bluuebunny/crossref_metadata_2025_split huggingface dataset:
Zinc-Dependent Suppression of TNF-α Production Is Mediated by Protein Kinase A-Induced Inhibition of Raf-1, IκB Kinase β, and NF-κB
Authors: von Bülow Verena , Dubben Svenja , Engelhardt Gabriela , Hebel Silke , Plümäkers Birgit , Heine Holger , Rink Lothar , Haase Hajo 
Published: April 2014

Abstract
Excessive and permanent cytokine production in response to bacterial LPS causes cell and tissue damage, and hence organ failure during sepsis. We have previously demonstrated that zinc treatment prevents LPS-induced TNF-α expression and production in human monocytes by inhibiting cyclic nucleotide phosphodiesterase (PDE) activity and expression, and subsequent elevation of the cyclic nucleotide cGMP. In the present study, we investigated the molecular mechanism by which cGMP signaling affects the LPS-induced signaling cascade to suppress TNF-α transcription and release from monocytes. Zinc-mediated cGMP elevation led to cross activation of protein kinase A. This zinc-induced protein kinase A activation inhibited Raf-1 activity by phosphorylation at serine 259, preventing activation of Raf-1 by phosphorylation of serine 338. By this mechanism, zinc suppressed LPS-induced activation of IκB kinase β (IKKβ) and NF-κB, and subsequent TNF-α production. Our study shows that PDE inhibition by zinc modulates the monocytic immune response by selectively intervening in the Raf-1/IKKβ/NF-κB pathway, which may constitute a common mechanism for the anti-inflammatory action of PDE inhibitors.
Impaired Plasmacytoid Dendritic Cell Innate Immune Responses in Patients with Herpes Virus-Associated Acute Retinal Necrosis
Authors: Kittan Nicolai A. , Bergua Antonio , Haupt Sabrina , Donhauser Norbert , Schuster Philipp , Korn Klaus , Harrer Thomas , Schmidt Barbara 
Published: April 2014

Abstract
Plasmacytoid dendritic cells (PDC), the main producers of type I IFNs in the blood, are important for the recognition and control of viral and bacterial infections. Because several viruses induce IFN-α production, severe courses of herpes virus infections in nonimmunocompromised patients may be related to numerical or functional PDC deficits. To evaluate this hypothesis, PBMC and PDC were repeatedly isolated from nine patients with acute retinal necrosis (ARN), caused by herpes simplex or varicella zoster virus. The patients experienced meningitis/encephalitis and frequent infections in childhood (n = 2), recurrent herpes virus infections at unusual localizations (n = 2), ocular surgery (n = 1), infections (n = 4), and stress around ARN (n = 6). The median percentage of isolated PDC was significantly lower in patients compared with 18 age-matched healthy controls (p &lt; 0.001), confirmed by FACS analysis using peripheral blood, and was extremely low during acute disease. PDC counts dropped in five controls suffering from respiratory infections or diarrhea. IFN-α production in PDC and PBMC exposed to different stimuli was significantly lower in patients than in controls (p &lt; 0.05). Anergy to these stimuli was observed on four occasions, in particular during acute disease. PDC of patients showed up-regulated IFN regulatory factor-7 mRNA levels and evidence of in vivo activation (CD80) and maturation (CD83) (p &lt; 0.05). CD8+ cell responses were significantly lower in patients vs controls (p = 0.04). These data support a risk factor model in which numerical and functional deficits in PDC-mediated innate immune responses contribute to an impaired control of latent herpes virus infections and subsequent development of ARN.
Cutting Edge: An In Vivo Requirement for STAT3 Signaling in TH17 Development and TH17-Dependent Autoimmunity
Authors: Harris Timothy J. , Grosso Joseph F. , Yen Hung-Rong , Xin Hong , Kortylewski Marcin , Albesiano Emilia , Hipkiss Edward L. , Getnet Derese , Goldberg Monica V. , Maris Charles H. , Housseau Franck , Yu Hua , Pardoll Drew M. , Drake Charles G. 
Published: April 2014

Abstract
STAT3 activation has been observed in several autoimmune diseases, suggesting that STAT3-mediated pathways promote pathologic immune responses. We provide in vivo evidence that the fundamental role of STAT3 signaling in autoimmunity relates to its absolute requirement for generating TH17 T cell responses. We show that STAT3 is a master regulator of this pathogenic T cell subtype, acting at multiple levels in vivo, including TH17 T cell differentiation and cytokine production, as well as induction of RORγt and the IL-23R. Neither naturally occurring TH17 cells nor TH17-dependent autoimmunity occurs when STAT3 is ablated in CD4 cells. Furthermore, ablation of STAT3 signaling in CD4 cells results in increased TH1 responses, indicating that STAT3 signaling skews TH responses away from the TH1 pathway and toward the TH17 pathway. Thus, STAT3 is a candidate target for TH17-dependent autoimmune disease immunotherapy that could selectively inhibit pathogenic immune pathways.
CD8+CD28− T Regulatory Lymphocytes Inhibiting T Cell Proliferative and Cytotoxic Functions Infiltrate Human Cancers
Authors: Filaci Gilberto , Fenoglio Daniela , Fravega Marco , Ansaldo Gianluca , Borgonovo Giacomo , Traverso Paolo , Villaggio Barbara , Ferrera Alessandra , Kunkl Annalisa , Rizzi Marta , Ferrera Francesca , Balestra Piercesare , Ghio Massimo , Contini Paola , Setti Maurizio , Olive Daniel , Azzarone Bruno , Carmignani Giorgio , Ravetti Jean Louis , Torre Giancarlo , Indiveri Francesco 
Published: April 2014

Abstract
Tumor growth is allowed by its ability to escape immune system surveillance. An important role in determining tumor evasion from immune control might be played by tumor-infiltrating regulatory lymphocytes. This study was aimed at characterizing phenotype and function of CD8+CD28− T regulatory cells infiltrating human cancer. Lymphocytes infiltrating primitive tumor lesion and/or satellite lymph node from a series of 42 human cancers were phenotypically studied and functionally analyzed by suppressor assays. The unprecedented observation was made that CD8+CD28− T regulatory lymphocytes are almost constantly present and functional in human tumors, being able to inhibit both T cell proliferation and cytotoxicity. CD4+CD25+ T regulatory lymphocytes associate with CD8+CD28− T regulatory cells so that the immunosuppressive activity of tumor-infiltrating regulatory T cell subsets, altogether considered, may become predominant. The infiltration of regulatory T cells seems tumor related, being present in metastatic but not in metastasis-free satellite lymph nodes; it likely depends on both in situ generation (via cytokine production) and recruitment from the periphery (via chemokine secretion). Collectively, these results have pathogenic relevance and implication for immunotherapy of cancer.
TLR2 Signaling Renders Quiescent Naive and Memory CD4+ T Cells More Susceptible to Productive Infection with X4 and R5 HIV-Type 1
Authors: Thibault Sandra , Tardif Mélanie R. , Barat Corinne , Tremblay Michel J. 
Published: April 2014

AbstractIt has been recently demonstrated that circulating microbial products are responsible for a systemic immune activation in individuals infected with HIV-type 1. Bacterial products carry structural conserved motifs recognized by TLRs. Some TLR members are expressed in primary human CD4+ T cells but the precise functional role played by these pattern recognition receptors is still imprecise. In this study, we report that engagement of TLR2 in quiescent naive and memory CD4+ T cells leads to the acquisition of an effector-like phenotype. Interestingly, engagement of TLR2 renders both cell subsets more susceptible to productive infection with X4 virions and a higher virus production was seen with R5 viruses. It can be proposed that exposure of resting CD4+ T cells to pathogen-derived products that can engage TLR2 induces the acquisition of an effector-like phenotype in naive and memory CD4+ T lymphocytes, a phenomenon that might result in an acceleration of virus replication, immune dysregulation, and HIV-type 1-mediated disease progression.
Neonatal FcR Expression in Bone Marrow-Derived Cells Functions to Protect Serum IgG from Catabolism
Authors: Akilesh Shreeram , Christianson Gregory J. , Roopenian Derry C. , Shaw Andrey S. 
Published: April 2014

Abstract
The neonatal FcR (FcRn) is a receptor that protects IgG from catabolism and is important in maintaining high serum Ab levels. A major site of expression of FcRn is vascular endothelial cells where FcRn functions to extend the serum persistence of IgG by recycling internalized IgG back to the surface. Because FcRn is expressed in other tissues, it is unclear whether endothelial cells are the only site of IgG protection. In this study, we used FcRn-deficient mice and specific antiserum to determine the tissue distribution of FcRn in the adult mouse. In addition to its expression in the vascular endothelium of several organs, we found FcRn to be highly expressed in bone marrow-derived cells and professional APCs in different tissues. Experiments using bone marrow chimeras showed that FcRn expression in these cells acted to significantly extend the half-life of serum IgG indicating that in addition to the vascular endothelium, bone marrow-derived phagocytic cells are a major site of IgG homeostasis.
Genetic Variation in PTPN22 Corresponds to Altered Function of T and B Lymphocytes
Authors: Rieck Mary , Arechiga Adrian , Onengut-Gumuscu Suna , Greenbaum Carla , Concannon Patrick , Buckner Jane H. 
Published: April 2014

Abstract
A variant of the PTPN22 gene, 1858C/T, is associated with an increased risk for the development of a wide array of autoimmune disorders. It is known that the protein tyrosine phosphatase Lyp encoded by this gene has an inhibitory effect on the proximal TCR signaling pathways. However, the consequences of carrying this variant and the mechanism by which it contributes to the development of autoimmunity are poorly understood. In this study, we demonstrate that homozygosity for this variant results in a profound deficit in T cell responsiveness to Ag stimulation. Heterozygosity for the variant allele is associated with reduced responsiveness of CD4+ memory T cells, characterized by diminished calcium mobilization, expression of CD25, and IL-10 production upon TCR stimulation. Additionally, the presence of the variant allele is associated with an increase in circulating memory T cells. We further demonstrate that these effects are not limited to the T cell compartment. Individuals with the variant allele have fewer memory B cells and these cells display a reduced response to stimulation via the BCR indicative of a B cell intrinsic defect. By identifying an immunologic phenotype in healthy subjects which correlates with the PTPN22 1858C/T genotype, we can now explore specific hypotheses regarding pathogenesis of diseases associated with the PTPN22 1858T variant.
Live Attenuated Lentivirus Infection Elicits Polyfunctional Simian Immunodeficiency Virus Gag-Specific CD8+ T Cells with Reduced Apoptotic Susceptibility in Rhesus Macaques that Control Virus Replication after Challenge with Pathogenic SIVmac239
Authors: Genescà Meritxell , Rourke Tracy , Li Jun , Bost Kristen , Chohan Barinderpaul , McChesney Michael B. , Miller Christopher J. 
Published: April 2014

Abstract
HIV-specific CD8+ T cells that secrete multiple cytokines in response to Ag stimulation are associated with the control of virus replication during chronic HIV infection. To determine whether the presence of polyfunctional CD8+ T cell responses distinguishes protected and unprotected monkeys in a live attenuated lentivirus model, SIV Gag peptide-specific CD8+ T cell responses of simian HIV (SHIV) 89.6-vaccinated, SIVmac239-challenged rhesus macaques were compared in two monkeys that controlled challenge virus replication and two that did not. The ratio of Bcl-2+ Gag-specific CD8+ T cells to caspase-3+ Gag-specific CD8+ T cells was higher in the vaccinated-protected animals compared with unprotected monkeys. In addition, polyfunctional SIV-specific CD8+ T cells were consistently detected through 12 wk postchallenge in the protected animals but not in the unprotected animals. In the unprotected monkeys, there was an increased frequency of CD8+ T cells expressing markers associated with effector memory T cells. Further, there was increased annexin V expression in central memory T cells of the unprotected animals before challenge. Thus, monkeys that control viral replication after live attenuated SHIV infection have polyfunctional SIV-specific CD8+ T cells with an increased survival potential. Importantly, the differences in the nature of the SIV-specific CD8+ T cell response in the protected and unprotected animals are present during acute stages postchallenge, before different antigenic levels are established. Thus, the polyfunctional capacity and increased survival potential of CD8+ SIV-specific T cells may account for live attenuated, SHIV89.6-mediated protection from uncontrolled SIV replication.
TLR3-Dependent Induction of Nitric Oxide Synthase in RAW 264.7 Macrophage-Like Cells via a Cytosolic Phospholipase A2/Cyclooxygenase-2 Pathway
Authors: Pindado José , Balsinde Jesús , Balboa María A. 
Published: April 2014

AbstractdsRNA is a by-product of viral replication capable of inducing an inflammatory response when recognized by phagocyte cells. In this study, we identify group IVA cytosolic phospholipase A2 (cPLA2α) as an effector of the antiviral response. Treatment of RAW 264.7 murine macrophage-like cells with the dsRNA analog polyinosinic:polycytidylic acid (poly-IC) promotes the release of free arachidonic acid that is subsequently converted into PGE2 by the de novo-synthesized cyclooxygenase-2 (COX-2) enzyme. These processes are blocked by the selective cPLA2α inhibitor pyrrophenone, pointing out to cPLA2α as the effector involved. In keeping with this observation, the cPLA2α phosphorylation state increases after cellular treatment with poly-IC. Inhibition of cPLA2α expression and activity by either small interfering RNA (siRNA) or pyrrophenone leads to inhibition of the expression of the inducible NO synthase (iNOS) gene. Moreover, COX-2-derived PGE2 production appears to participate in iNOS expression, because siRNA inhibition of COX-2 also leads to inhibition of iNOS, the latter of which is restored by exogenous addition of PGE2. Finally, cellular depletion of TLR3 by siRNA inhibits COX-2 expression, PGE2 generation, and iNOS induction by poly-IC. Collectively, these findings suggest a model for macrophage activation in response to dsRNA, whereby engagement of TLR3 leads to cPLA2α-mediated arachidonic acid mobilization and COX-2-mediated PGE2 production, which cooperate to induce the expression of iNOS.
Regulatory T Cells Prevent CD8 T Cell Maturation by Inhibiting CD4 Th Cells at Tumor Sites
Authors: Chaput Nathalie , Darrasse-Jèze Guillaume , Bergot Anne-Sophie , Cordier Corinne , Ngo-Abdalla Stacie , Klatzmann David , Azogui Orly 
Published: April 2014

Abstract
Natural regulatory T cells (Tregs) are present in high frequencies among tumor-infiltrating lymphocytes and in draining lymph nodes, supposedly facilitating tumor development. To investigate their role in controlling local immune responses, we analyzed intratumoral T cell accumulation and function in the presence or absence of Tregs. Tumors that grew in normal BALB/c mice injected with the 4T1 tumor cell line were highly infiltrated by Tregs, CD4 and CD8 cells, all having unique characteristics. Most infiltrating Tregs expressed low levels of CD25Rs and Foxp3. They did not proliferate even in the presence of IL-2 but maintained a strong suppressor activity. CD4 T cells were profoundly anergic and CD8 T cell proliferation and cytotoxicity were severely impaired. Depletion of Tregs modified the characteristics of tumor infiltrates. Tumors were initially invaded by activated CD4+CD25− T cells, which produced IL-2 and IFN-γ. This was followed by the recruitment of highly cytotoxic CD8+ T cells at tumor sites leading to tumor rejection. The beneficial effect of Treg depletion in tumor regression was abrogated when CD4 helper cells were also depleted. These findings indicate that the massive infiltration of tumors by Tregs prevents the development of a successful helper response. The Tregs in our model prevent Th cell activation and subsequent development of efficient CD8 T cell activity required for the control of tumor growth.
Maintenance of Surrogate Light Chain Expression Induces Developmental Delay in Early B Cell Compartment
Authors: Martin Denise A. , Lu Liwei , Cascalho Marilia , Wu Gillian E. 
Published: April 2014

Abstract
The production of a mature B cell requires passage through a number of developmental checkpoints. The pre-BCR plays a critical role in passage through the pro-B cell/pre-B cell checkpoint, and thus plays a central role in regulating the differentiation of a B cell. Due to the significance of this receptor, it is imperative that pre-BCR expression and function are precisely regulated. In this study, we have investigated a system in which the regulation of the pre-BCR is altered. We have found that continued expression of components of the pre-BCR (λ5) resulted in a delay in the kinetics of B cell maturation. Pro-B cells from normal mouse bone marrow retrovirally infected with λ5 exhibited a delay in differentiation. As compared with wild-type cells at the same time point, there is a reduction in the presence of cell surface markers that indicate developmental progression, and there is a 6- to 16-fold decrease in the production of Ig-positive cells in B cell maturation assays. The capacity to alter B cell progression by modifying and extending pre-BCR expression argues that the receptor and its associated signals play a unique role in directing developmental outcomes.
Discriminating between Different Pathways of Memory CD8+ T Cell Differentiation
Authors: Ganusov Vitaly V. 
Published: April 2014

Abstract
Despite the rapid accumulation of quantitative data on the dynamics of CD8+ T cell responses following acute viral or bacterial infections of mice, the pathways of differentiation of naive CD8+ T cells into memory during an immune response remain controversial. Currently, three models have been proposed. In the “stem cell-associated differentiation” model, following activation, naive T cells differentiate into stem cell-like memory cells, which then convert into terminally differentiated short-lived effector cells. In the “linear differentiation” model, following activation, naive T cells first differentiate into effectors, and after Ag clearance, effectors convert into memory cells. Finally, in the “progressive differentiation” model, naive T cells differentiate into memory or effector cells depending on the amount of specific stimulation received, with weaker stimulation resulting in formation of memory cells. This study investigates whether the mathematical models formulated from these hypotheses are consistent with the data on the dynamics of the CD8+ T cell response to lymphocytic choriomeningitis virus during acute infection of mice. Findings indicate that two models, the stem cell-associated differentiation model and the progressive differentiation model, in which differentiation of cells is strongly linked to the number of cell divisions, fail to describe the data at biologically reasonable parameter values. This work suggests additional experimental tests that may allow for further discrimination between different models of CD8+ T cell differentiation in acute infections.
Antigen Presentation by Exosomes Released from Peptide-Pulsed Dendritic Cells Is not Suppressed by the Presence of Active CTL
Authors: Luketic Lea , Delanghe Jordan , Sobol Paul T. , Yang Pingchang , Frotten Erin , Mossman Karen L. , Gauldie Jack , Bramson Jonathan , Wan Yonghong 
Published: April 2014

Abstract
Despite the potency of dendritic cells (DCs) as a vaccine carrier, they are short-lived and sensitive to CTL-mediated elimination. Thus, it is believed that the longevity of Ag presentation by peptide-pulsed DC is limited in vivo. Surprisingly, however, we found that although the majority of injected DCs disappeared from the draining lymph nodes within 7 days, Ag presentation persisted for at least 14 days following DC immunization. This prolonged Ag presentation was not mediated by the remaining injected DCs or through Ag transfer to endogenous APCs. We provide evidence that exosomes released by DCs might be responsible for the persistence of Ag presentation. Functional exosomes could be recovered from the draining lymph nodes of C57BL/6 mice following DC vaccination and, in contrast to DCs, T cell stimulation by exosomes in vivo was not affected by the presence of CTL. Our findings demonstrate that Ag presentation following delivery of DC vaccines persists for longer than expected and indicate that the exosome may play a previously unrecognized role in Ag presentation following DC vaccination. Furthermore, our study reinforces the application of exosomes as a vaccination platform and suggests that exosome-based vaccines may be advantageous for booster immunizations due to their resistance to CTL.
CD8+ CTL Priming by Exact Peptide Epitopes in Incomplete Freund’s Adjuvant Induces a Vanishing CTL Response, whereas Long Peptides Induce Sustained CTL Reactivity
Authors: Bijker Martijn S. , van den Eeden Susan J. F. , Franken Kees L. , Melief Cornelis J. M. , Offringa Rienk , van der Burg Sjoerd H. 
Published: April 2014

Abstract
Therapeutic vaccination trials, in which patients with cancer were vaccinated with minimal CTL peptide in oil-in-water formulations, have met with limited success. Many of these studies were based on the promising data of mice studies, showing that vaccination with a short synthetic peptide in IFA results in protective CD8+ T cell immunity. By use of the highly immunogenic OVA CTL peptide in IFA as a model peptide-based vaccine, we investigated why minimal CTL peptide vaccines in IFA performed so inadequately to allow full optimization of peptide vaccination. Injection of the minimal MHC class I-binding OVA257–264 peptide in IFA transiently activated CD8+ effector T cells, which eventually failed to undergo secondary expansion or to kill target cells, as a result of a sustained and systemic presentation of the CTL peptides gradually leaking out of the IFA depot without systemic danger signals. Complementation of this vaccine with the MHC class II-binding Th peptide (OVA323–339) restored both secondary expansion and in vivo effector functions of CD8+ T cells. Simply extending the CTL peptide to a length of 30 aa also preserved these CD8+ T cell functions, independent of T cell help, because the longer CTL peptide was predominantly presented in the locally inflamed draining lymph node. Importantly, these functional differences were reproduced in two additional model Ag systems. Our data clearly show why priming of CTL with minimal peptide epitopes in IFA is suboptimal, and demonstrate that the use of longer versions of these CTL peptide epitopes ensures the induction of sustained effector CD8+ T cell reactivity in vivo.