Bystander CD4+ T cells: crossroads between innate and adaptive immunity

T cells are the central mediators of both humoral and cellular adaptive immune responses. Highly specific receptor-mediated clonal selection and expansion of T cells assure antigen-specific immunity. In addition, encounters with cognate antigens generate immunological memory, the capacity for long-term, antigen-specific immunity against previously encountered pathogens. However, T-cell receptor (TCR)-independent activation, termed “bystander activation”, has also been found. Bystander-activated T cells can respond rapidly and secrete effector cytokines even in the absence of antigen stimulation. Recent studies have rehighlighted the importance of antigen-independent bystander activation of CD4⁺ T cells in infection clearance and autoimmune pathogenesis, suggesting the existence of a distinct innate-like immunological function performed by conventional T cells. In this review, we discuss the inflammatory mediators that activate bystander CD4⁺ T cells and the potential physiological roles of these cells during infection, autoimmunity, and cancer.Subject terms: T cells, CD4-positive T cells     

Role of lipid rafts in innate immunity and phagocytosis of polystyrene latex microspheres

Understanding of the association of phagocytosis of polymers with signaling of innate immunity of macrophages is the major purpose of this study. Polymer conjugates have been utilized for clinical therapy of cancer and infections, such as Mycobacterium tuberculosis, as effective vectors of drug-delivery systems. They are incorporated through phagocytosis into macrophages and activate innate immunity signaling, which plays a crucial role in its therapeutic and side effects. Macrophage phagocytosis of polystyrene latex microspheres was examined and assayed by treatment of macrophages with the cholesterol depletor methyl-β-cyclodextrin (MβCD) or the sphingolipid depletor n-octyl-β-D-glucopyranoside (OGP). Expressions of various mRNAs during phagocytosis were quantified by real-time PCR. Phagocytosis of polystyrene latex microspheres by various macrophages, such as murine monocyte-derived macrophage J774, rat alveolar macrophage NR8383, and murine Kupffer cell KC13-2, was suppressed by treatment with MβCD or OGP in a concentration-dependent manner. The expression of mRNAs of TNFα, IL-1β, IL-6 and CXCL10 genes induced by lipopolysaccharide (LPS) was not suppressed by treatment with MβCD in J774 cells. Moreover, genes that were induced by LPS were up-regulated even in the absence of LPS by the phagocytosis of polymer conjugates, but such up-regulations were not suppressed by the treatment with MβCD. It was shown that lipid rafts play a significant role in incorporation of polymer conjugates through phagocytosis of macrophages, but their association with signal transduction in innate immunity is very limited.     

Polymorphisms in genes involved in innate immunity and susceptibility to benzene-induced hematotoxicity

Benzene, a recognized hematotoxicant and carcinogen, can damage the human immune system. We studied the association between single nucleotide polymorphisms (SNPs) in genes involved in innate immunity and benzene hematotoxicity in a cross-sectional study of workers exposed to benzene (250 workers and 140 controls). A total of 1,236 tag SNPs in 149 gene regions of six pathways were included in the analysis. Six gene regions were significant for their association with white blood cell (WBC) counts (MBP, VCAM1, ALOX5, MPO, RAC2, and CRP) based on gene-region (P<0.05) and SNP analyses (FDR<0.05). VCAM1 rs3176867, ALOX5 rs7099684, and MPO rs2071409 were the three most significant SNPs. They showed similar effects on WBC subtypes, especially granulocytes, lymphocytes, and monocytes. A 3-SNP block in ALOXE3 (rs7215658, rs9892383, and rs3027208) showed a global association (omnibus P = 0.0008) with WBCs even though the three SNPs were not significant individually. Our study suggests that polymorphisms in innate immunity genes may play a role in benzene-induced hematotoxicity; however, independent replication is necessary.     

Mesoporous sodium four-coordinate aluminosilicate nanoparticles modulate dendritic cell pyroptosis and activate innate and adaptive immunity

Pyroptosis is a programmed cell death widely studied in cancer cells for tumour inhibition, but rarely in dendritic cell (DC) activation for vaccine development. Here, we report the synthesis of sodium stabilized mesoporous aluminosilicate nanoparticles as DC pyroptosis modulators and antigen carriers. By surface modification of sodium-stabilized four-coordinate aluminium species on dendritic mesoporous silica nanoparticles, the resultant Na-^IVAl-DMSN significantly activated DC through caspase-1 dependent pyroptosis via pH responsive intracellular ion exchange. The released proinflammatory cellular contents further mediated DC hyperactivation with prolonged cytokine release. In vivo studies showed that Na-^IVAl-DMSN induced enhanced cellular immunity mediated by natural killer (NK) cells, cytotoxic T cells, and memory T cells as well as humoral immune response. Our results provide a new principle for the design of next-generation nanoadjuvants for vaccine applications.

Na-^IVAl-DMSN acts as both antigen carriers and modulators to “hyperactivate” dendritic cells (DCs) via potassium (K⁺) efflux dependent pyroptosis, eventually leading to enhanced adaptive and innate immunity.     

Bioceramics and pharmaceuticals: A remarkable synergy

The research on controlled drug delivery systems using bioceramics as host matrices presents two distinct sides; one route aims at embedding pharmaceuticals in biomaterials designed for the reconstruction or regeneration of living tissues, in order to counteract inflammatory responses, infections, bone carcinomas and so forth, while the other route deals with the more traditional drug introduction systems, i.e. oral administration.The incorporation of pharmaceuticals to bioceramic matrices could be very interesting in clinical practice. It is rather common in these days for an orthopedic surgeon working in bone reconstruction to use bioceramics. An added value to the production of these ceramics would be the optional addition of pharmaceuticals such as antibiotics, anti-inflammatories, anti-carcinogens, etc. In this sense, if we take into account the infections statistics at hip joint prostheses, the incidence varies between 2 and 4%, reaching up to a 45% in bolts used as external fixation. One of the main problems in these situations is the access to the infected area of the bone, in order to deliver the adequate antibiotic. If the pharmaceutical could be included within the implant itself, the added value would be straightforward.And if the bioceramic is bioactive, and therefore precursor of new bone tissue, the capability to introduce peptides, proteins or growth factors at its pores could accelerate the bone regeneration processes. We are facing a fine example of multidisciplinary research, where the so-called transversal supply of knowledge from and between the domains of materials science, biology and medicine will empower the know-how and applications that shall, undoubtedly, give rise to new advances in science and technology.     

The acylation state of mycobacterial lipomannans modulates innate immunity response through toll-like receptor 2

Detection of Mycobacterium tuberculosis antigens by professional phagocytes via toll-like receptors (TLR) contributes to controlling chronic M. tuberculosis infection. Lipomannans (LM), which are major lipoglycans of the mycobacterial envelope, were recently described as agonists of TLR2 with potent activity on proinflammatory cytokine regulation. LM correspond to a heterogeneous population of acyl- and glyco-forms. We report here the purification and the complete structural characterization of four LM acyl-forms from Mycobacterium bovis BCG using MALDI MS and 2D (1)H-(31)P NMR analyses. All this biochemical work provided the tools to investigate the implication of LM acylation degree on its proinflammatory activity. The latter was ascribed to the triacylated LM form, essentially an agonist of TLR2, using TLR2/TLR1 heterodimers for signaling. Altogether, these findings shed more light on the molecular basis of LM recognition by TLR.     

Synthesis and bioactivity of fluorescence- and biotin-labeled lipid A analogues for investigation of recognition mechanism in innate immunity

Fluorescence- and biotin-labeled lipid A analogues were synthesized for the investigation of bacterial lipopolysaccharide (LPS)/lipid A recognition in the innate immune system. For the introduction of the labeling moiety, a hydrophilic glutaryl-glucose linker was used for maintaining the bioactivity and also for preventing self-aggregation, which causes quenching of the fluorescence. We also observed the biological activity of the labeled compounds.     

Ultra-sensitive radionuclide spectrometry: Radiometrics and mass spectrometry synergy

Summary Recent developments in radiometrics and mass spectrometry techniques for ultra-sensitive analysis of radionuclides in the marine environment are reviewed. In the radiometrics sector the dominant development has been the utilization of large HPGe detectors in underground laboratories with anti-cosmic or anti-Compton shielding for the analysis of short and medium-lived radionuclides in the environment. In the mass spectrometry sector, applications of inductively coupled plasma mass spectrometry (ICP-MS) and accelerator mass spectrometry (AMS) for the analysis of long-lived radionuclides in the environment are the most important recent achievements. The recent developments do not only considerably decrease the detection limits for several radionuclides (up to several orders of magnitude), but they also enable to decrease sample volumes so that sampling, e.g., of the water column can be much easier and more effective. A comparison of radiometrics and mass spectrometry results for the analysis of radionuclides in the marine environment shows a reasonable agreement - within quoted uncertainties, for wide range of activities and different sample matrices analyzed.     

Catalysis under ultrasonic irradiation: a sound synergy

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Trends in radiometrics and mass spectrometry technologies: synergy in environmental analyses

The dominant development in the radiometrics techniques for the analysis of short and medium-lived radionuclides in the environment was the utilisation of large volume Ge detectors in underground laboratories with additional anti-cosmic shielding. In the mass spectrometry sector, applications of Accelerator Mass Spectrometry (AMS) and Inductively Coupled Plasma Mass Spectrometry (ICPMS) for the analysis of long-lived radionuclides in the environment are the most important recent achievements. These developments in both sectors did not only considerably decrease the detection limits for several radionuclides (up to several orders of magnitude), but they also enable to decrease sample volumes so that sampling, e.g. of the water column, can be much easier and more effective. Applications of radiometrics and mass spectrometry techniques in isotope oceanography, specifically on the distribution of ³H, ¹⁴C, ⁹⁰Sr, ¹²⁹I, ¹³⁷Cs, ²³⁹Pu and ²⁴⁰Pu in the water column of the North Pacific and South Indian Oceans are presented and discussed.     

Noble metal nanoparticles meet molecular cages: A tale of integration and synergy

Noble metal nanoparticles attract growing interest owing to their high surface-to-volume ratio and unique optical, electric and catalytic properties. Fine-tuning these properties and broadening potential applications can be envisaged if nanoparticles are coupled to supramolecular cages that afford a highly tailorable inner environment as well as rich endo-/exo-functionalization. Due to rich chemical/physical properties of cages, integration of multiple host-guest interactions in confined cavities through endo-molecular design has been achieved. Such cages provide ideal confined templates for size-controlled synthesis of ultrafine nanoparticles with superior catalytic activities. Moreover, exo-functionalization of cages offers huge opportunities to couple with nanoparticles, generating cage-nanoparticle hybrids or hierarchical assemblies that combine merits of both. The present review provides recent advances in cage-mediated nanoparticle systems with synergistic effects and integrated functions, and demonstrates their applications in catalysis, sensing, chiral amplification, plasmonic switches, imaging and cell therapy. Finally, we highlight key challenges and identify emerging directions in the coming years.     

Multicomponent reactions and ionic liquids: a perfect synergy for eco-compatible heterocyclic synthesis

The efficiency of a chemical synthesis can be nowadays measured, not only by parameters like selectivity and overall yield, but also by its raw material, time, human resources and energy requirements, as well as the toxicity and hazard of the chemicals and the protocols involved. The development of multicomponent reactions (MCRs) in the presence of task-specific ionic liquids (ILs), used not only as environmentally benign reaction media, but also as catalysts, is a new approach that meet with the requirements of sustainable chemistry. The aim of this tutorial review is to highlight the synergistic effect of the combined use of MCRs and ILs for the development of new eco-compatible methodologies for heterocyclic chemistry.     

Deprotonative metalation using ate compounds: synergy, synthesis, and structure building

Historically, single-metal organometallic species such as organolithium compounds have been the reagents of choice in synthetic organic chemistry for performing deprotonation reactions. Over the past few years, a complementary new class of metalating agents has started to emerge. Owing to a variable central metal (magnesium, zinc, or aluminum), variable ligands (both in their nature and number), and a variable second metallic center (an alkali metal such as lithium or sodium), "ate" complexes are highly versatile bases that exhibit a synergic chemistry which cannot be replicated by the homometallic magnesium, zinc, or aluminum compounds on their own. Deprotonation accomplished by using these organometallic ate complexes has opened up new perspectives in organic chemistry with unprecedented reactivities and sometimes unusual and unpredictable regioselectivities.     

Hydrogenated titania: synergy of surface modification and morphology improvement for enhanced photocatalytic activity

Surface-hydrogenated anatase TiO(2) (TiO(2)-H) nanowire-microspheres were prepared by converting protonated titanate nanotube to TiO(2)-H under a hydrogen atmosphere. We show that TiO(2)-H nanowire-microspheres have Ti-H and O-H bonds on their surface and exhibit improved visible-light absorption and highly enhanced photocatalytic activity.     

Analysis of the cellular Aspergillus fumigatus proteome that reacts with sera from rabbits developing an acquired immunity after experimental aspergillosis

Invasive aspergillosis caused by the mould Aspergillus fumigatus is a life‐threatening lung or systemic infection in the immunocompromised host. In this study, a protective immune response against the disease was achieved in two infected rabbits, and the cellular fungal antigenic proteome that mediated such a response was investigated against the background of vaccine development efforts. Altogether, 59 different Aspergillus proteins were found becoming reactive in the course of the developing immunity, many of which are described in this context for the first time. These included proteins related to oxidative stress management, glycolysis and other metabolic pathways. As oxidative stress is suspected to be one of the major defense mechanisms, the results may indicate at least in part a continuous response of the pathogen to evade the host's immune system. In addition, proteins with suspected cell surface association or crucial function for fungal cell development were identified. As these antigens are newly recognized during the process of the developing immunoprotection, they may not only represent valuable infection markers but also importantly broaden the list of possible vaccine candidates.     

Bioaffinity chromatography: synergy between interactive chromatography and molecular recognition for the separation and analysis of macromolecules

Affinity chromatography, commonly regarded as an integral tool in macromolecular separation sciences, also provides an analytical method to study structure-function relationships of macromolecular interaction processes and to design recognition molecules. The latter, as found recently for the case of antisense peptides, may be useful as affinity agents in immobilized forms to effect new types of biomolecular separation.     

Polypropylene multifilament yarn filled with clay and/or graphite: Study of a potential synergy

In this study, clay and/or graphite particles have been added in various quantities to polypropylene matrix by melt blending. The morphology and more particularly the dispersion of particles in these composites have been compared by transmission electron microscopy (TEM). Their thermal stability has also been studied by thermogravimetric analysis (TGA). The experimental results reveal that the addition of 5 wt % of graphite particles or clay improves the thermal stability in air of the matrix by about 50 and 90 °C, respectively. In a second step, these blends have been melt‐spun to produce multifilament yarns. The experiments have shown that the addition of graphite particles up to 5 wt % do not reduce the spinnability of the polypropylene, while the incorporation of more than 1 wt % of clay was causing difficulties for the spinning and more particularly for the drawing step. However, a slight improvement of the Young's modulus of the filaments reinforced with 1 wt % of Cloisite®15A is observed when the filaments are drawn up. The flammability of the different blends used as knitted fabrics has finally been evaluated with a mass loss calorimeter at 35 kW/m². An atypical behavior has been highlighted for all blends and will be discussed. © 2010 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 48: 1185–1195, 2010