Variation in the sequence of T‐cell epitopes between dengue virus (DENV) serotypes is believed to alter memory T‐cell responses during second heterologous infections. We identified a highly conserved, novel, HLA‐B57‐restricted epitope on the DENV NS1 protein. We predicted higher frequencies of B57‐NS126–34‐specific CD8+ T cells in peripheral blood mononuclear cells from individuals undergoing secondary rather than primary DENV infection. However, high tetramer‐positive T‐cell frequencies during acute infection were seen in only one of nine subjects with secondary infection. B57‐NS126–34‐specific and other DENV epitope‐specific CD8+ T cells, as well as total CD8+ T cells, expressed an activated phenotype (CD69+ and/or CD38+) during acute infection. In contrast, expression of CD71 was largely limited to DENV epitope‐specific CD8+ T cells. In vitro stimulation of cell lines indicated that CD71 expression was differentially sensitive to stimulation by homologous and heterologous variant peptides. CD71 may represent a useful marker of antigen‐specific T‐cell activation. 相似文献
Three medium‐bandgap polymers based on a 4,5‐ethylene‐2,7‐dithienyl carbazole as the electron‐donating unit and different 5,6‐dialkoxy‐2,1,3‐benzothiadiazoles as the electron‐accepting units, are synthesized as polymer donors for photovoltaic applications. The three copolymers possess highest occupied molecular oribital (HOMO) levels around ?5.47 eV and medium bandgaps of about 1.94 eV. The solar cells with polymer:[6,6]‐phenyl C71‐butyric acid methyl ester (PC71BM) = 1:4 as the active layer, show an especially high open‐circuit voltage (Voc) of 0.95 V and attain good power conversion efficiency up to 5.91%. The hole mobilities of the active layer films, measured by space‐charge‐limited current (SCLC), are up to 3.5 × 10?4 cm2 V?1 s?1. Given the favorable medium bandgaps, low‐lying HOMO levels, and good hole mobilities, these copolymers are promising candidates for the construction of a highly efficient front cell to harvest the shorter wavelength band of the solar radiation in a tandem solar cell with high Voc.
An MRI method based on the Bloch‐Siegert (BS) shift phenomenon was recently proposed as a fast and precise way to map a radio frequency (RF) transmit field (B1+ field). For MRI at high field, the mapping sensitivity of this approach was limited by tissue heating associated with a BS irradiation pulse. To mitigate this, we investigated the possibility of lowering the off‐resonance frequency of this pulse since theoretical analysis indicated that the sensitivity of Bloch‐Siegert based B1+ mapping could be substantially improved when irradiating closer to resonance. Using optimized irradiation pulse shape and gradient crushers to minimize direct excitation effects, in vivo experiments on human brains at 7 T confirmed improved sensitivity with this approach. Improved sensitivity translated into an 80% reduction in B1+ estimation errors without increasing tissue heating. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. 相似文献
A novel series of poly(p‐xylylene) homopolymer and copolymers containing thermally cross‐linkable cyclohexenyl moiety are prepared via base‐catalyzed Gilch route to yield high‐molecular‐weight polymers. The resulting polymers are highly soluble in a wide range of organic solvents and could be solution cast into flexible and transparent films. The polymers are thermally stable up to 350 °C and the glass transition temperature (Tg) is in the range of 136 ? 250 °C. They undergo thermal cross‐linking via the cyclohexenyl moiety. The cross‐linked polymer exhibits a high Tg of 294 °C, a low coefficient of thermal expansion (CTE) of 45 ppm K?1. A low dielectric constant of 2.5 and a very low dielectric loss tan δ of 0.0004 at 1 GHz are obtained, which are superior to conventional interconnect polymers. 相似文献
Although a major function of B cells is to mediate humoral immunity by producing antigen‐specific antibodies, a specific subset of B cells is important for immune suppression, which is mainly mediated by the secretion of the anti‐inflammatory cytokine interleukin‐10 (IL‐10). However, the mechanism by which IL‐10 is induced in B cells has not been fully elucidated. Here, we report that IκBNS, an inducible nuclear IκB protein, is important for Toll‐like receptor (TLR)‐mediated IL‐10 production in B cells. Studies using IκBNS knockout mice revealed that the number of IL‐10‐producing B cells is reduced in IκBNS?/? spleens and that the TLR‐mediated induction of cytoplasmic IL‐10‐positive cells and IL‐10 secretion in B cells are impaired in the absence of IκBNS. The impairment of IL‐10 production by a lack of IκBNS was not observed in TLR‐triggered macrophages or T‐cell‐receptor‐stimulated CD4+ CD25+ T cells. In addition, IκBNS‐deficient B cells showed reduced expression of Prdm1 and Irf4 and failed to generate IL‐10+ CD138+ plasmablasts. These results suggest that IκBNS is selectively required for IL‐10 production in B cells responding to TLR signals, so defining an additional role for IκBNS in the control of the B‐cell‐mediated immune responses. 相似文献
Although regulatory T‐cells (Tregs) have been shown to be expanded in acute dengue, their role in pathogenesis and their relationship to clinical disease severity and extent of viraemia have not been fully evaluated. The frequency of Tregs was assessed in 56 adult patients with acute dengue by determining the proportion of forkhead box protein 3 (FoxP3) expressing CD4+ CD25+T‐cells (FoxP3+ cells). Dengue virus (DENV) viral loads were measured by quantitative real‐time polymerase chain reaction (PCR) and DENV‐specific T‐cell responses were measured by ex‐vivo interferon (IFN)‐γ enzyme‐linked immunospot (ELISPOT) assays to overlapping peptide pools of DENV‐NS3, NS1 and NS5. CD45RA and CCR4 were used to phenotype different subsets of T‐cells and their suppressive potential was assessed by their expression of cytotoxic T lymphocyte‐antigen 4 (CTLA‐4) and Fas. While the frequency of FoxP3+ cells in patients was significantly higher (P < 0·0001) when compared to healthy individuals, they did not show any relationship with clinical disease severity or the degree of viraemia. The frequency of FoxP3+ cells did not correlate with either ex‐vivo IFN‐γ DENV‐NS3‐, NS5‐ or NS1‐specific T‐cell responses. FoxP3+ cells of patients with acute dengue were predominantly CD45RA+ FoxP3low, followed by CD45RA‐FoxP3low, with only a small proportion of FoxP3+ cells being of the highly suppressive effector Treg subtype. Expression of CCR4 was also low in the majority of T‐cells, with only CCR4 only being expressed at high levels in the effector Treg population. Therefore, although FoxP3+ cells are expanded in acute dengue, they predominantly consist of naive Tregs, with poor suppressive capacity. 相似文献
The purpose of this study is to develop and evaluate a custom‐designed 7 T MRI coil and explore its use for upper extremity applications. An RF system composed of a transverse electromagnetic transmit coil and an eight‐channel receive‐only array was developed for 7 T upper extremity applications. The RF system was characterized and evaluated using scattering parameters and B1+ mapping. Finite difference time domain simulations were performed to evaluate the B1+ field distribution and specific absorption rate for the forearm region of the upper extremity. High‐resolution 7 T images were acquired and compared with those at 3 T. The simulation and experimental results show very good B1+ field homogeneity across the forearm. High‐resolution images of musculotendinous, osseocartilaginous, and neurovascular structures in the upper extremity are presented with T1 volumetric interpolated breath‐hold examination, T2 double‐echo steady state, T2* susceptibility weighted imaging (SWI), diffusion tensor imaging, and time‐of‐flight sequences. Comparison between 3 T and 7 T is shown. Intricate contextual anatomy can be delineated in synovial, fibrocartilaginous, interosseous, and intraosseous trabecular structures of the forearm, as well as palmar and digital vascular anatomy (including microvascular detail in SWI). Ultra‐high‐field 7 T imaging holds great potential in improving the sensitivity and specificity of upper extremity imaging, especially in wrist and hand pathology secondary to bone, ligament, nerve, vascular, and other soft or hard tissue etiology. 相似文献
Vitamin D deficiency is associated with increased incidence and severity of various immune‐mediated diseases. Active vitamin D (1α,25‐dihydroxyvitamin D3; 1,25(OH)2D3) up‐regulates CD4+ T‐cell expression of the purine ectonucleotidase CD39, a molecule that is associated with the generation of anti‐inflammatory adenosine. Here we aimed to investigate the direct impact of 1,25(OH)2D3 on expression of the downstream ecto‐5′‐nucleotidase CD73 by human CD4 T cells, and components of the transforming growth factor‐β (TGF‐β) pathway, which have been implicated in the modulation of CD73 by murine T cells. At 10?8 to 10?7 m , 1,25(OH)2D3 significantly increased expression of CD73 on peripheral human CD4+ T cells. Although 1,25(OH)2D3 did not affect the mRNA expression of latent TGF‐β1, 1,25(OH)2D3 did up‐regulate expression of TGF‐β‐associated molecules [latency‐associated peptide (LAP), glycophorin A repetitions predominant (GARP), GP96, neuropilin‐1, thrombospondin‐1 and αv integrin] which is likely to have contributed to the observed enhancement in TGF‐β bioactivity. CD73 was highly co‐expressed with LAP and GARP following 1,25(OH)2D3 treatment, but unexpectedly, each of these cell surface molecules was expressed primarily on CD4+ Foxp3– T cells, rather than CD4+ Foxp3+ T cells. Notably, neutralization of TGF‐β significantly impaired 1,25(OH)2D3‐mediated induction of CD73. Collectively, we show that 1,25(OH)2D3 enhances expression of CD73 on CD4+ Foxp3– T cells in a process that is at least partially TGF‐β‐dependent. These data reveal an additional contributing mechanism by which vitamin D may be protective in immune‐mediated disease. 相似文献
Human immunodeficiency virus (HIV)‐1 causes T cell anergy and affects T cell maturation. Various mechanisms are responsible for impaired anti‐HIV‐1‐specific responses: programmed death (PD)‐1 molecule and its ligand PD‐L1 are negative regulators of T cell activity and their expression is increased during HIV‐1 infection. This study examines correlations between T cell maturation, expression of PD‐1 and PD‐L1, and the effects of their blockade. Peripheral blood mononuclear cells (PBMC) from 24 HIV‐1+ and 17 uninfected individuals were phenotyped for PD‐1 and PD‐L1 expression on CD4+ and CD8+ T cell subsets. The effect of PD‐1 and PD‐L1 blockade on proliferation and interferon (IFN)‐γ production was tested on eight HIV‐1+ patients. Naive (CCR7+CD45RA+) CD8+ T cells were reduced in HIV‐1 aviraemic (P = 0·0065) and viraemic patients (P = 0·0130); CD8 T effector memory subsets [CCR7‐CD45RA–(TEM)] were increased in HIV‐1+ aviraemic (P = 0·0122) and viraemic (P = 0·0023) individuals versus controls. PD‐1 expression was increased in CD4 naive (P = 0·0496), central memory [CCR7+CD45RA– (TCM); P = 0·0116], TEM (P = 0·0037) and CD8 naive T cells (P = 0·0133) of aviraemic HIV‐1+versus controls. PD‐L1 was increased in CD4 TEMRA (CCR7‐CD45RA+, P = 0·0119), CD8 TEM (P = 0·0494) and CD8 TEMRA (P = 0·0282) of aviraemic HIV‐1+versus controls. PD‐1 blockade increased HIV‐1‐specific proliferative responses in one of eight patients, whereas PD‐L1 blockade restored responses in four of eight patients, but did not increase IFN‐γ‐production. Alteration of T cell subsets, accompanied by increased PD‐1 and PD‐L1 expression in HIV‐1 infection contributes to anergy and impaired anti‐HIV‐1‐specific responses which are not rescued when PD‐1 is blocked, in contrast to when PD‐L1 is blocked, due possibly to an ability to bind to receptors other than PD‐1. 相似文献
The role of Th17 cells in the pathogenesis of autoantibody‐mediated diseases is unclear. Here, we assessed the contribution of Th17 cells to the pathogenesis of experimental autoimmune myasthenia gravis (EAMG), which is induced by repetitive immunizations with Torpedo californica acetylcholine receptor (tAChR). We show that a significant fraction of tAChR‐specific CD4+ T cells is producing IL‐17. IL‐17ko mice developed fewer or no EAMG symptoms, although the frequencies of tAChR‐specific CD4+ T cells secreting IL‐2, IFN‐γ, or IL‐21, and the percentage of FoxP3+ Treg cells were similar to WT mice. Even though the total anti‐tAChR antibody levels were equal, the complement fixating IgG2b subtype was reduced in IL‐17ko as compared to WT mice. Most importantly, pathogenic anti‐murine AChR antibodies were significantly lower in IL‐17ko mice. Furthermore, we confirmed the role of Th17 cells in EAMG pathogenesis by the reconstitution of TCR β/δko mice with WT or IL‐17ko CD4+ T cells. In conclusion, we show that the level of IgG2b and the loss of B‐cell tolerance, which results in pathogenic anti‐murine AChR‐specific antibodies, are dependent on IL‐17 production by CD4+ T cells. Thus, we describe here for the first time how Th17 cells are involved in the induction of classical antibody‐mediated autoimmunity. 相似文献
Systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), are often characterized by a failure of self‐tolerance and result in an uncontrolled activation of B cells and effector T cells. Interleukin (IL)‐2 critically maintains homeostasis of regulatory T cells (Treg) and effector T cells in the periphery. Previously, we identified the cAMP‐responsive element modulator α (CREMα) as a major factor responsible for decreased IL‐2 production in T cells from SLE patients. Additionally, using a transgenic mouse that specifically over‐expresses CREMα in T cells (CD2CREMαtg), we provided in‐vivo evidence that CREMα indeed suppresses IL‐2 production. To analyse the effects of CREMα in an autoimmune prone mouse model we introduced a Fas mutation in the CD2CREMαtg mice (FVB/Fas–/–CD2CREMαtg). Overexpression of CREMα strongly accelerated the lymphadenopathy and splenomegaly in the FVB/Fas–/– mice. This was accompanied by a massive expansion of double‐negative (DN) T cells, enhanced numbers of interferon (IFN)‐γ‐producing T cells and reduced percentages of Tregs. Treatment of FVB/Fas–/–CD2CREMαtg mice with IL‐2 restored the percentage of Tregs and reversed increased IFN‐γ production, but did not affect the number of DNTs. Our data indicate that CREMα contributes to the failure of tolerance in SLE by favouring effector T cells and decreasing regulatory T cells, partially mediated by repression of IL‐2 in vivo . 相似文献
Lithium is the first‐line mood stabilizer for the treatment of patients with bipolar disorder. However, its mechanisms of action and transport across the blood–brain barrier remain poorly understood. The contribution of lithium‐7 magnetic resonance imaging (7Li MRI) to investigate brain lithium distribution remains limited because of the modest sensitivity of the lithium nucleus and the expected low brain concentrations in humans and animal models. Therefore, we decided to image lithium distribution in the rat brain ex vivo using a turbo‐spin‐echo imaging sequence at 17.2 T. The estimation of lithium concentrations was performed using a phantom replacement approach accounting for B1 inhomogeneities and differential T1 and T2 weighting. Our MRI‐derived lithium concentrations were validated by comparison with inductively coupled plasma‐mass spectrometry (ICP‐MS) measurements ([Li]MRI = 1.18[Li]MS, R = 0.95). Overall, a sensitivity of 0.03 mmol/L was achieved for a spatial resolution of 16 μL. Lithium distribution was uneven throughout the brain (normalized lithium content ranged from 0.4 to 1.4) and was mostly symmetrical, with consistently lower concentrations in the metencephalon (cerebellum and brainstem) and higher concentrations in the cortex. Interestingly, low lithium concentrations were also observed close to the lateral ventricles. The average brain‐to‐plasma lithium ratio was 0.34 ± 0.04, ranging from 0.29 to 0.39. Brain lithium concentrations were reasonably correlated with plasma lithium concentrations, with Pearson correlation factors ranging from 0.63 to 0.90. 相似文献
VZV‐reactivation may lead to symptomatic central nervous system (CNS) diseases, but identification of VZV as causative pathogen of CNS‐diseases is challenging. This study was performed to characterize VZV‐specific T cells from cerebrospinal fluid (CSF) and blood of patients with active CNS‐disease and to determine whether this may improve differential diagnosis. 27 patients with pleocytosis in the CSF were recruited and classified into three groups (10 VZV‐related, 10 non‐VZV‐related, 7 unclear). VZV‐specific CD4+ T cells were quantified in CSF and blood after simultaneous stimulation with a VZV‐antigen lysate and detection of cytokines (IFN‐γ, IL‐2, TNF‐α) and CTLA‐4. Polyclonal stimulation served as positive control. VZV‐specific CD4+ T‐cell frequencies were highest in both CSF (p = 0.0001) and blood (p = 0.011) of patients with VZV‐infection, and were enriched at the site of infection (p = 0.002). While cytokine‐expression profiles only showed minor differences between the groups, CTLA‐4‐expression levels on VZV‐specific T cells from CSF and blood were significantly increased in VZV‐related CNS‐infections (p = 0.0002 and p<0.0001) and clearly identified VZV‐related CNS‐diseases (100% sensitivity and 100% specificity). Polyclonally stimulated T cells did not show any quantitative and phenotypical differences between the groups. Increased frequency and CTLA‐4‐expression of VZV‐specific T cells from CSF or blood are specifically found in patients with VZV‐related CNS‐infection. 相似文献