Aya , Kawauchi Hideyuki , Kiyono Hiroshi 
Published: April 2014

AbstractThe lymphoid chemokines CCL19 and CCL21 are known to be crucial both for lymphoid cell trafficking and for the structural organization of lymphoid tissues such as nasopharynx-associated lymphoid tissue (NALT). However, their role in allergic responses remains unclear, and so our current study aims to shed light on the role of CCL19/CCL21 in the development of allergic rhinitis. After nasal challenge with OVA, OVA-sensitized plt (paucity of lymph node T cells) mice, which are deficient in CCL19/CCL21, showed more severe allergic symptoms than did identically treated wild-type mice. OVA-specific IgE production, eosinophil infiltration, and Th2 responses were enhanced in the upper airway of plt mice. Moreover, in plt mice, the number of CD4+CD25+ regulatory T cells declined in the secondary lymphoid tissues, whereas the number of Th2-inducer-type CD8α−CD11b+ myeloid dendritic cells (m-DCs) increased in cervical lymph nodes and NALT. Nasal administration of the plasmid-encoding DNA of CCL19 resulted in the reduction of m-DCs in the secondary lymphoid tissues and the suppression of allergic responses in plt mice. These results suggest that CCL19/CCL21 act as regulatory chemokines for the control of airway allergic disease and so may offer a new strategy for the control of allergic disease.
CD86 Has Sustained Costimulatory Effects on CD8 T Cells
Authors: Thomas Ian J. , Petrich de Marquesini Liliana G. , Ravanan Rommel , Smith Richard M. , Guerder Sylvie , Flavell Richard A. , Wraith David C. , Wen Li , Wong F. Susan 
Published: April 2014

Abstract
CD80 and CD86 both costimulate T cell activation. Their individual effects in vivo are difficult to study as they are coordinately up-regulated on APCs. We have studied mice expressing rat insulin promoter (RIP)-CD80 and RIP-CD86 on the NOD and NOD.scid genetic background to generate in vivo models, using diabetes as a readout for cytotoxic T cell activation. Accelerated spontaneous diabetes onset was observed in NOD-RIP-CD80 mice and the transfer of diabetes from 6-wk-old NOD mice to NOD.scid-RIP-CD80 mice was greater compared with NOD-RIP-CD86 and NOD.scid-RIP-CD86 mice, respectively. However, the secondary in vivo response was maintained if T cells were activated through CD86 costimulation compared with CD80. This was demonstrated by greater ability to cause recurrent diabetes in NOD-RIP-CD86 diabetic mice transplanted with 6-wk-old NOD islets and adoptively transferred diabetes from diabetic NOD-RIP-CD86 mice to NOD.scid mice. In vitro, CD80 costimulation enhanced cytotoxicity, proliferation, and cytokine secretion in activated CD8 T cells compared with CD86 costimulation. We demonstrated increased CTLA-4 and programmed death-1 inhibitory molecule expression following costimulation by both CD80 and CD86 (CD80 &gt; CD86). Furthermore, T cells stimulated by CD80 were more susceptible to inhibition by CD4+CD25+ T cells. Overall, while CD86 does not stimulate an initial response as strongly as CD80, there is greater sustained activity that is seen even in the absence of continued costimulation. These functions have implications for the engineered use of costimulatory molecules in altering immune responses in a therapeutic setting.