bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lyme Arthritis Synovial γδ T Cells Instruct Dendritic Cells via Fas Ligand
Authors: Collins Cheryl , Wolfe Julie , Roessner Karen , Shi Cuixia , Sigal Leonard H. , Budd Ralph C. 
Published: April 2014

Abstract
γδ T cells participate in the innate immune response to a variety of infectious microorganisms. They also link to the adaptive immune response through their induction of maturation of dendritic cells (DC) during the early phase of an immune response when the frequency of Ag-specific T cells is very low. We observe that in the presence of Borrelia burgdorferi, synovial Vδ1 T cells from Lyme arthritis synovial fluid potently induce maturation of DC, including production of IL-12, and increased surface expression of CD40 and CD86. The activated DC are then able to stimulate the Vδ1 T cells to up-regulate CD25. Both of these processes are initiated primarily by Fas stimulation rather than CD40 activation of DC via high expression of Fas ligand by the Vδ1 T cells. DC are resistant to Fas-induced death due to expression of high levels of the Fas inhibitor c-FLIP. This effect serves to divert Fas-mediated signals from the caspase cascade to the ERK MAPK and NF-κB pathways. The findings affirm the importance of the interaction of certain T cell populations with DC during the early phases of the innate immune response. They also underscore the view that as levels of c-FLIP increase, Fas signaling can be diverted from induction of apoptosis to pathways leading to cell effector function.
Murine Plasmacytoid Dendritic Cells Produce IFN-γ upon IL-4 Stimulation
Authors: Suto Akira , Nakajima Hiroshi , Tokumasa Naoki , Takatori Hiroaki , Kagami Shin-ichiro , Suzuki Kotaro , Iwamoto Itsuo 
Published: April 2014

Abstract
IL-4 plays a key role in inducing IL-4 production in CD4+ T cells, functioning as an important determinant for Th2 cell differentiation. We show here that IL-4 induces IFN-γ production in B220+ plasmacytoid dendritic cells (PDCs). By searching for cell populations that produce IFN-γ upon IL-4 stimulation, we found that PDCs were a major IFN-γ-producing cell upon IL-4 stimulation in wild-type and Rag-2−/− splenocytes. Isolated PDCs, but not CD11b+ DCs or CD8+ DCs, produced IFN-γ upon IL-4 stimulation. In vivo, the depletion of PDCs by anti-Ly6G/C Ab prevented IFN-γ production induced by IL-4 administration. We also found that IL-4 induced IFN-γ production, but not IL-12 or IFN-α production, in PDCs and also strongly enhanced CpG oligodeoxynucleotide-induced IFN-γ production, but not CpG oligodeoxynucleotide-induced IL-12 or IFN-α production. However, IL-4 did not induce IFN-γ production in Stat6−/− PDCs. Moreover, IL-4 induced Stat4 expression in PDCs through a Stat6-dependent mechanism, and only the Stat4-expressing PDCs produced IFN-γ. Furthermore, IL-4 did not induce IFN-γ production in Stat4−/− PDCs. These results indicate that PDCs preferentially produce IFN-γ upon IL-4 stimulation by Stat6- and Stat4-dependent mechanisms.
TLR9- and FcεRI-Mediated Responses Oppose One Another in Plasmacytoid Dendritic Cells by Down-Regulating Receptor Expression
Authors: Schroeder John T. , Bieneman Anja P. , Xiao HuiQing , Chichester Kristin L. , Vasagar Kavitha , Saini Sarbjit , Liu Mark C. 
Published: April 2014

Abstract
Plasmacytoid dendritic cells (pDC) express not only TLR9 molecules through which ligation with CpG DNA favors Th1 responses but also possess IgE receptors (FcεRI) implicated in allergen presentation and induction of Th2 responses. This dichotomy prompted an investigation to determine whether TLR9- and IgE receptor-mediated responses oppose one another in pDC by affecting receptor expression and associated functional responses. Results showed that IgE cross-linking reduced TLR9 in pDC and inhibited the capacity of these cells to secrete IFN-α when stimulated with the CpG oligodeoxynucleotide (ODN)-2216. In contrast, an ∼15-fold reduction in FcεRIα mRNA and a loss in surface protein were seen in pDC first exposed to TLR9 ligation with ODN-2216. Results indicated that type I IFNs partly mediated this effect, as rIFN-α also caused a significant ∼4-fold reduction in FcεRIα mRNA. Finally, this reduction in FcεRIα mediated by ODN-2216 correlated with a selective suppression of allergen-induced CD4+ T cell proliferation, but not of responses resulting from tetanus toxoid. Overall, these results imply mechanisms by which specific innate and IgE-dependent immune responses counterregulate one another at the dendritic cell level and may have significant impact on whether an ensuing response is either of Th1 or Th2 in nature.
JNK1 Is Essential for CD8+ T Cell-Mediated Tumor Immune Surveillance
Authors: Gao Yunfei , Tao Jian , Li Ming O. , Zhang Dongqing , Chi Hongbo , Henegariu Octavian , Kaech Susan M. , Davis Roger J. , Flavell Richard A. , Yin Zhinan 
Published: April 2014

Abstract
JNK1 has divergent roles in regulating the effector functions of CD4+ and CD8+ T cells. However, the function of JNK1 in tumor immune surveillance is unknown. In this study, we show that similar to IFN-γ−/− mice, JNK1−/− mice are highly susceptible to tumor development after inoculation of both melanoma cell line B16 and lymphoma cell line EL-4. Using T cell depletion and reconstitution approaches, we show that CD8+ T cells, but not CD4+ T cells, from JNK1−/− mice are responsible for tumor susceptibility. JNK1−/− CD8+ T cells have an intrinsic defect in early IFN-γ gene transcription and production after activation by either anti-CD3/anti-CD28 Abs or dendritic cells loaded with specific Ag in vitro. The impaired IFN-γ production in JNK1−/− CD8+ T cells is associated with reduced expression of both T-bet and Eomesodermin, indicating that JNK1 regulates the transcription program of CD8+ T cells. Finally, JNK1−/− CD8+ T cells showed reduced perforin expression and impaired CTL function. Taken together, our results demonstrate that JNK1 plays an important role in tumor immune surveillance through regulating the effector functions of CD8+ T cells.
Recognition of Fresh Human Tumor by Human Peripheral Blood Lymphocytes Transduced with a Bicistronic Retroviral Vector Encoding a Murine Anti-p53 TCR
Authors: Cohen Cyrille J. , Zheng Zhili , Bray Regina , Zhao Yangbing , Sherman Linda A. , Rosenberg Steven A. , Morgan Richard A. 
Published: April 2014

AbstractThe p53 protein is markedly up-regulated in a high proportion of human malignancies. Using an HLA-A2 transgenic mouse model, it was possible to isolate high-avidity murine CTLs that recognize class I-restricted human p53 epitopes. We isolated the α- and β-chain of a TCR from a highly avid murine CTL clone that recognized the human p53264–272 epitope. These genes were cloned into a retroviral vector that mediated high efficiency gene transfer into primary human lymphocytes. Efficiencies of &gt;90% for gene transfer into lymphocytes were obtained without selection for transduced cells. The p53 TCR-transduced lymphocytes were able to specifically recognize with high-avidity, peptide-pulsed APCs as well as HLA-A2.1+ cells transfected with either wild-type or mutant p53 protein. p53 TCR-transduced cells demonstrated recognition and killing of a broad spectrum of human tumor cell lines as well as recognition of fresh human tumor cells. Interestingly, both CD8+ and CD4+ subsets were capable of recognizing and killing target cells, stressing the potential application of such a CD8-independent TCR molecule that can mediate both helper and cytotoxic responses. These results suggest that lymphocytes genetically engineered to express anti-p53 TCR may be of value for the adoptive immunotherapy of patients with a variety of common malignancies.
IL-12 and IL-10 Expression Synergize to Induce the Immune-Mediated Eradication of Established Colon and Mammary Tumors and Lung Metastasis
Authors: Lopez M. Verónica , Adris Soraya K. , Bravo Alicia I. , Chernajovsky Yuti , Podhajcer Osvaldo L. 
Published: April 2014

AbstractPreclinical studies demonstrated that certain cytokines are potentially useful for the induction of antitumor immune responses. However, their administration in clinical settings was only marginally useful and evoked serious toxicity. In this study, we demonstrate that the combination of autologous inactivated tumor cells expressing IL-12 and IL-10 induced tumor remission in 50–70% of mice harboring large established colon or mammary tumors and spontaneous lung metastases, with the consequent establishment of an antitumor immune memory. Mice treatment with tumor cells expressing IL-12 was only marginally effective, while expression of IL-10 was not effective at all. Administration of the combined immunotherapy stimulated the recruitment of a strong inflammatory infiltrate that correlated with local, increased expression levels of the chemokines MIP-2, MCP-1, IFN-γ-inducible protein-10, and TCA-3 and the overexpression of IFN-γ, but not IL-4. The combined immunotherapy was also therapeutically effective on established lung metastases from both colon and mammary tumors. The antitumor effect of the combined immunotherapy was mainly dependent on CD8+ cells although CD4+ T cells also played a role. The production of IFN-γ and IL-4 by spleen cells and the development of tumor-specific IgG1 and IgG2a Abs indicate that each cytokine stimulated its own Th pathway and that both arms were actively engaged in the antitumor effect. This study provides the first evidence of a synergistic antitumor effect of IL-12 and IL-10 suggesting that a Th1 and a Th2 cytokine can be effectively combined as a novel rational approach for cancer immunotherapy.
Molecular Signatures Distinguish Human Central Memory from Effector Memory CD8 T Cell Subsets
Authors: Willinger Tim , Freeman Tom , Hasegawa Hitoshi , McMichael Andrew J. , Callan Margaret F. C. 
Published: April 2014

Abstract
Memory T cells are heterogeneous in terms of their phenotype and functional properties. We investigated the molecular profiles of human CD8 naive central memory (TCM), effector memory (TEM), and effector memory RA (TEMRA) T cells using gene expression microarrays and phospho-protein-specific intracellular flow cytometry. We demonstrate that TCM have a gene expression and cytokine signaling signature that lies between that of naive and TEM or TEMRA cells, whereas TEM and TEMRA are closely related. Our data define the molecular basis for the different functional properties of central and effector memory subsets. We show that TEM and TEMRA cells strongly express genes with known importance in CD8 T cell effector function. In contrast, TCM are characterized by high basal and cytokine-induced STAT5 phosphorylation, reflecting their capacity for self-renewal. Altogether, our results distinguish TCM and TEM/TEMRA at the molecular level and are consistent with the concept that TCM represent memory stem cells.
Respiratory Syncytial Virus Infection of Monocyte-Derived Dendritic Cells Decreases Their Capacity to Activate CD4 T Cells
Authors: de Graaff Patricia M. A. , de Jong Esther C. , van Capel Toni M. , van Dijk Mariska E. A. , Roholl Paul J. M. , Boes Jolande , Luytjes Willem , Kimpen Jan L. L. , van Bleek Grada M. 
Published: April 2014

AbstractRespiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in children, the elderly, and immune-compromised individuals. CD4 and CD8 T cells play a crucial role in the elimination of RSV from the infected lung, but T cell memory is not sufficient to completely prevent reinfections. The nature of the adaptive immune response depends on innate immune reactions initiated after interaction of invading pathogens with host APCs. For respiratory pathogens myeloid dendritic cell (DC) precursors that are located underneath the epithelial cell layer lining the airways may play a crucial role in primary activation of T cells and regulating their functional potential. In this study, we investigated the role of human monocyte-derived DC in RSV infection. We showed that monocyte-derived DC can be productively infected, which results in maturation of the DC judged by the up-regulation of CD80, CD83, CD86, and HLA class II molecules. However, RSV infection of DC caused impaired CD4 T cell activation characterized by a lower T cell proliferation and ablation of cytokine production in activated T cells. The suppressive effect was caused by an as yet unidentified soluble factor produced by RSV-infected DC.
Signaling through a Mutant IFN-γ Receptor
Authors: Costa-Pereira Ana P. , Hermanns Heike M. , Is’harc Hayaatun , Williams Timothy M. , Watling Diane , Arulampalam Velmurugesan , Newman Sally J. , Heinrich Peter C. , Kerr Ian M. 
Published: April 2014

Abstract
Activation of STAT1 and the IFN-γ response are thought to be mediated exclusively through the Y440 motif of the human IFNGR1 receptor subunit. Contrary to this accepted dogma, here it is shown that IFNGR1 with a mutant (Y440F) motif, when stably expressed in IFNGR1-negative human fibroblasts at levels similar to wild type, can sustain a substantial IFN-γ response. The mutant receptor supports selective induction of IFN-γ-inducible genes but is notably defective in the CIITA, class II HLA, suppressor of cytokine signaling and antiviral responses. Remarkably, similar selective defects are observed in human fibrosarcoma cells expressing a mutant JAK1. The phenotypes are novel and appear distinct from those observed in response to the inhibition of known additional pathways. Data from different cell types further emphasizes the importance of cellular background in determining the response.
Epigenetic Control of Highly Homologous Killer Ig-Like Receptor Gene Alleles
Authors: Chan Huei-Wei , Miller Jeffrey S. , Moore Mikel B. , Lutz Charles T. 
Published: April 2014

Abstract
Mature human NK lymphocytes express the highly homologous killer Ig-like receptor (KIR) genes in a stochastic fashion, and KIR transcription precisely correlates with allele-specific DNA methylation. In this study, we demonstrate that CpG methylation of a minimal KIR promoter inhibited transcription. In human peripheral blood NK cells and long-term cell lines, expressed KIR genes were associated with a moderate level of acetylated histone H3 and H4 and trimethylated histone H3 lysine 4. Histone modifications were preferentially associated with the transcribed allele in NK cell lines with monoallelic KIR expression. Although reduced, a substantial amount of histone acetylation and H3 lysine 4 trimethylation also was associated with nonexpressed KIR genes. DNA hypomethylation correlated with increased chromatin accessibility, both in vitro and in vivo. Treatment of NK cell lines and developing NK cells with the DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine, caused a dramatic increase in KIR RNA and protein expression, but little change in histone modification. Our findings suggest that KIR transcription is primarily controlled by DNA methylation.
The Cyclic AMP Response Element Modulator Regulates Transcription of the TCR ζ-Chain
Authors: Tenbrock Klaus , Kyttaris Vasileios C. , Ahlmann Martina , Ehrchen Jan Mauno , Tolnay Mate , Melkonyan Harutyun , Mawrin Christian , Roth Johannes , Sorg Clemens , Juang Yuang-Taung , Tsokos George C. 
Published: April 2014

Abstract
Systemic lupus erythematosus T cells display decreased amounts of TCR ζ mRNA that results in part from limited binding of the transcriptional enhancer Elf-1 to the TCR ζ promoter. We have identified a new cis-binding site for the cAMP response element (CRE) modulator (CREM) on the TCR ζ promoter, centered on the −390 nucleotide. Transfection of T cells with an antisense CREM α plasmid reduced the binding of CREM to the TCR ζ promoter, as shown by chromatin and reporter chromatin immunoprecipitation assays, and enhanced the production of TCR ζ mRNA and protein. Mutagenesis of the −390 CRE site prevented the binding of CREM to the TCR ζ promoter. The mechanism of CREM-mediated repression appears to be chromatin dependent, because antisense CREM promotes the acetylation of histones on the TCR ζ promoter. Finally, we established an enhanced binding of CREM to the TCR ζ-chain promoter in systemic lupus erythematosus cells compared with control T cells. Our studies demonstrate that CREM α binds to the TCR ζ promoter and repress its activity.
The High Frequency Indian Rhesus Macaque MHC Class I Molecule, Mamu-B*01, Does Not Appear to Be Involved in CD8+ T Lymphocyte Responses to SIVmac239
Authors: Loffredo John T. , Sidney John , Piaskowski Shari , Szymanski Andrew , Furlott Jessica , Rudersdorf Richard , Reed Jason , Peters Bjoern , Hickman-Miller Heather D. , Bardet Wilfried , Rehrauer William M. , O’Connor David H. , Wilson Nancy A. , Hildebrand William H. , Sette Alessandro , Watkins David I. 
Published: April 2014

Abstract
Although the SIV-infected Indian rhesus macaque (Macaca mulatta) is the animal model most widely used for studying HIV infection, our current understanding of the functional macaque MHC class I molecules is limited. To date, SIV-derived CD8+ T lymphocyte epitopes from only three high frequency macaque MHC class I molecules have been extensively characterized. In this study, we defined the peptide-binding properties of the high frequency Indian rhesus macaque class I molecule, Mamu-B*01 (∼26%). We first identified a preliminary binding motif by eluting and sequencing endogenously bound Mamu-B*01 ligands. We further characterized the peptide-binding characteristics using panels of single amino acid substitution analogs. Using this detailed motif, 507 peptides derived from SIVmac239 were identified and tested for their Mamu-B*01 binding capacity. Surprisingly, only 11 (2.2%) of these motif-containing peptides bound with IC50 values ≤500 nM. We assessed the immunogenicity of these peptides using freshly isolated PBMC from ten Mamu-B*01+ SIV-infected rhesus macaques in IFN-γ ELISPOT and IFN-γ/TNF-α intracellular cytokine staining assays. Lymphocytes from these SIV-infected macaques responded to none of these peptides. Furthermore, there was no sequence variation indicative of escape in the regions of the virus that encoded these peptides. Additionally, we could not confirm previous reports of SIV-derived Mamu-B*01-restricted epitopes in the Env and Gag proteins. Our results suggest that the high frequency MHC class I molecule, Mamu-B*01, is not involved in SIV-specific CD8+ T lymphocyte responses.
TNF Receptor-Associated Factor 6-Dependent CD40 Signaling Primes Macrophages to Acquire Antimicrobial Activity in Response to TNF-α
Authors: Andrade Rosa M. , Wessendarp Matthew , Portillo Jose-Andres C. , Yang Jun-Qi , Gomez Francisco J. , Durbin Joan E. , Bishop Gail A. , Subauste Carlos S. 
Published: April 2014

AbstractIFN-γ is considered an essential stimulus that allows macrophages to acquire activity against intracellular pathogens in response to a second signal such as TNF-α. However, protection against important pathogens can take place in the absence of IFN-γ through mechanisms that are still dependent on TNF-α. Engagement of CD40 modulates antimicrobial activity in macrophages. However, it is not known whether CD40 can replace IFN-γ as priming signal for induction of this response. We show that CD40 primes mouse macrophages to acquire antimicrobial activity in response to TNF-α. The effect of CD40 was not caused by modulation of IL-10 and TGF-β production or TNFR expression and did not require IFN-αβ signaling. Induction of antimicrobial activity required cooperation between TNFR-associated factor 6-dependent CD40 signaling and TNFR2. These results support a paradigm where TNFR-associated factor 6 signaling downstream of CD40 alters the pattern of response of macrophages to TNF-α leading to induction of antimicrobial activity.
Differential TLR Recognition of Leptospiral Lipid A and Lipopolysaccharide in Murine and Human Cells
Authors: Nahori Marie-Anne , Fournié-Amazouz Edith , Que-Gewirth Nanette S. , Balloy Viviane , Chignard Michel , Raetz Christian R. H. , Saint Girons Isabelle , Werts Catherine 
Published: April 2014

Abstract
Leptospira interrogans is a spirochete that is responsible for leptospirosis, a zoonotic disease. This bacterium possesses an unusual LPS that has been shown to use TLR2 instead of TLR4 for signaling in human cells. The structure of its lipid A was recently deciphered. Although its overall hexa-acylated disaccharide backbone is a classical feature of all lipid A forms, the lipid A of L. interrogans is peculiar. In this article, the functional characterization of this lipid A was studied in comparison to whole parental leptospiral LPS in terms of cell activation and use of TLR in murine and human cells. Lipid A from L. interrogans did not coagulate the Limulus hemolymph. Although leptospiral lipid A activated strongly murine RAW cells, it did not activate human monocytic cells. Results obtained from stimulation of peritoneal-elicited macrophages from genetically deficient mice for TLR2 or TLR4 clearly showed that lipid A stimulated the cells through TLR4 recognition, whereas highly purified leptospiral LPS utilized TLR2 as well as TLR4. In vitro experiments with transfected human HEK293 cells confirmed that activation by lipid A occurred only through murine TLR4-MD2 but not through human TLR4-MD2, nor murine or human TLR2. Similar studies with parental leptospiral LPS showed that TLR2/TLR1 were the predominant receptors in human cells, whereas TLR2 but also TLR4 contributed to activation in murine cells. Altogether these results highlight important differences between human and mouse specificity in terms of TLR4-MD2 recognition that may have important consequences for leptospiral LPS sensing and subsequent susceptibility to leptospirosis.
Nef Is Physically Recruited into the Immunological Synapse and Potentiates T Cell Activation Early after TCR Engagement
Authors: Fenard David , Yonemoto Wes , de Noronha Carlos , Cavrois Marielle , Williams Samuel A. , Greene Warner C. 
Published: April 2014

Abstract
The HIV-1 protein Nef enhances viral pathogenicity and accelerates disease progression in vivo. Nef potentiates T cell activation by an unknown mechanism, probably by optimizing the intracellular environment for HIV replication. Using a new T cell reporter system, we have found that Nef more than doubles the number of cells expressing the transcription factors NF-κB and NFAT after TCR stimulation. This Nef-induced priming of TCR signaling pathways occurred independently of calcium signaling and involved a very proximal step before protein kinase C activation. Engagement of the TCR by MHC-bound Ag triggers the formation of the immunological synapse by recruiting detergent-resistant membrane microdomains, termed lipid rafts. Approximately 5–10% of the total cellular pool of Nef is localized within lipid rafts. Using confocal and real-time microscopy, we found that Nef in lipid rafts was recruited into the immunological synapse within minutes after Ab engagement of the TCR/CD3 and CD28 receptors. This recruitment was dependent on the N-terminal domain of Nef encompassing its myristoylation. Nef did not increase the number of cell surface lipid rafts or immunological synapses. Recently, studies have shown a specific interaction of Nef with an active subpopulation of p21-activated kinase-2 found only in the lipid rafts. Thus, the corecruitment of Nef and key cellular partners (e.g., activated p21-activated kinase-2) into the immunological synapse may underlie the increased frequency of cells expressing transcriptionally active forms of NF-κB and NFAT and the resultant changes in T cell activation.