bluuebunny/crossref_metadata_2025_split huggingface dataset:
Strong and Durable TCR Clustering at the T/Dendritic Cell Immune Synapse Is Not Required for NFAT Activation and IFN-γ Production in Human CD4+ T Cells
Authors: Blanchard Nicolas , Decraene Maud , Yang Kun , Miro-Mur Francesc , Amigorena Sebastian , Hivroz Claire 
Published: April 2014

AbstractThe exact function of TCR clustering and organized macromolecular patterns at the immune synapse between APCs and T lymphocytes is unclear. Using human immature or mature dendritic cells (DCs) and autologous CD4+ effector T cells, we demonstrate that, within a given conjugate, mature DCs induce strong and long-lasting TCR clustering and protein kinase C-θ translocation in a superantigen dose-dependent manner. Moreover, mature DCs promote CD43 exclusion in a dose-independent manner. In contrast, immature DCs are less potent at inducing these molecular rearrangements. Using these models to correlate T cell functions with the frequency, the intensity, and the duration of TCR clustering, we show, in Jurkat T cells, that weak and transient TCR clustering is sufficient to promote TCR down-modulation, protein kinase C-θ translocation at the synapse, and substantial NFAT transcriptional activation. Moreover, we show, in CD4+ T cell blasts, that strong TCR clustering is required for neither TCR down-modulation nor optimal IFN-γ production. Together, our results demonstrate that some CD4+ functional responses, such as cytokine production, are independent of central supramolecular activation cluster formation.
Diabetes Incidence Is Unaltered in Glutamate Decarboxylase 65-Specific TCR Retrogenic Nonobese Diabetic Mice: Generation by Retroviral-Mediated Stem Cell Gene Transfer
Authors: Arnold Paula Y. , Burton Amanda R. , Vignali Dario A. A. 
Published: April 2014

Abstract
TCR transgenic mice are valuable tools for dissecting the role of autoantigen-specific T cells in the pathogenesis of type 1 diabetes but are time-consuming to generate and backcross onto congenic strains. To circumvent these limitations, we developed a new approach to rapidly generate mice expressing TCR using retroviral-mediated stem cell gene transfer and a novel picornavirus-like 2A peptide to link the TCR α- and β-chains in a single retroviral vector. We refer to these as retrogenic (Rg) mice to avoid confusion with conventional transgenic mice. Our approach was validated by demonstrating that Rg nonobese diabetic (NOD)-scid mice expressing the diabetogenic TCRs, BDC2.5 and 4.1, generate clonotype-positive T cells and develop diabetes. We then expressed three TCR specific for either glutamate decarboxylase (GAD) 206–220 or GAD 524–538 or for hen egg lysozyme 11–25 as a control in NOD, NOD-scid, and B6.H2g7 mice. Although T cells from these TCR Rg mice responded to their respective Ag in vitro, the GAD-specific T cells exhibited a naive, resting phenotype in vivo. However, T cells from Rg mice challenged with Ag in vivo became activated and developed into memory cells. Neither of the GAD-reactive TCR accelerated or protected mice from diabetes, nor did activated T cells transfer or protect against diabetes in NOD-scid recipients, suggesting that GAD may not be a primary target for diabetogenic T cells. Generation of autoantigen-specific TCR Rg mice represents a powerful approach for the analysis of a wide variety of autoantigens.
Prevention of Diabetes in Nonobese Diabetic Mice Mediated by CD1d-Restricted Nonclassical NKT Cells
Authors: Duarte Nadia , Stenström Martin , Campino Susana , Bergman Marie-Louise , Lundholm Marie , Holmberg Dan , Cardell Susanna L. 
Published: April 2014

Abstract
A role for regulatory lymphocytes has been demonstrated in the pathogenesis of type 1 diabetes in the NOD mouse but the nature of these cells is debated. CD1d-restricted NKT lymphocytes have been implicated in this process. Previous reports of reduced diabetes incidence in NOD mice in which the numbers of NKT cells are artificially increased have been attributed to the enhanced production of IL-4 by these cells and a role for classical NKT cells, using the Vα14-Jα18 rearrangement. We now show that overexpression in NOD mice of CD1d-restricted TCR Vα3.2+Vβ9+ NKT cells producing high levels of IFN-γ but low amounts of IL-4 leads to prevention of type 1 diabetes, demonstrating a role for nonclassical CD1d-restricted NKT cells in the regulation of autoimmune diabetes.
Functional and Genetic Analysis of Two CD8 T Cell Subsets Defined by the Level of CD45RC Expression in the Rat
Authors: Xystrakis Emmanuel , Cavailles Pierre , Dejean Anne S. , Cautain Bastien , Colacios Céline , Lagrange Dominique , van de Gaar Marie-Jose , Bernard Isabelle , Gonzalez-Dunia Daniel , Damoiseaux Jan , Fournié Gilbert J. , Saoudi Abdelhadi 
Published: April 2014

AbstractDifferential cytokine production by T cells plays an important role in the outcome of the immune response. We show that the level of CD45RC expression differentiates rat CD8 T cells in two subpopulations, CD45RChigh and CD45RClow, that have different cytokine profiles and functions. Upon in vitro stimulation, in an Ag-presenting cell-independent system, CD45RChigh CD8 T cells produce IL-2 and IFN-γ while CD45RClow CD8 T cells produce IL-4, IL-10, and IL-13. In vitro, these subsets also exhibit different cytotoxic and suppressive functions. The CD45RChigh/CD45RClow CD8 T cell ratio was determined in Lewis (LEW) and Brown-Norway (BN) rats. These two rat strains differ with respect to the Th1/Th2 polarization of their immune responses and to their susceptibility to develop distinct immune diseases. The CD45RChigh/CD45RClow CD8 T cell ratio is higher in LEW than in BN rats, and this difference is dependent on hemopoietic cells. Linkage analysis in a F2(LEW × BN) intercross identified two quantitative trait loci on chromosomes 9 and 20 controlling the CD45RChigh/CD45RClow CD8 T cell ratio. This genetic control was confirmed in congenic rats. The region on chromosome 9 was narrowed down to a 1.2-cM interval that was found to also control the IgE response in a model of Th2-mediated disorder. Identification of genes that control the CD45RChigh/CD45RClow CD8 T cell subsets in these regions could be of great interest for the understanding of the pathophysiology of immune-mediated diseases.
IL-15Rα Is a Negative Regulator of TCR-Activated Proliferation in CD4+ T Cells
Authors: Lee Jan-Mou , Chung Chen-Yen , Chiang Wei-Wei , Liou Yae-Huei , Chen Chian-Feng , Liao Nan-Shih 
Published: April 2014

AbstractAlthough IL-15 is known to be a T cell growth factor, the function in T cells of IL-15Rα, its high affinity receptor, remains unclear. We found that murine IL-15Rα−/− CD4+ T cells hyperproliferated in response to TCR stimulation, in vitro and in vivo, and displayed a lower TCR activation threshold than wild-type CD4+ T cells. TCR-induced activation of Zap70 and of the phospholipase C-γ1-NFATp, Ras-ERK-c-Fos, and Rac-JNK-c-Jun pathways was all augmented in IL-15Rα−/− CD4+ T cells. This in turn led to earlier IL-2Rα induction and higher IL-2 production, which most likely contribute to the hyperproliferation of IL-15Rα−/− CD4+ T cells. Exogenous IL-15 reduced levels of TCR-activated signals, transcription factors, IL-2, and IL-2Rα, and division in wild-type CD4+ T cells. These results reveal IL-15Rα to be a negative regulator for CD4+ T cell activation and demonstrate a novel layer of regulation of TCR signaling by a cytokine system.
Fas-Mediated Inhibition of CD4+ T Cell Priming Results in Dominance of Type 1 CD8+ T Cells in the Immune Response to the Contact Sensitizer Trinitrophenyl
Authors: Martin Stefan F. , Dudda Jan C. , Delattre Virginie , Bachtanian Eva , Leicht Cornelia , Burger Beate , Weltzien Hans Ulrich , Simon Jan C. 
Published: April 2014

AbstractOne of the unusual properties of chemically reactive haptens is their capacity to simultaneously generate immunogenic determinants for hapten-specific CD8+ and CD4+ T cells. Surprisingly, however, a clear dominance of CD8+ effector T cells is observed in murine contact hypersensitivity to various haptens and upon T cell priming with hapten-modified APCs in vitro. In this study we show that trinitrophenyl-specific CD8+ T cells actively prevent CD4+ T cell priming in vitro. This process requires cell-cell contact and is dependent on the expression of Fas on the CD4+ T cells. Our results reveal an important Fas-dependent mechanism for the regulation of hapten-specific CD4+ T cell responses by CD8+ T cells, which causes the dominance of CD8+ effector T cells and the active suppression of a CD4+ T cell response. Moreover, our demonstration of reduced contact hypersensitivity to trinitrophenyl in the absence of Fas, but not of perforin and/or granzymes A and B, underlines the important role of Fas as a pathogenetic factor for contact hypersensitivity.
Coinfection Modulates Inflammatory Responses and Clinical Outcome of Helicobacter felis and Toxoplasma gondii Infections
Authors: Stoicov Calin , Whary Mark , Rogers Arlin B. , Lee Frederick S. , Klucevsek Kristine , Li Hanchen , Cai Xun , Saffari Reza , Ge Zhongming , Khan Imtiaz A. , Combe Crescent , Luster Andrew , Fox James G. , Houghton JeanMarie 
Published: April 2014

Abstract
The host immune response plays a critical role in determining disease manifestations of chronic infections. Inadequate immune response may fail to control infection, although in other cases the specific immune response may be the cause of tissue damage and disease. The majority of patients with chronic infections are infected by more than one organism yet the interaction between multiple active infections is not known, nor is the impact on disease outcome clear. Using the BALB/c strain of mice, we show that Toxoplasma gondii infection in a host infected with Helicobacter felis alters the natural outcome of T. gondii infection, allowing uncontrolled tachyzoite replication and severe organ damage. Survival rates decrease from 95% in T. gondii infection alone to 50% in dual-infected mice. In addition, infection with T. gondii alters the specific H. felis immune response, converting a previously resistant host to a susceptible phenotype. Gastric mucosal IFN-γ and IL-12 were significantly elevated and IL-10 substantially reduced in dual-infected mice. These changes were associated with severe gastric mucosal inflammation, parietal cell loss, atrophy, and metaplastic cell changes. These data demonstrate the profound interactions between the immune response to unrelated organisms, and suggest these types of interactions my impact clinical disease.
Intracellularly Expressed TLR2s and TLR4s Contribution to an Immunosilent Environment at the Ocular Mucosal Epithelium
Authors: Ueta Mayumi , Nochi Tomonori , Jang Myoung-Ho , Park Eun Jeong , Igarashi Osamu , Hino Ayako , Kawasaki Satoshi , Shikina Takashi , Hiroi Takachika , Kinoshita Shigeru , Kiyono Hiroshi 
Published: April 2014

Abstract
Epithelial cells are key players in the first line of defense offered by the mucosal immune system against invading pathogens. In the present study we sought to determine whether human corneal epithelial cells expressing Toll-like receptors (TLRs) function as pattern-recognition receptors in the innate immune system and, if so, whether these TLRs act as a first line of defense in ocular mucosal immunity. Incubation of human primary corneal epithelial cells and the human corneal epithelial cell line (HCE-T) with peptidoglycan or LPS did not lead to activation, at the level of DNA transcription, of NF-κB or the secretion of inflammation-associated molecules such as IL-6, IL-8, and human β-defensin-2. However, when incubated with IL-1α to activate NF-κB, the production by these cells of such inflammatory mediators was enhanced. Human corneal epithelial cells were observed to express both TLR2- and TLR4-specific mRNA as well as their corresponding proteins intracellularly, but not at the cell surface. However, even when LPS was artificially introduced into the cytoplasm, it did not lead to the activation of epithelial cells. Taken together, our results demonstrate that the intracellular expression of TLR2 and TLR4 in human corneal epithelial cells fails to elicit innate immune responses and therefore, perhaps purposely, contributes to an immunosilent environment at the ocular mucosal epithelium.
n-Nonanoyl-CC Chemokine Ligand 14, a Potent CC Chemokine Ligand 14 Analogue That Prevents the Recruitment of Eosinophils in Allergic Airway Inflammation
Authors: Forssmann Ulf , Hartung Inka , Bälder Ralf , Fuchs Barbara , Escher Sylvia E. , Spodsberg Nikolaj , Dulkys Yasmin , Walden Michael , Heitland Aleksandra , Braun Armin , Forssmann Wolf-Georg , Elsner Jörn 
Published: April 2014

AbstractCCR3 is responsible for tissue infiltration of eosinophils, basophils, mast cells, and Th2 cells, particularly in allergic diseases. In this context, CCR3 has emerged as a target for the treatment of allergic asthma. It is well known that the N-terminal domain of chemokines is crucial for receptor binding and, in particular, its activation. Based on this background, we investigated a number of N-terminally truncated or modified peptides derived from the chemokine CCL14/hemofiltrate CC chemokine-1 for their ability to modulate the activity of CCR3. Among 10 derivatives tested, n-nonanoyl (NNY)-CCL14[10–74] (NNY-CCL14) was the most potent at evoking the release of reactive oxygen species and inducing chemotaxis of human eosinophils. In contrast, NNY-CCL14 has inactivating properties on human eosinophils, because it is able to induce internalization of CCR3 and to desensitize CCR3-mediated intracellular calcium release and chemotaxis. In contrast to naturally occurring CCL11, NNY-CCL14 is resistant to degradation by CD26/dipeptidyl peptidase IV. Because inhibition of chemokine receptors through internalization is a reasonable therapeutic strategy being pursued for HIV infection, we tested a potential inhibitory effect of NNY-CCL14 in two murine models of allergic airway inflammation. In both OVA- and Aspergillus fumigatus-sensitized mice, i.v. treatment with NNY-CCL14 resulted in a significant reduction of eosinophils in the airways. Moreover, airway hyper-responsiveness was shown to be reduced by NNY-CCL14 in the OVA model. It therefore appears that an i.v. administered agonist internalizing and thereby inhibiting CCR3, such as NNY-CCL14, has the potential to alleviate CCR3-mediated diseases.
IL-17 Markedly Up-Regulates β-Defensin-2 Expression in Human Airway Epithelium via JAK and NF-κB Signaling Pathways
Authors: Kao Cheng-Yuan , Chen Yin , Thai Philip , Wachi Shinichiro , Huang Fei , Kim Christy , Harper Richart W. , Wu Reen 
Published: April 2014

AbstractUsing microarray gene expression analysis, we first observed a profound elevation of human β-defensin-2 (hBD-2) message in IL-17-treated primary human airway epithelial cells. Further comparison of this stimulation with a panel of cytokines (IL-1α, 1β, 2–13, and 15–18; IFN-γ; GM-CSF; and TNF-α) demonstrated that IL-17 was the most potent cytokine to induce hBD-2 message (&gt;75-fold). IL-17-induced stimulation of hBD-2 was time and dose dependent, and this stimulation also occurred at the protein level. Further studies demonstrated that hBD-2 stimulation was attenuated by IL-17R-specific Ab, but not by IL-1R antagonist or the neutralizing anti-IL-6 Ab. This suggests an IL-17R-mediated signaling pathway rather than an IL-17-induced IL-1αβ and/or IL-6 autocrine/paracrine loop. hBD-2 stimulation was sensitive to the inhibition of the JAK pathway, and to the inhibitors that affect NF-κB translocation and the DNA-binding activity of its p65 NF-κB subunit. Transient transfection of airway epithelial cells with an hBD-2 promoter-luciferase reporter gene expression construct demonstrated that IL-17 stimulated promoter-reporter gene activity, suggesting a transcriptional mechanism for hBD-2 induction. These results support an IL-17R-mediated signaling pathway involving JAK and NF-κB in the transcriptional stimulation of hBD-2 gene expression in airway epithelium. Because IL-17 has been identified in a number of airway diseases, especially diseases related to microbial infection, these findings provide a new insight into how IL-17 may play an important link between innate and adaptive immunity, thereby combating infection locally within the airway epithelium.
15-Deoxy-Δ12,14-Prostaglandin J2 Inhibits IFN-Inducible Protein 10/CXC Chemokine Ligand 10 Expression in Human Microglia: Mechanisms and Implications
Authors: Si Qiusheng , Zhao Meng-Liang , Morgan Anna C. A. , Brosnan Celia F. , Lee Sunhee C. 
Published: April 2014

AbstractRegulation of cytokine and chemokine expression in microglia may have implications for CNS inflammatory disorders. In this study we examined the role of the cyclopentenone PG 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) in microglial inflammatory activation in primary cultures of human fetal microglia. 15d-PGJ2 potently inhibited the expression of microglial cytokines (IL-1, TNF-α, and IL-6). We found that 15d-PGJ2 had differential effects on the expression of two α-chemokines; whereas the Glu-Lys-Arg (ELR)− chemokine IFN-inducible protein-10/CXCL10 was inhibited, the ELR+ chemokine IL-8/CXCL8 was not inhibited. These findings were shown in primary human microglia and the human monocytic cells line THP-1 cells, using diverse cell stimuli such as bacterial endotoxin, proinflammatory cytokines (IL-1 and TNF-α), IFN-β, and HIV-1. Furthermore, IL-8/CXCL8 expression was induced by 15d-PGJ2 alone or in combination with TNF-α or HIV-1. Combined results from EMSA, Western blot analysis, and immunocytochemistry showed that 15d-PGJ2 inhibited NF-κB, Stat1, and p38 MAPK activation in microglia. Adenoviral transduction of super-repressor IκBα, dominant negative MKK6, and dominant negative Ras demonstrated that NF-κB and p38 MAPK were involved in LPS-induced IFN-inducible protein 10/CXCL10 production. Interestingly, although LPS-induced IL-8/CXCL8 was dependent on NF-κB, the baseline or 15d-PGJ2-mediated IL-8/CXCL8 production was NF-κB independent. Our results demonstrate that 15d-PGJ2 has opposing effects on the expression of two α-chemokines. These data may have implications for CNS inflammatory diseases.
Short- and Long-Term Effects of IL-1 and TNF Antagonists on Periodontal Wound Healing
Authors: Zhang Xuemei , Kohli Malika , Zhou Qingde , Graves Dana T. , Amar Salomon 
Published: April 2014

AbstractThe present study tested the effects of local injection of IL-1 and TNF soluble receptors on a periodontal wound-healing model in nonhuman primates. In this model, periodontal lesions were developed for 16 wk, followed by open flap surgery. Starting at the time of surgery, groups of animals received localized injections of both soluble cytokine receptors or else PBS three times per week for 3, 14, or 35 days. Periodontal wound healing was analyzed for each group at the end of the treatment regimen. Fourteen days after surgery, a significant decrease was observed between the animals treated with soluble receptors and the untreated group with respect to recruitment of inflammatory cells in deep gingival connective tissue. Concurrent apoptosis of inflammatory cells in those tissues increased significantly in treated animals compared with untreated animals. All other outcome parameters of periodontal wound healing were likewise significantly improved in treated animals compared with untreated animals. In marked contrast, however, 35 days after surgery, there was a significant increase in the number of inflammatory cells that had infiltrated into deep gingival connective tissue in treated compared with untreated animals. Outcome parameters of periodontal wound healing worsened in treated animals when compared with untreated. These results indicate that proinflammatory cytokines may play different functional roles in early vs late phases of periodontal wound healing. Short-term blockade of IL-1 and TNF may facilitate periodontal wound healing, whereas prolonged blockade may have adverse effects.
Mechanism of Action of Transmembrane Activator and Calcium Modulator Ligand Interactor-Ig in Murine Systemic Lupus Erythematosus
Authors: Ramanujam Meera , Wang Xiaobo , Huang Weiqing , Schiffer Lena , Grimaldi Christine , Akkerman Alla , Diamond Betty , Madaio Michael P. , Davidson Anne 
Published: April 2014

Abstract
B cell-activating factor belonging to the TNF family (BAFF) blockade prevents the onset of disease in systemic lupus erythematosus (SLE)-prone NZB/NZW F1 mice. To determine the mechanism of this effect, we administered a short course of TACI-Ig with and without six doses of CTLA4-Ig to 18- to 20-wk-old NZB/NZW F1 mice and evaluated the effect on B and T cell subsets and on anti-dsDNA Ab-producing B cells. Even a brief exposure to TACI-Ig had a beneficial effect on murine SLE; CTLA4-Ig potentiated this effect. The combination of TACI-Ig and CTLA4-Ig resulted in a temporary decrease in serum IgG levels. However, after cessation of treatment, high titers of IgG anti-dsDNA Abs appeared in the serum and IgG Abs deposited in the kidneys. Despite the appearance of pathogenic autoantibodies, the onset of proteinuria was markedly delayed; this was associated with prolonged depletion of B cells past the T1 stage, a decrease in the size of the spleen and lymph nodes, and a decrease in the absolute number of activated and memory CD4+ T cells. TACI-Ig treatment normalized serum levels of IgM that are markedly elevated in NZB/W F1 mice; this appeared to be due to a prolonged effect on the ability of the splenic microenvironment to support short-lived IgM plasma cells. Finally, a short course of combination TACI-Ig and CTLA4-Ig prolonged life and even reversed proteinuria in aged NZB/W F1 mice, suggesting that BAFF blockade may be an effective therapeutic strategy for active SLE.
C Protein-Induced Myocarditis and Subsequent Dilated Cardiomyopathy: Rescue from Death and Prevention of Dilated Cardiomyopathy by Chemokine Receptor DNA Therapy
Authors: Matsumoto Yoh , Tsukada Yukiko , Miyakoshi Akira , Sakuma Hiroshi , Kohyama Kuniko 
Published: April 2014

AbstractSevere experimental autoimmune myocarditis and subsequent dilated cardiomyopathy (DCM) were successfully produced in Lewis rats by immunization with recombinant cardiac C protein. Seventy-five percent of immunized rats died between days 15 and 49 postimmunization, and all of the survived rats showed typical DCM characterized by the presence of ventricular dilatation and extensive fibrosis. Immunopathological and chemokine analysis during the acute phase revealed that there were marked macrophage infiltration with myocyte necrosis and up-regulation of MCP-1 and IFN-γ-inducible protein-10 (IP-10). Based on these findings, we prepared plasmid DNAs encoding the binding site of CCR2 and CXCR3, which are receptors for MCP-1 and IP-10, respectively. The culture supernatant of cells transfected with these DNAs inhibited the migration of T cells and macrophages induced by MCP-1 and IP-10. Remarkably, administration of the DNAs to C protein-immunized rats prevented the disease progression and rescued animals from death. The present study has demonstrated for the first time that gene therapy targeting the chemokine receptor could be a powerful tool for the control of experimental autoimmune myocarditis and DCM.
Cutting Edge: Murine Dendritic Cells Require IL-15Rα to Prime NK Cells
Authors: Koka Rima , Burkett Patrick , Chien Marcia , Chai Sophia , Boone David L. , Ma Averil 
Published: April 2014

AbstractNK cells protect hosts against viral pathogens and transformed cells, and dendritic cells (DCs) play important roles in activating NK cells. We now find that murine IL-15Rα-deficient DCs fail to support NK cell cytolytic activity and elaboration of IFN-γ, despite the fact that these DCs express normal levels of costimulatory molecules and IL-12. By contrast, IL-15Rα expression on NK cells is entirely dispensable for their activation by DCs. In addition, blockade with anti-IL-15Rα and anti-IL-2Rβ but not anti-IL-2Rα-specific Abs prevents NK cell activation by wild-type DCs. Finally, presentation of IL-15 by purified IL-15Rα/Fc in trans synergizes with IL-12 to support NK cell priming. These findings suggest that murine DCs require IL-15Rα to present IL-15 in trans to NK cells during NK cell priming.