bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple NF-κB and IFN Regulatory Factor Family Transcription Factors Regulate CCL19 Gene Expression in Human Monocyte-Derived Dendritic Cells
Authors: Pietilä Taija E. , Veckman Ville , Lehtonen Anne , Lin Rongtuan , Hiscott John , Julkunen Ilkka 
Published: April 2014

Abstract
CCL19 chemokine has a central role in dendritic cell (DC) biology regulating DC traffic and recruitment of naive T cells to the vicinity of activated DCs. In this study, we have analyzed the regulation of CCL19 gene expression in human monocyte-derived DCs. DCs infected with Salmonella enterica or Sendai virus produced CCL19 at late times of infection. The CCL19 promoter was identified as having two putative NF-κB binding sites and one IFN-stimulated response element (ISRE). Transcription factor binding experiments demonstrated that Salmonella or Sendai virus infection increased the binding of classical p50+p65 and alternative p52+RelB NF-κB proteins to both of the CCL19 promoter NF-κB elements. Interestingly, Salmonella or Sendai virus infection also increased the binding of multiple IFN regulatory factors (IRFs), STAT1, and STAT2, to the ISRE element. Enhanced binding of IRF1, IRF3, IRF7, and IRF9 to the CCL19 promoter ISRE site was detected in Salmonella or Sendai virus-infected cell extracts. The CCL19 promoter in a luciferase reporter construct was activated by the expression of NF-κB p50+p65 or p52+RelB dimers. IRF1, IRF3, and IRF7 proteins also activated CCL19 promoter in the presence of Sendai virus infection. CCL19 promoter constructs mutated at NF-κB and/or ISRE sites were only weakly activated. Ectopic expression of RIG-I (ΔRIG-I, CARDIF) or TLR3/4 (TRIF, MyD88, IKKε, or TBK1) signaling pathway components induced CCL19 promoter activity, suggesting that these pathways are important in CCL19 gene expression. Our experiments reveal that expression of the CCL19 gene is regulated by a combined action of several members of the NF-κB, IRF, and STAT family transcription factors.
IL-7/STAT5 Cytokine Signaling Pathway Is Essential but Insufficient for Maintenance of Naive CD4 T Cell Survival in Peripheral Lymphoid Organs
Authors: Seki Yoh-ichi , Yang Jianying , Okamoto Mariko , Tanaka Shinya , Goitsuka Ryo , Farrar Michael A. , Kubo Masato 
Published: April 2014

Abstract
Constitutive expression of suppressors of cytokine signaling (SOCS)1 in T lineage in vivo attenuated cytokine signaling and resulted in a dramatic reduction in the number of naive CD44lowCD62Lhigh CD4 T cells in the spleen. After adoptive transfer of thymocytes from SOCS1 transgenic mice into normal recipients, naive CD4 T cells rapidly disappeared from the spleen within 1 wk. Likewise, T cell-specific deletion of STAT5a/b in vivo resulted in a similar phenotype characterized by loss of naive CD4 T cells. Thus, STAT5-mediated signaling is crucial for promoting naive T cell survival. However, forced expression of constitutively active STAT5 failed to rescue CD4 T cells in SOCS1 transgenic mice, implying that STAT5 activation is necessary but not sufficient for naive CD4 T cell survival. Although blockade of the IL-7R, a SOCS1 target, resulted in clear inhibition of naive T cell survival, the effect occurred 3 wk after anti-IL-7R Ab treatment, but not at earlier time points. These results suggest that IL-7-mediated STAT5 activation is essential for long-term survival of naive CD4 cells after export from thymus, and that another SOCS1-sensitive cytokine is critical for short-term naive T cell survival.
The Net Effect of Costimulatory Blockers Is Dependent on the Subset and Activation Status of the Autoreactive T Cells
Authors: Zhang Ping , Sun Deming , Ke Yan , Kaplan Henry J. , Shao Hui 
Published: April 2014

Abstract
In this study, we investigated whether CD4 and CD8 autoreactive T cells have different costimulatory requirements for their activation in vitro by testing the effect of a panel of Abs specific for various costimulatory molecules. Our results showed that CD8 interphotoreceptor retinoid-binding protein-specific T cells are more dependent on costimulatory molecules for activation than their CD4 counterparts. Interphotoreceptor retinoid-binding protein-specific T cells are less dependent on costimulatory molecules in the secondary response than the primary response. We also showed that blockade of costimulatory molecules can either promote or inhibit the proliferation of autoreactive T cells, depending on the degree of activation of the cells. Our results show that anti-costimulatory molecule treatment can have diverse actions on autoreactive T cell subsets, the net effect being determined by the subset of immune cells affected and the type and dose of treatment used.
Hepatitis B Virus Sensitizes Hepatocytes to TRAIL-Induced Apoptosis through Bax
Authors: Liang Xiaohong , Liu Yugang , Zhang Qiu , Gao Lifen , Han Lihui , Ma Chunhong , Zhang Lining , Chen Youhai H. , Sun Wensheng 
Published: April 2014

Abstract
Hepatitis B virus (HBV) infection afflicts &gt;300 million people worldwide and is a leading cause of hepatocyte death, cirrhosis, and hepatocellular carcinoma. While the morphological characteristics of dying hepatocytes are well documented, the molecular mechanisms leading to the death of hepatocytes during HBV infection are not well understood. TRAIL, the TNF-related apoptosis-inducing ligand, has recently been implicated in the death of hepatocytes under certain inflammatory but not normal conditions. To determine the potential roles of TRAIL in HBV-induced hepatitis, we examined the effects of HBV and its X protein (HBx) on TRAIL-induced hepatocyte apoptosis both in vivo and in vitro. We found that hepatitis and hepatic cell death in HBV transgenic mice were significantly inhibited by a soluble TRAIL receptor that blocks TRAIL function. We also found that HBV or HBx transfection of a hepatoma cell line significantly increased its sensitivity to TRAIL-induced apoptosis. The increase in TRAIL sensitivity were associated with a dramatic up-regulation of Bax protein expression. Knocking down Bax expression using Bax-specific small interference RNA blocked HBV-induced hepatitis and hepatocyte apoptosis. The degradation of caspases 3 and 9, but not that of Bid or caspase-8, was preferentially affected by Bax knockdown. These results establish that HBV sensitizes hepatocytes to TRAIL-induced apoptosis through Bax and that Bax-specific small interference RNA can be used to inhibit HBV-induced hepatic cell death.
Th1 and Type 1 Cytotoxic T Cells Dominate Responses in T-bet Overexpression Transgenic Mice That Develop Contact Dermatitis
Authors: Ishizaki Kazusa , Yamada Akiko , Yoh Keigyou , Nakano Takako , Shimohata Homare , Maeda Atsuko , Fujioka Yuki , Morito Naoki , Kawachi Yasuhiro , Shibuya Kazuko , Otsuka Fujio , Shibuya Akira , Takahashi Satoru 
Published: April 2014

Abstract
Contact dermatitis in humans and contact hypersensitivity (CHS) in animal models are delayed-type hypersensitivity reactions mediated by hapten-specific T cells. Recently, it has become clear that both CD4+ Th1 and CD8+ type 1 cytotoxic T (Tc1) cells can act as effectors in CHS reactions. T-bet has been demonstrated to play an important role in Th1 and Tc1 cell differentiation, but little is known about its contribution to CHS. In the present study, we used C57BL/6 mice transgenic (Tg) for T-bet to address this issue. These Tg mice, which overexpressed T-bet in their T lymphocytes, developed dermatitis characterized by swollen, flaky, and scaly skin in regions without body hair. Skin histology showed epidermal hyperkeratosis, neutrophil, and lymphocyte infiltration similar to that seen in contact dermatitis. T-bet overexpression in Tg mice led to elevated Th1 Ig (IgG2a) and decreased Th2 Ig (IgG1) production. Intracellular cytokine analyses demonstrated that IFN-γ was increased in both Th1 and Tc1 cells. Furthermore, Tg mice had hypersensitive responses to 2,4-dinitrofluorobenzene, which is used for CHS induction. These results suggest that the level of expression of T-bet might play an important role in the development of contact dermatitis and that these Tg mice should be a useful model for contact dermatitis.
Streptococcal Preparation OK-432 Promotes Fusion Efficiency and Enhances Induction of Antigen-Specific CTL by Fusions of Dendritic Cells and Colorectal Cancer Cells
Authors: Koido Shigeo , Hara Eiichi , Homma Sadamu , Torii Akira , Mitsunaga Makoto , Yanagisawa Satoru , Toyama Yoichi , Kawahara Hidejiro , Watanabe Michiaki , Yoshida Seiya , Kobayashi Susumu , Yanaga Katsuhiko , Fujise Kiyotaka , Tajiri Hisao 
Published: April 2014

Abstract
Dendritic/tumor fusion cell (FC) vaccine is an effective approach for various types of cancer but has not yet been standardized. Antitumor activity can be modulated by different mechanisms such as dendritic cell (DC) maturation state. This study addressed optimal strategies for FC preparations to enhance Ag-specific CTL activity. We have created three types of FC preparations by alternating fusion cell partners: 1) immature DCs fused with autologous colorectal carcinoma cells (Imm-FCs); 2) Imm-FCs followed by stimulation with penicillin-inactivated Streptococcus pyogenes (OK-432) (Imm-FCs/OK); and 3) OK-432-stimulated DCs directly fused to autologous colorectal carcinoma cells (OK-FCs). Both OK-FCs and Imm-FCs/OK coexpressed the CEA, MUC1, and significantly higher levels of CD86, CD83, and IL-12 than those obtained with Imm-FCs. Short-term culture of fusion cell preparations promoted the fusion efficiency. Interestingly, OK-FCs were more efficient in stimulating CD4+ and CD8+ T cells capable of high levels of IFN-γ production and cytolysis of autologous tumor or semiallogeneic targets. Moreover, OK-FCs are more effective inducer of CTL activation compared with Imm-FCs/OK on a per fusion cell basis. The pentameric assay confirmed that CEA- and MUC1-specific CTL was induced simultaneously by OK-FCs at high frequency. Furthermore, the cryopreserved OK-FCs retained stimulatory capacity for inducing antitumor immunity. These results suggest that OK-432 promotes fusion efficiency and induction of Ag-specific CTL by fusion cells. We conclude that DCs fused after stimulation by OK-432 may have the potential applicability to the field of antitumor immunotherapy and may provide a platform for adoptive immunotherapy in the clinical setting.
Anti-TCR Antibody Treatment Activates a Novel Population of Nonintestinal CD8αα+TCRαβ+ Regulatory T Cells and Prevents Experimental Autoimmune Encephalomyelitis
Authors: Tang Xiaolei , Maricic Igor , Kumar Vipin 
Published: April 2014

Abstract
CD8αα+CD4−TCRαβ+ T cells are a special lineage of T cells found predominantly within the intestine as intraepithelial lymphocytes and have been shown to be involved in the maintenance of immune homeostasis. Although these cells are independent of classical MHC class I (class Ia) molecules, their origin and function in peripheral lymphoid tissues are unknown. We have recently identified a novel subset of nonintestinal CD8αα+CD4−TCRαβ+ regulatory T cells (CD8αα Tregs) that recognize a TCR peptide from the conserved CDR2 region of the TCR Vβ8.2-chain in the context of a class Ib molecule, Qa-1a, and control- activated Vβ8.2+ T cells mediating experimental autoimmune encephalomyelitis. Using flow cytometry, spectratyping, and real-time PCR analysis of T cell clones and short-term lines, we have determined the TCR repertoire of the CD8αα regulatory T cells (Tregs) and found that they predominantly use the TCR Vβ6 gene segment. In vivo injection of anti-TCR Vβ6 mAb results in activation of the CD8αα Tregs, inhibition of the Th1-like pathogenic response to the immunizing Ag, and protection from experimental autoimmune encephalomyelitis. These data suggest that activation of the CD8αα Tregs present in peripheral lymphoid organs other than the gut can be exploited for the control of T cell-mediated autoimmune diseases.
The Insulin-Specific T Cells of Nonobese Diabetic Mice Recognize a Weak MHC-Binding Segment in More Than One Form
Authors: Levisetti Matteo G. , Suri Anish , Petzold Shirley J. , Unanue Emil R. 
Published: April 2014

AbstractSeveral naturally occurring anti-insulin CD4 T cells were isolated from islet infiltrates of NOD mice. In accordance with the results of others, these T cells recognized the segment of the β-chain from residues 9–23. Peptides encompassing the B:(9–23) sequence bound weakly to I-Ag7 in two main contiguous registers in which two residues at the carboxyl end, P20Gly and P21Glu, influenced binding and T cell reactivity. Naturally occurring insulin-reactive T cells exhibited differing reactivities with the carboxyl-terminal amino acids, although various single residue changes in either the flanks or the core segments affected T cell responses. The insulin peptides represent another example of a weak MHC-binding ligand that is highly immunogenic, giving rise to distinct populations of autoimmune T cells.
Unexpected Role of B and T Lymphocyte Attenuator in Sustaining Cell Survival during Chronic Allostimulation
Authors: Hurchla Michelle A. , Sedy John R. , Murphy Kenneth M. 
Published: April 2014

AbstractB and T lymphocyte attenuator (BTLA; CD272) can deliver inhibitory signals to B and T cells upon binding its ligand herpesvirus entry mediator. Because CD28, CTLA-4, programmed death-1, and ICOS regulate the development of acute graft-vs-host disease (GVHD), we wished to assess if BTLA also played a role in this T cell-mediated response. In the nonirradiated parental-into-F1 model of acute GVHD, BTLA+/+ and BTLA−/− donor lymphocytes showed equivalent engraftment and expansion during the first week of the alloresponse. Unexpectedly, BTLA−/− donor T cells failed to sustain GVHD, showing a decline in surviving donor cell numbers beginning at day 9 and greatly reduced by day 11. Similarly, inhibition of BTLA-herpesvirus entry mediator engagement by in vivo administration of a blocking anti-BTLA Ab also caused reduced survival of donor cells. Microarray analysis revealed several genes that were differentially expressed by BTLA−/− and BTLA+/+ donor CD4+ T cells preceding the decline in BTLA−/− donor T cells. Several genes influencing Th cell polarization were differentially expressed by BTLA+/+ and BTLA−/− donor cells. Additionally, the re-expression of the IL-7Rα subunit that occurs in BTLA+/+ donor cells after 1 wk of in vivo allostimulation was not observed in BTLA−/− donor CD4+ cells. The striking loss of BTLA−/− T cells in this model indicates a role for BTLA activity in sustaining CD4+ T cell survival under the conditions of chronic stimulation in the nonirradiated parental-into-F1 GVHD.
Pertussis Toxin by Inducing IL-6 Promotes the Generation of IL-17-Producing CD4 Cells
Authors: Chen Xin , Howard O. M. Zack , Oppenheim Joost J. 
Published: April 2014

AbstractCompelling evidence has now demonstrated that IL-17-producing CD4 cells (Th17) are a major contributor to autoimmune pathogenesis, whereas CD4+CD25+ T regulatory cells (Treg) play a major role in suppression of autoimmunity. Differentiation of proinflammatory Th17 and immunosuppressive Treg from naive CD4 cells is reciprocally related and contingent upon the cytokine environment. We and others have reported that in vivo administration of pertussis toxin (PTx) reduces the number and function of mouse Treg. In this study, we have shown that supernatants from PTx-treated mouse splenic cells, which contained IL-6 and other proinflammatory cytokines, but not PTx itself, overcame the inhibition of proliferation seen in cocultures of Treg and CD4+CD25− T effector cells. This stimulatory effect could be mimicked by individual inflammatory cytokines such as IL-1β, IL-6, and TNF-α. The combination of these cytokines synergistically stimulated the proliferation of CD4+CD25− T effector cells despite the presence of Treg with a concomitant reduction in the percentage of FoxP3+ cells and generation of IL-17-expressing cells. PTx generated Th17 cells, while inhibiting the differentiation of FoxP+ cells, from naive CD4 cells when cocultured with bone marrow-derived dendritic cells from wild-type mice, but not from IL-6−/− mice. In vivo treatment with PTx induced IL-17-secreting cells in wild-type mice, but not in IL-6−/− mice. Thus, in addition to inhibiting the development of Treg, the immunoadjuvant activity of PTx can be attributable to the generation of IL-6-dependent IL-17-producing CD4 cells.
NK Cells Negatively Regulate Antigen Presentation and Tumor-Specific CTLs in a Syngeneic Lymphoma Model
Authors: Barber Melissa A. , Zhang Tong , Gagne Bethany A. , Sentman Charles L. 
Published: April 2014

Abstract
NK cells are known to kill tumor cells and produce proinflammatory cytokines that lead to the generation of tumor-specific CTLs. Many studies have used MHC class I-deficient tumor cells and/or adjuvants that induce NK cell responses. In this study, the focus was on less-immunogenic lymphoma cells that express MHC class I as a model to study NK cell responses to tumors that do not directly stimulate NK cell activation. When RMA tumor cells that expressed a truncated version of OVA, or RMA cells alone, were injected into mice that were depleted of NK cells, the mice developed an increased number of tumor-specific CTLs, increased IFN-γ responses, and a higher amount of Ag presentation in draining LNs compared with mice with intact NK cells. These data suggest that NK cells can inhibit the development of effective adaptive immunity in the absence of signals that trigger NK cell activation.
Up-Regulation of Gene Related to Anergy in Lymphocytes Is Associated with Notch-Mediated Human T Cell Suppression
Authors: Kostianovsky Alex M. , Maier Lisa M. , Baecher-Allan Clare , Anderson Ana C. , Anderson David E. 
Published: April 2014

Abstract
A growing body of literature indicates that the Notch pathway can influence the activation and differentiation of peripheral murine T cells, though comparatively little is known about the effects of Notch signaling in human T cells. In the present report we demonstrate that Jagged-1-induced Notch signaling (using immobilized Jagged-1 fusion protein) during stimulation of purified human CD4+ and CD8+ T cells potently inhibits T cell proliferation and effector function, including both Th1- and Th2-associated cytokines. Inhibition of T cell activation is not due to apoptosis or disruption of proximal TCR signaling, but is associated with up-regulation of GRAIL (gene related to anergy in lymphocytes) in CD4+ T cells, with modest effects on other E3 ubiquitin ligases such as c-Cbl and Itch. When evaluated for its effects on CD4+ T cell differentiation, Jagged-1-mediated signaling inhibits T cell cytokine secretion with no significant effect on proliferative responses. Collectively, these data demonstrate that Notch signaling in human T cells induced by Jagged-1 promotes a novel form of T cell hyporesponsiveness that differs from anergy, whereby primary T cell proliferation and cytokine secretion are potently inhibited, and effector function but not proliferative capacity are ameliorated upon secondary stimulation.
Airway Epithelial STAT3 Is Required for Allergic Inflammation in a Murine Model of Asthma
Authors: Simeone-Penney Marina C. , Severgnini Mariano , Tu Powen , Homer Robert J. , Mariani Thomas J. , Cohn Lauren , Simon Amy R. 
Published: April 2014

Abstract
The STAT3 transcription factor is critical for cytokine signaling and the acute phase response, but its role in allergic asthma is largely undefined. To investigate the role of STAT3 in mediating allergic inflammation, we used chemical and genetic approaches to inactivate STAT3 in the airway epithelium of mice. In a murine model of chronic asthma, we demonstrate that the administration of house dust mite (HDM) leads to robust STAT3 activation in the airway epithelium, smooth muscle, and immune cells in the lungs of C57BL/6 mice. To investigate the role of STAT3 in HDM-induced airway inflammation, a conditional knockout of STAT3 in the airway epithelium was generated, e-STAT3−/−. We determined that e-STAT3−/− mice had a significant decrease in HDM-induced airway eosinophilia, lung Th2 accumulation, and chemokines compared with wild-type animals. Importantly, the e-STAT3−/− mice had a significant decrease in airway hyperresponsiveness to methacholine. The administration of two STAT kinase inhibitors diminished STAT3 activation and markedly abrogated the HDM-induced lung inflammation. These findings suggest that STAT3 acts as a novel epithelial regulator of the allergic response by altering Th2 cell recruitment and effector function, and thus, targeting this molecule may provide the basis for a novel asthma therapy.
Sensitization to TLR7 Agonist in IFN-β-Preactivated Dendritic Cells
Authors: Severa Martina , Remoli Maria Elena , Giacomini Elena , Annibali Viviana , Gafa Valerie , Lande Roberto , Tomai Mark , Salvetti Marco , Coccia Eliana M. 
Published: April 2014

Abstract
TLRs interact with a growing list of pathogen-derived products and these interactions drive the activation of innate and adaptive immune responses. Dendritic cells (DC) play a key role in these events expressing a heterogeneous repertoire of TLRs. We have previously demonstrated the production of type I IFNs in DC following bacterial infections and TLR triggering. In this study, we sought to characterize the transcriptome specifically induced in human DC by IFN-β production stimulated upon LPS treatment. To this aim, by using cDNA microarrays, we compared the transcriptome of DC following LPS treatment in the absence or presence of neutralizing anti-type I IFN Abs. Interestingly, we found that the expression of TLR7 was induced during LPS-induced maturation of DC in a type I IFN-dependent manner. The induction of TLR7 in maturing DC was mainly a consequence of the transcriptional activity of IRF-1, whose binding site was located within TLR7 promoter. Moreover, we also demonstrated that “priming” of immature DC, that usually express TLR8 but not TLR7, with exogenous IFN-β induced a functionally active TLR7. In fact, treatment with the TLR7-specific ligand 3M-001 up-regulated the expression of CD83, CD86, and CD38 in IFN-β-primed DC but not in immature DC. Therefore, a robust enhancement in proinflammatory as well as regulatory cytokines was observed. These data suggest that TLR4-mediated type I IFN release activates specific transcription programs in DC amplifying the expression of pathogen sensors to correctly and combinatorially respond to a bacterial as well as viral infection.
Fcγ Receptor IIB on Dendritic Cells Enforces Peripheral Tolerance by Inhibiting Effector T Cell Responses
Authors: Desai Dharmesh D. , Harbers Stephanie O. , Flores Marcella , Colonna Lucrezia , Downie Matthew P. , Bergtold Amy , Jung Steffen , Clynes Raphael 
Published: April 2014

Abstract
The uptake of immune complexes by FcRs on APCs augments humoral and cellular responses to exogenous Ag. In this study, CD11c+ dendritic cells are shown to be responsible in vivo for immune complex-triggered priming of T cells. We examine the consequence of Ab-mediated uptake of self Ag by dendritic cells in the rat insulin promoter-membrane OVA model and identify a role for the inhibitory FcγRIIB in the maintenance of peripheral CD8 T cell tolerance. Effector differentiation of diabetogenic OT-I CD8+ T cells is enhanced in rat insulin promoter-membrane OVA mice lacking FcγRIIB, resulting in a high incidence of diabetes. FcγRIIB-mediated inhibition of CD8 T cell priming results from suppression of both DC activation and cross-presentation through activating FcγRs. Further FcγRIIB on DCs inhibited the induction of OVA-specific Th1 effectors, limiting Th1-type differentiation and memory T cell accumulation. In these MHC II-restricted responses, the presence of FcγRIIB only modestly affected initial CD4 T cell proliferative responses, suggesting that FcγRIIB limited effector cell differentiation primarily by inhibiting DC activation. Thus, FcγRIIB can contribute to peripheral tolerance maintenance by inhibiting DC activation alone or by also limiting processing of exogenously acquired Ag.