bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of HLA-B27-Restricted Peptides from the Chlamydia trachomatis Proteome with Possible Relevance to HLA-B27-Associated Diseases
Authors: Kuon Wolfgang , Holzhütter Hermann-Georg , Appel Heiner , Grolms Martina , Kollnberger Simon , Traeder Alexander , Henklein Peter , Weiss Elisabeth , Thiel Andreas , Lauster Roland , Bowness Paul , Radbruch Andreas , Kloetzel Peter-Michael , Sieper Joachim 
Published: April 2014

Abstract
The association of HLA-B27 with ankylosing spondylitis and reactive arthritis is the strongest one known between an MHC class I Ag and a disease. We have searched the proteome of the bacterium Chlamydia trachomatis for HLA-B27 binding peptides that are stimulatory for CD8+ cells both in a model of HLA-B27 transgenic mice and in patients. This was done by combining two biomathematical computer programs, the first of which predicts HLA-B27 peptide binding epitopes, and the second the probability of HLA-B27 peptide generation by the proteasome system. After preselection, immunodominant peptides were identified by Ag-specific flow cytometry. Using this approach we have identified for the first time nine peptides derived from different C. trachomatis proteins that are stimulatory for CD8+ T cells. Eight of these nine murine-derived peptides were recognized by cytotoxic T cells. The same strategy was used to identify B27-restricted chlamydial peptides in three patients with reactive arthritis. Eleven peptides were found to be stimulatory for patient-derived CD8+ T cells, of which eight overlapped those found in mice. Additionally, we applied the tetramer technology, showing that a B27/chlamydial peptide containing one of the chlamydial peptides stained CD8+ T cells in patients with Chlamydia-induced arthritis. This comprehensive approach offers the possibility of clarifying the pathogenesis of B27-associated diseases.
A Possible Role for CXCR4 and Its Ligand, the CXC Chemokine Stromal Cell-Derived Factor-1, in the Development of Bone Marrow Metastases in Neuroblastoma
Authors: Geminder Hila , Sagi-Assif Orit , Goldberg Lilach , Meshel Tsipi , Rechavi Gideon , Witz Isaac P. , Ben-Baruch Adit 
Published: April 2014

AbstractThe homing of hemopoietic stem cells to the bone marrow is mediated by specific interactions occurring between CXCR4, which is expressed on hemopoietic stem cells, and its ligand, stromal cell-derived factor-1 (SDF-1), a CXC chemokine secreted by bone marrow stromal cells. In the present study we evaluated the possibility that neuroblastoma cells use a mechanism similar to that used by hemopoietic stem cells to home to the bone marrow and adhere to bone marrow stromal cells. Our study suggests that CXCR4 expression may be a general characteristic of neuroblastoma cells. SH-SY5Y neuroblastoma cells express not only CXCR4, but also its ligand, SDF-1. CXCR4 expression on SH-SY5Y neuroblastoma cells is tightly regulated by tumor cell-derived SDF-1, as demonstrated by the ability of neutralizing Abs against human SDF-1α to up-regulate CXCR4 expression on the tumor cells. The reduction in CXCR4 expression following short term exposure to recombinant human SDF-1α can be recovered as a result of de novo receptor synthesis. Recombinant human SDF-1α induces the migration of CXCR4-expressing SH-SY5Y neuroblastoma cells in CXCR4- and heterotrimeric G protein-dependent manners. Furthermore, SH-SY5Y cells interact at multiple levels with bone marrow components, as evidenced by the fact that bone marrow-derived constituents promote SH-SY5Y cell migration, adhesion to bone marrow stromal cells, and proliferation. These results suggest that SH-SY5Y neuroblastoma cells are equipped with adequate machinery to support their homing to the bone marrow. Therefore, the ability of neuroblastoma tumors to preferentially form metastases in the bone marrow may be influenced by a set of complex CXCR4-SDF-1 interactions.
Retrovirally Transduced Human Dendritic Cells Can Generate T Cells Recognizing Multiple MHC Class I and Class II Epitopes from the Melanoma Antigen Glycoprotein 100
Authors: Lapointe Réjean , Royal Richard E. , Reeves Mark E. , Altomare Ivy , Robbins Paul F. , Hwu Patrick 
Published: April 2014

Abstract
Involvement of tumor-Ag specific CD4+ and CD8+ T cells could be critical in the generation of an effective immunotherapy for cancer. In an attempt to optimize the T cell response against defined tumor Ags, we previously developed a method allowing transgene expression in human dendritic cells (DCs) using retroviral vectors. One advantage of using gene-modified DCs is the potential ability to generate CD8+ T cells against multiple class I-restricted epitopes within the Ag, thereby eliciting a broad antitumor immune response. To test this, we generated tumor-reactive CD8+ T cells with DCs transduced with the melanoma Ag gp100, for which a number of HLA-A2-restricted epitopes have been described. Using gp100-transduced DCs, we were indeed able to raise T cells recognizing three distinct HLA-A2 epitopes within the Ag, gp100154–162, gp100209–217, and gp100280–288. We next tested the ability of transduced DCs to raise class II-restricted CD4+ T cells. Interestingly, stimulation with gp100-transduced DCs resulted in the generation of CD4+ T cells specific for a novel HLA-DRβ1*0701-restricted epitope of gp100. The minimal determinant of this epitope was defined as gp100174–190 (TGRAMLGTHTMEVTVYH). These observations suggest that retrovirally transduced DCs have the capacity to present multiple MHC class I- and class II-restricted peptides derived from a tumor Ag, thereby eliciting a robust immune response against that Ag.
Secondhand Smoke Induces Allergic Sensitization in Mice
Authors: Rumold Robert , Jyrala Minna , Diaz-Sanchez David 
Published: April 2014

Abstract
Epidemiological studies have suggested increased prevalence of atopy in children of maternal smokers. Although secondhand smoke or environmental tobacco smoke (ETS) has been shown to augment allergic responses, its role in atopic sensitization is still controversial. We studied whether ETS could initiate a Th2 response and thus induce primary allergic sensitization. Mice were exposed for 10 consecutive days to either 1% aerosolized OVA, ETS (5 cigarettes), or both ETS and OVA. C57BL/6 mice receiving both ETS and OVA developed OVA-specific IgE and IgG1, 12, 14, and 25 days after the initial exposure, whereas those receiving OVA alone did not. Thirty days after the initial challenge (20 days after its completion), mice were re-exposed to OVA. Bronchoalveolar lavage performed 24 h later revealed an influx of eosinophils in the group initially challenged with both ETS and OVA, but not in those exposed to ETS alone or OVA alone. Increases in IL-5, GM-CSF, and IL-2 were observed in bronchoalveolar lavage from this OVA/ETS-exposed group, whereas IFN-γ levels were significantly inhibited. These results suggest that ETS can induce allergic sensitization to a normally harmless Ag, and they may explain why secondhand smoke is a major risk factor for the development of allergy in children.
Cutting Edge: Requirement for IL-15 in the Generation of Primary and Memory Antigen-Specific CD8 T Cells
Authors: Schluns Kimberly S. , Williams Kristina , Ma Averil , Zheng Xin X. , Lefrançois Leo 
Published: April 2014

Abstract
IL-15 and IL-15Rα are required for generation of memory-phenotype CD8 T cells in unimmunized mice. However, the role of IL-15 in primary expansion and generation of Ag-specific memory CD8 T cells in vivo has not been investigated. We characterized the CD8 T cell response against vesicular stomatitis virus (VSV) in IL-15−/− and IL-15Rα−/− mice. Surprisingly, IL-15 was required for primary expansion of VSV-specific CD8 T cells. The generation of VSV-specific memory CD8 T cells was also impaired without IL-15 signaling, and this defect correlated with a decrease in memory CD8 T cell turnover. Despite minimal proliferation without IL-15, a subset of memory cells survived long-term. IL-15Rα expression was low on naive CD8 T cells, up-regulated on Ag-specific effector cells, and sustained on memory cells. Thus, IL-15 was important for the generation and the subsequent maintenance of antiviral memory CD8 T cells.
Cutting Edge: Selective Impairment of CD8+ T Cell Function in Mice Lacking the TNF Superfamily Member LIGHT
Authors: Tamada Koji , Ni Jian , Zhu Gefeng , Fiscella Michele , Teng Baiqin , van Deursen Jan M. A. , Chen Lieping 
Published: April 2014

Abstract
Interactions of LIGHT and its receptors, herpesvirus entry mediator on T cells and lymphotoxin β receptor on stromal cells, are implicated in the regulation of lymphoid organogenesis, costimulation of T cells, and activation of dendritic cells. In this work we report that LIGHT-deficient mice had normal lymphoid organs with T cells and APCs that normally responded to Ag stimulation and normally stimulated T cells. Although the number of Vβ8+ T cells in naive LIGHT+/+ and LIGHT−/− mice was identical, Vβ8+CD8+ T cell proliferation in response to staphylococcal enterotoxin B was significantly lower in LIGHT−/− mice. Consistently, induction and cytokine secretion of CD8+ CTL to MHC class I-restricted peptide was also reduced in LIGHT−/− mice. However, the proliferative response of Vβ8+CD4+ T cells to staphylococcal enterotoxin B was comparable in LIGHT−/− and LIGHT+/+ mice. Our results suggest that LIGHT is required for activation of normal CD8+ T cells but not CD4+ T cells.
Evidence for a Dual Mechanism for IL-10 Suppression of TNF-α Production That Does Not Involve Inhibition of p38 Mitogen-Activated Protein Kinase or NF-κB in Primary Human Macrophages
Authors: Denys Agnes , Udalova Irina A. , Smith Clive , Williams Lynn M. , Ciesielski Cathleen J. , Campbell Jamie , Andrews Caroline , Kwaitkowski Dominic , Foxwell Brian M. J. 
Published: April 2014

Abstract
IL-10 is a potent anti-inflammatory cytokine and inhibitor of TNF-α production. The molecular pathways by which IL-10 inhibits TNF-α production are obscure, with diverse mechanisms having been published. In this study, a new approach has been taken for the study of human cells. Adenovirus was used to deliver TNF-α promoter-based luciferase reporter genes to primary human monocytic cells. The reporter genes were highly responsive to macrophage activation and appeared to mirror the behavior of the endogenous TNF-α gene. When added, either with or after the stimulus, IL-10 required the 3′ untranslated region of the TNF-α gene to inhibit luciferase mRNA and protein expression, indicating a posttranscriptional mechanism. However, if macrophages were incubated with IL-10 before activation, inhibition of gene expression was also mediated by the 5′ promoter, suggesting a transcriptional mechanism. To our knowledge, this is the first time that a dual mechanism for IL-10 function has been demonstrated. Studies to elucidate the mechanisms underlying the inhibition of TNF-α production addressed the effect of IL-10 on the activation of p38 mitogen-activated protein kinase and NF-κB. However, these studies could demonstrate no requirement for the inhibition of p38 mitogen-activated protein kinase or NF-κB activation as potential mechanisms. Overall, these results may explain the diversity previously ascribed to the complex mechanisms of IL-10 anti-inflammatory activity.
Modulation of Dendritic Cell Differentiation and Maturation by Decoy Receptor 3
Authors: Hsu Tsui-Ling , Chang Yung-Chi , Chen Siu-Ju , Liu Yong-Jun , Chiu Allen W. , Chio Chung-Ching , Chen Lieping , Hsieh Shie-Liang 
Published: April 2014

AbstractDecoy receptor 3 (DcR3), a soluble receptor belonging to the TNFR superfamily, is a receptor for both Fas ligand (FasL) and LIGHT. It has been demonstrated that DcR3 is up-regulated in lung and colon cancers, thus promoting tumor growth by neutralizing the cytotoxic effects of FasL and LIGHT. In this study, we found that DcR3.Fc profoundly modulated dendritic cell differentiation and maturation from CD14+ monocytes, including the up-regulation of CD86/B7.2, and the down-regulation of CD40, CD54/ICAM-1, CD80/B7.1, CD1a, and HLA-DR. Moreover, DcR3-treated dendritic cells suppressed CD4+ T cell proliferation in an allogeneic MLR and up-regulated IL-4 secretion of CD4+CD45RA+ T cells. This suggests that DcR3.Fc may act not only as a decoy receptor to FasL and LIGHT, but also as an effector molecule to skew T cell response to the Th2 phenotype.
Immunostimulatory CpG-DNA Activates Murine Microglia
Authors: Dalpke Alexander H. , Schäfer Martin K.-H. , Frey Markus , Zimmermann Stefan , Tebbe Johannes , Weihe Eberhard , Heeg Klaus 
Published: April 2014

AbstractBacterial DNA containing motifs of unmethylated CpG dinucleotides (CpG-DNA) triggers innate immune cells through the pattern recognition receptor Toll-like receptor 9 (TLR-9). CpG-DNA possesses potent immunostimulatory effects on macrophages, dendritic cells, and B lymphocytes. Therefore, CpG-DNA contributes to inflammation during the course of bacterial infections. In contrast to other TLR-dependent microbial patterns, CpG-DNA is a strong inductor of IL-12. Thus, it acts as a Th1-polarizing agent that can be utilized as potent vaccine adjuvant. To assess the role of CpG-DNA in immune reactions in the CNS, we analyzed the effects of CpG-DNA on microglial cells in vitro and in vivo. Primary microglial cells as well as microglial cell lines express TLR-9 mRNA. Consequently, CpG-DNA activated microglial cells in vitro and induced TNF-α, IL-12p40, IL-12p70, and NO. Furthermore, MHC class II, B7-1, B7-2, and CD40 molecules were up-regulated. In addition, phagocytic activity of microglia was enhanced. After intracerebroventricular injection of CpG-DNA, microglial cells were activated and produced TNF-α and IL-12p40 transcripts, as shown by in situ hybridization. These results indicate that microglia is sensitive to CpG-DNA. Thus, bacterial DNA containing CpG motifs could not only play an important role during infections of the CNS, but also might trigger and sustain Th1-dominated immunopathogenic reactions.
Expression of CD94/NKG2-A on Human T Lymphocytes Is Induced by IL-12: Implications for Adoptive Immunotherapy
Authors: Derre Laurent , Corvaisier Murielle , Pandolfino Marie-Christine , Diez Elisabeth , Jotereau Francine , Gervois Nadine 
Published: April 2014

Abstract
NK cell receptors (NKRs) are expressed on a subset of human T cells, predominantly CD8+, within which they can modulate TCR-mediated functions. In an attempt to identify the mechanisms leading to NKR expression, we analyzed the capacity of IL-12 to modulate the expression by T cells of the components of the CD94/NKG2-A inhibitory receptor, a member of the C-type lectin-like family of NKR. We show that IL-12 induces the expression of NKG2-A and/or CD94 by CD8+ T cells in culture, and that this induction was mediated neither by IFN-γ nor by IL-15. We also show, using the redirected killing assay, that IL-12-induced expression of both CD94 and NKG2-A led to the acquisition by T cells of a functional inhibitory receptor. Expression of the CD94/NKG2-A inhibitory receptor was also induced by IL-12 during T cell Ag stimulation so that in the presence of this cytokine a high proportion of melanoma-reactive CTL induced from PBL by melanoma peptide stimulation expressed this receptor. This study emphasizes the implication of IL-12 in the modulation of immune responses through NKR induction.
Human B Cells Become Highly Responsive to Macrophage-Inflammatory Protein-3α/CC Chemokine Ligand-20 After Cellular Activation Without Changes in CCR6 Expression or Ligand Binding
Authors: Liao Fang , Shirakawa Aiko-Konno , Foley John F. , Rabin Ronald L. , Farber Joshua M. 
Published: April 2014

AbstractCCR6 is the only known receptor for the chemokine macrophage-inflammatory protein (MIP)-3α/CC chemokine ligand (CCL)20. We have shown previously that CCR6 is expressed on peripheral blood B cells, but CCR6 activity on these cells is low in in vitro assays. We report that MIP-3α/CCL20-induced calcium flux and chemotaxis can be enhanced significantly on peripheral blood and tonsillar B cells after activation by cross-linking surface Ag receptors. Of particular interest is the fact that the enhanced activity on B cells was not associated with an increase in CCR6 expression as assessed by levels of receptor mRNA, surface staining, or MIP-3α/CCL20 binding sites, or by a change in the affinity of the receptor for ligand. These data convincingly demonstrate that responses to a chemokine can be regulated solely by changes in the downstream pathways for signal transduction resulting from Ag receptor activation, and establish CCR6 as an efficacious receptor on human B cells.
Death Ligand TRAIL Induces No Apoptosis but Inhibits Activation of Human (Auto)antigen-Specific T Cells
Authors: Lünemann Jan D. , Waiczies Sonia , Ehrlich Stefan , Wendling Uwe , Seeger Bibiane , Kamradt Thomas , Zipp Frauke 
Published: April 2014

Abstract
TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, induces apoptosis in susceptible cells, which can be both malignant and nontransformed. Despite homologies among the death ligands, there are great differences between the TRAIL system on the one hand and the TNF and CD95 systems on the other hand. In particular, TRAIL-induced apoptosis differs between rodents and man. Studies on animal models of autoimmune diseases suggested an influence of TRAIL on T cell growth and effector functions. Because we previously demonstrated that TRAIL does not induce apoptosis in human (auto)antigen-specific T cells, we now asked whether TRAIL exhibits other immunoregulatory properties in these cells. Active TRAIL inhibited calcium influx through store-operated calcium release-activated calcium channels, IFN-γ/IL-4 production, and proliferation. These effects were independent of APC, Ag specificity, and Th differentiation, and no differences were detected between healthy donors and multiple sclerosis patients. TRAIL affected neither the expression of the cell cycling inhibitor p27Kip1 nor the capacity of T cells to produce IL-2 upon Ag rechallenge, indicating that signaling via TRAIL receptor does not induce T cell anergy. Instead, the TRAIL-induced hypoproliferation could be attributed to the down-regulation of the cyclin-dependent kinase 4, indicating a G1 arrest of the cell cycle. Thus, although it does not contribute to mechanisms of peripheral T cell tolerance such as clonal anergy or deletion by apoptosis, TRAIL can directly inhibit activation of human T cells via blockade of calcium influx.
Human Vγ2Vδ2 T Cells Augment Migration-Inhibitory Factor Secretion and Counteract the Inhibitory Effect of Glucocorticoids on IL-1β and TNF-α Production
Authors: Wang Lisheng , Das Hiranmoy , Kamath Arati , Li Lin , Bukowski Jack F. 
Published: April 2014

Abstract
In immune cells, proinflammatory cytokine gene expression is regulated by glucocorticoids, whereas migration-inhibitory factor (MIF), a pleiotropic cytokine, has the unique property of counteracting the inhibitory effect of glucocorticoids on TNF-α and IL-1β secretion. A few lines of evidence suggest that γδ T cells play an important role in immunoregulation. However, it is unknown whether human γδ T cells participate in regulating MIF secretion, and how γδ T cells, glucocorticoids, and cytokines converge to give a unified physiological response. In this study, we demonstrate that human Vγ2Vδ2 T cells augment MIF secretion. Remarkably, these Vγ2Vδ2 T cells, functioning similarly to MIF in part, counteracted inhibition of dexamethasone on production of IL-1β and TNF-α. SCID mice reconstituted with human PBMC that were mock depleted of Vδ2 T cells and repeatedly infected with lethal dose of Escherichia coli had shorter survival time than those reconstituted with PBMC that were depleted of Vδ2 T cells. Thus, human Vγ2Vδ2 T cells are likely to play broad-spectrum roles in immunoregulation and immunopathology by influencing MIF secretion and the immunomodulatory function of glucocorticoids.
4-1BB Ligand-Mediated Costimulation of Human T Cells Induces CD4 and CD8 T Cell Expansion, Cytokine Production, and the Development of Cytolytic Effector Function
Authors: Wen Tao , Bukczynski Jacob , Watts Tania H. 
Published: April 2014

Abstract
4-1BB (CD137) is a costimulatory member of the TNFR family expressed on activated T cells. Its ligand, 4-1BBL, is expressed on activated APC. In the mouse, CD8 T cells are preferentially activated by agonistic anti-murine 4-1BB Abs. However, murine 4-1BBL can stimulate both CD4 and CD8 T cells. To date, there are only limited data on the effects of 4-1BBL on human T cell responses. To further understand the role of 4-1BBL in human T cell responses, we compared human CD4 and CD8 T cell responses to transfected human 4-1BBL plus TCR-mediated stimulation. Both human CD4 and CD8 T cells responded to 4-1BBL. The presence of 4-1BBL on the APC led to increased expansion, cytokine production, and the development of cytolytic effector function by human T cells. In unfractionated T cell cultures, CD4 and CD8 T cells could expand to a similar extent in response to signals through the TCR and 4-1BB, as measured by CFSE labeling and by quantitating T cell numbers in the cultures. In contrast to the results with total T cells, isolated CD8 T cells produced less IL-2 and expanded to a lesser extent than isolated CD4 T cells responding to 4-1BBL. Thus, 4-1BBL is most effective when both CD4 and CD8 T cells are included in the cultures. CD28 and 4-1BB were found to synergize in the induction of IL-2 by human T cells, and CTLA-Ig partially blocked 4-1BBL-dependent IL-2 production. However, a portion of the 4-1BBL-mediated effects were independent of CD28-B7 interaction.
IFN-αβ Promote Priming of Antigen-Specific CD8+ and CD4+ T Lymphocytes by Immunostimulatory DNA-Based Vaccines
Authors: Cho Hearn Jay , Hayashi Tomoko , Datta Sandip K. , Takabayashi Kenji , Van Uden John Henry , Horner Anthony , Corr Maripat , Raz Eyal 
Published: April 2014

AbstractImmunostimulatory sequence (ISS) DNA containing unmethylated CpG dinucleotides stimulate NK and APC to secrete proinflammatory cytokines, including IFN-αβ and -γ, TNF-α, and IL-6 and -12, and to express costimulatory surface molecules such as CD40, B7-1, and B7-2. Although ISS DNA has little direct effect on T cells by these criteria, immunization of wild-type mice with ISS DNA and OVA results in Ag-specific CTL and Th1-type T helper activity. This investigation examines the mechanisms by which ISS DNA primes CD8+ and CD4+ lymphocyte activities. In this report we demonstrate that ISS DNA regulates the expression of costimulatory molecules and TAP via a novel autocrine or paracrine IFN-αβ pathway. Coordinated regulation of B7 costimulation and TAP-dependent cross-presentation results in priming of Ag-specific CD8+ CTL, whereas CD40, B7, and IL-12 costimulation is required for priming of CD4+ Th cells by ISS-based vaccines.