Role of Interleukin 12 and Costimulators in T Cell Anergy In Vivo

The induction of T cell anergy in vivo is thought to result from antigen recognition in the absence of co-stimulation and inflammation, and is associated with a block in T cell proliferation and Th1 differentiation. Here we have examined the role of interleukin (IL)-12, a potent inducer of Th1 responses, in regulating this process. T cell tolerance was induced by the administration of protein antigen without adjuvant in normal mice, and in recipients of adoptively transferred T cells from T cell receptor transgenic mice. The administration of IL-12 at the time of tolerance induction stimulates Th1 differentiation, but does not promote antigen-specific T cell proliferation. Conversely, inhibiting CTLA-4 engagement during anergy induction reverses the block in T cell proliferation, but does not promote full Th1 differentiation. T cells exposed to tolerogenic antigen in the presence of both IL-12 and anti–CTLA-4 antibody are not anergized, and behave identically to T cells which have encountered immunogenic antigen. These results suggest that two processes contribute to the induction of anergy in vivo; CTLA-4 engagement, which leads to a block in the ability of T cells to proliferate to antigen, and the absence of a prototypic inflammatory cytokine, IL-12, which prevents the differentiation of T cells into Th1 effector cells. The combination of IL-12 and anti–CTLA-4 antibody is sufficient to convert a normally tolerogenic stimulus to an immunogenic one

Eosinophil and T Cell Markers Predict Functional Decline in COPD Patients

BACKGROUND. The major marker utilized to monitor COPD patients is forced expiratory volume in one second (FEV1). However, asingle measurement of FEV1 cannot reliably predict subsequent decline. Recent studies indicate that T lymphocytes and eosinophils are important determinants of disease stability in COPD. We therefore measured cytokine levels in the lung lavage fluid and plasma of COPD patients in order to determine if the levels of T cell or eosinophil related cytokines were predictive of the future course of the disease. METHODS. Baseline lung lavage and plasma samples were collected from COPD subjects with moderately severe airway obstruction and emphysematous changes on chest CT. The study participants were former smokers who had not had a disease exacerbation within the past six months or used steroids within the past two months. Those subjects who demonstrated stable disease over the following six months (ΔFEV1 % predicted = 4.7 ± 7.2; N = 34) were retrospectively compared with study participants who experienced a rapid decline in lung function (ΔFEV1 % predicted = -16.0 ± 6.0; N = 16) during the same time period and with normal controls (N = 11). Plasma and lung lavage cytokines were measured from clinical samples using the Luminex multiplex kit which enabled the simultaneous measurement of several T cell and eosinophil related cytokines. RESULTS AND DISCUSSION. Stable COPD participants had significantly higher plasma IL-2 levels compared to participants with rapidly progressive COPD (p = 0.04). In contrast, plasma eotaxin-1 levels were significantly lower in stable COPD subjects compared to normal controls (p < 0.03). In addition, lung lavage eotaxin-1 levels were significantly higher in rapidly progressive COPD participants compared to both normal controls (p < 0.02) and stable COPD participants (p < 0.05). CONCLUSION. These findings indicate that IL-2 and eotaxin-1 levels may be important markers of disease stability in advanced emphysema patients. Prospective studies will need to confirm whether measuring IL-2 or eotaxin-1 can identify patients at risk for rapid disease progression.National Heart, Lung, and Blood Institute (NO1-HR-96140, NO1-HR-96141-001, NO1-HR-96144, NO1-HR-96143; NO1-HR-96145; NO1-HR-96142, R01HL086936-03); The Flight Attendant Medical Research Institute; the Jo-Ann F. LeBuhn Center for Chest Diseas

Genome Wide Transcriptome Analysis of Dendritic Cells Identifies Genes with Altered Expression in Psoriasis

Activation of dendritic cells by different pathogens induces the secretion of proinflammatory mediators resulting in local inflammation. Importantly, innate immunity must be properly controlled, as its continuous activation leads to the development of chronic inflammatory diseases such as psoriasis. Lipopolysaccharide (LPS) or peptidoglycan (PGN) induced tolerance, a phenomenon of transient unresponsiveness of cells to repeated or prolonged stimulation, proved valuable model for the study of chronic inflammation. Thus, the aim of this study was the identification of the transcriptional diversity of primary human immature dendritic cells (iDCs) upon PGN induced tolerance. Using SAGESeq approach, a tag-based transcriptome sequencing method, we investigated gene expression changes of primary human iDCs upon stimulation or restimulation with Staphylococcus aureus derived PGN, a widely used TLR2 ligand. Based on the expression pattern of the altered genes, we identified non-tolerizeable and tolerizeable genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (Kegg) analysis showed marked enrichment of immune-, cell cycle- and apoptosis related genes. In parallel to the marked induction of proinflammatory mediators, negative feedback regulators of innate immunity, such as TNFAIP3, TNFAIP8, Tyro3 and Mer are markedly downregulated in tolerant cells. We also demonstrate, that the expression pattern of TNFAIP3 and TNFAIP8 is altered in both lesional, and non-lesional skin of psoriatic patients. Finally, we show that pretreatment of immature dendritic cells with anti-TNF-α inhibits the expression of IL-6 and CCL1 in tolerant iDCs and partially releases the suppression of TNFAIP8. Our findings suggest that after PGN stimulation/restimulation the host cell utilizes different mechanisms in order to maintain critical balance between inflammation and tolerance. Importantly, the transcriptome sequencing of stimulated/restimulated iDCs identified numerous genes with altered expression to date not associated with role in chronic inflammation, underlying the relevance of our in vitro model for further characterization of IFNprimed iDCs

Search for MSSM Higgs bosons decaying to μ+μ-in proton-proton collisions at √s=13TeV

A search is performed for neutral non-standard-model Higgs bosons decaying to two muons in the context of the minimal supersymmetric standard model (MSSM). Proton-proton collision data recorded by the CMS experiment at the CERN Large Hadron Collider at a center-of-mass energy of 13TeVwere used, corresponding to an integrated luminosity of 35.9fb-1. The search is sensitive to neutral Higgs bosons produced via the gluon fusion process or in association with a bbquark pair. No significant deviations from the standard model expectation are observed. Upper limits at 95% confidence level are set in the context of the mmod+hand phenomenological MSSM scenarios on the parameter tanβas a function of the mass of the pseudoscalar Aboson, in the range from 130 to 600GeV. The results are also used to set a model-independent limit on the product of the branching fraction for the decay into a muon pair and the cross section for the production of a scalar neutral boson, either via gluon fusion, or in association with bquarks, in the mass range from 130 to 1000GeV

Measurement of double-differential cross sections for top quark pair production in pp collisions at [Formula: see text][Formula: see text] and impact on parton distribution functions.

Normalized double-differential cross sections for top quark pair ([Formula: see text]) production are measured in pp collisions at a centre-of-mass energy of 8[Formula: see text] with the CMS experiment at the LHC. The analyzed data correspond to an integrated luminosity of 19.7[Formula: see text]. The measurement is performed in the dilepton [Formula: see text] final state. The [Formula: see text] cross section is determined as a function of various pairs of observables characterizing the kinematics of the top quark and [Formula: see text] system. The data are compared to calculations using perturbative quantum chromodynamics at next-to-leading and approximate next-to-next-to-leading orders. They are also compared to predictions of Monte Carlo event generators that complement fixed-order computations with parton showers, hadronization, and multiple-parton interactions. Overall agreement is observed with the predictions, which is improved when the latest global sets of proton parton distribution functions are used. The inclusion of the measured [Formula: see text] cross sections in a fit of parametrized parton distribution functions is shown to have significant impact on the gluon distribution

Measurement of the WZ production cross section in pp collisions at [Formula: see text] and 8[Formula: see text] and search for anomalous triple gauge couplings at [Formula: see text].

The WZ production cross section is measured by the CMS experiment at the CERN LHC in proton-proton collision data samples corresponding to integrated luminosities of 4.9[Formula: see text] collected at [Formula: see text], and 19.6[Formula: see text] at [Formula: see text]. The measurements are performed using the fully-leptonic WZ decay modes with electrons and muons in the final state. The measured cross sections for [Formula: see text] are [Formula: see text] [Formula: see text] and [Formula: see text] [Formula: see text]. Differential cross sections with respect to the [Formula: see text] boson [Formula: see text], the leading jet [Formula: see text], and the number of jets are obtained using the [Formula: see text] data. The results are consistent with standard model predictions and constraints on anomalous triple gauge couplings are obtained

Studies of Bs2∗(5840)0 and Bs1(5830)0 mesons including the observation of the Bs2∗(5840)0→B0KS0 decay in proton-proton collisions at s=8TeV.

Measurements of Bs2∗(5840)0 and Bs1(5830)0 mesons are performed using a data sample of proton-proton collisions corresponding to an integrated luminosity of , collected with the CMS detector at the LHC at a centre-of-mass energy of 8TeV . The analysis studies P-wave Bs0 meson decays into B(∗)+K- and B(∗)0KS0 , where the B+ and B0 mesons are identified using the decays B+→J/ψK+ and B0→J/ψK∗(892)0 . The masses of the P-wave Bs0 meson states are measured and the natural width of the Bs2∗(5840)0 state is determined. The first measurement of the mass difference between the charged and neutral B∗ mesons is also presented. The Bs2∗(5840)0 decay to B0KS0 is observed, together with a measurement of its branching fraction relative to the Bs2∗(5840)0→B+K- decay