CD4 þ CD25 þ regulatory T cells (Treg) are potent immunosuppressive cells active in controlling normal pathological immune responses. The mechanisms of this suppression have been investigated under various conditions. In this report, tumor necrosis factor-related apoptosis inducing ligand (TRAIL)/death receptor 5 (DR5) was explored as one of the pivotal factors for the suppression and cytotoxicity induced by CD4 þ CD25 þ Treg. Cell death was involved in the suppression induced by activated CD4 þ CD25 þ Treg in vitro. The induction of CD4 þ T cell death was not mediated by the CD95/CD95L pathway, but rather depended upon the upregulation of TRAIL in the Treg. Blocking the TRAIL/DR5 pathway resulted in a significant reduction of the suppressive activity as well as the cytotoxic effects of Treg in vitro. Activated Treg displayed TRAIL-dependent cytotoxicity against CD4 þ T cells in vivo. The prolonged survival of allogeneic skin grafts induced by Treg was inhibited by DR5-blocking antibodies. Our findings suggest that the TRAIL/DR5 pathway is one of the mechanisms used by Treg to regulate immune responses both in vitro and in vivo.

Insulating BiFeO3 ceramics of single perovskite phase were prepared by rapid sintering using sol-gel derived fine powders. The ceramics are dense and consist of grains of 2–6μm in diameter. Their leakage current density remains lower than 3.02×10−4A∕cm2 under the poling field below 119kV∕cm. The main conduction mechanism from 15to119kV∕cm is space-charge-limited current relating to oxygen vacancies. The ceramics exhibit a saturated ferroelectric hysteresis loop with a large remanent polarization (2Pr=56μC∕cm2) under the applied field of 180kV∕cm. Weak ferromagnetism with remanent magnetization of 1.5×10−5μB∕Fe is observed at 10K.

The avian origin influenza A virus (IAV) H7N9 has caused a considerable number of human infections associated with high rates of death since its emergence in 2013. As a vital component of the host innate immune system, the nucleotide-binding domain leucine-rich repeat containing receptor, pyrin domain containing 3 (NLRP3) inflammasome plays a critical role against H1N1 viral infection. However, the function of NLRP3 inflammasome in host immunological responses to the lethal H7N9 virus is still obscure. Here, we demonstrated that mice deficient for NLRP3 inflammasome components, including NLRP3, caspase-1, and Apoptosis-associated speck-like protein containing a CARD (ASC), were less susceptible to H7N9 viral challenge than wild type (WT) controls. Inflammasome deficiency in these animals led to significantly milder mortality and less pulmonary inflammation compared with WT mice. Furthermore, IL-1 receptor deficient mice also exhibited a higher survival rate than WT controls. Thus, our study reveals that the NLRP3 inflammasome is deleterious for the host during H7N9 infection in mice, which is due to an overwhelming inflammatory response via caspase-1 activation and associated IL-1 signal. Therefore, fine-tuning the activity of NLRP3 inflammasome or IL-1 signaling may be beneficial for the host to control H7N9 associated lethal pathogenesis.

The Zika virus (ZIKV), a flavivirus transmitted by Aedes mosquitoes, has emerged as a global public health concern. Pre-existing cross-reactive antibodies against other flaviviruses could modulate immune responses to ZIKV infection by antibody-dependent enhancement, highlighting the importance of understanding the immunogenicity of the ZIKV envelope protein. In this study, we identified a panel of human monoclonal antibodies (mAbs) that target domain III (DIII) of the ZIKV envelope protein from a very large phage-display naive antibody library. These germline-like antibodies, sharing 98%–100% hoLogy with their corresponding germline IGHV genes, bound ZIKV DIII specifically with high affinities. One mAb, m301, broadly neutralized the currently circulating ZIKV strains and showed a synergistic effect with another mAb, m302, in neutralizing ZIKV in vitro and in a mouse model of ZIKV infection. Interestingly, epitope mapping and competitive binding studies suggest that m301 and m302 bind adjacent regions of the DIII C–C′ loop, which represents a recently identified cryptic epitope that is intermittently exposed in an uncharacterized virus conformation. This study extended our understanding of antigenic epitopes of ZIKV antibodies and has direct implications for the design of ZIKV vaccines.

Background Human leukocyte antigen (HLA)‐DP is much less studied than other HLA class II antigens, that is, HLA‐DR and HLA‐DQ, etc. However, the accumulating data have suggested the important roles of DP‐restricted responses in the context of cancer, allergy, and infectious disease. Lack of animal models expressing these genes as authentic cis‐haplotypes blocks our understanding for the role of HLA‐DP haplotypes in immunity. Methods To explore the potential cis‐acting control elements involved in the transcriptional regulation of the HLA‐DPA1/DPB1 gene, we performed the expression analysis using bacterial artificial chromosome (BAC)‐based transgenic humanized mice in the C57BL/6 background, which carried the entire HLA‐DP401 gene locus. We further developed a mouse model of Staphylococcus aureus pneumonia in HLA‐DP401 humanized transgenic mice, and performed the analysis on the expression pattern of HLA‐DP401 and immunological responses in the model. Results In this study, we screened and identified a BAC clone spanning the entire HLA‐DP gene locus. DNA from this clone was analyzed for integrity by pulsed‐field gel electrophoresis and then microinjected into fertilized mouse oocytes to produce transgenic founder animals. Nine sets of PCR primers for regional markers with an average distance of 15 kb between each primer were used to confirm the integrity of the transgene in the five transgenic lines carrying the HLA‐DPA1/DPB1 gene. Transgene copy numbers were determined by real‐time PCR analysis. HLA‐DP401 gene expression was analyzed at the mRNA and protein level. Although infection with S aureus Newman did not alter the percentage of immune cells in the spleen and thymus from the HLA‐DP401‐H2‐Aβ1 humanized mice. Increased expression of HLA‐DP401 was observed in the thymus of the humanized mice infected by S aureus. Conclusions We generated several BAC transgenic mice, and analyzed the expression of HLA‐DPA1/DPB1 in those mice. A model of S aureus‐induced pneumonia in the HLA‐DP401‐H2‐Aβ1−/− humanized mice was further developed, and S aureus infection upregulated the HLA‐DP401 expression in thymus of those humanized mice. These findings demonstrate the potential of those HLA‐DPA1/DPB1 transgenic humanized mice for developing animal models of infectious diseases and MHC‐associated immunological diseases.

A highly reactive thiourea-contained polycondensate, poly(dihydropyrimidin-2(1H)-thione) (poly-(DHPMT)) has been facilely synthesized via the Biginelli polycondensation using thiourea and a difunctional compound containing benzaldehyde and β-keto ester groups as monomers. The thiourea moiety in the polymer structure has similar reactivity as the thiourea, thus the poly(DHPMT) is an excellent polymer precusor for preparing new functional polymers through the postpolymerization modification (PPM) strategy. After simple reaction with functional haloalkanes, the parent poly(DHPMT) could be almost completely converted (>99%) to daughter polymers containing alkene or alkyne side groups. Then, the daughter polymers have been further transferred to granddaughter polymers through another PPM via thiol− ene or Cu(I)-catalyzed azide−alkyne cycloaddition (CuAAC) reactions. Besides, when 3-phenylpropargyl chloride was used as the reactant, a bright yellow fluorescent polymer could be simply achieved due to the in situ formed conjugated heterocycle in the polymer structure, further demonstrating the diversity of the functional polymers through PPM. Considering the easily available monomers, simple polycondensation, and the excellent reactivity of the thiourea moiety in the polymer structure, this thiourea-contained Biginilli polycondensate might be a versatile platform for new functional polymer preparation.S ince the middle of the twentieth century, the concept of a macromolecule has been formally accepted, and many strategies have been successfully developed to prepare polymers with designed functions. Among them, postpolymerization modification (PPM) might be one of the most important to prepare new functional polymers by modifying the reactive chain ends or side chains of polymer precursors. 1−5 The history of PPM could actually date back to 1840 when Hancock and Ludersdorf independently reported the first PPM by treating natural rubber with sulfur to produce a tough and elastic material. 6,7 Until now, some large-scale manufactured polymers, such as poly(vinyl alcohol) (PVA), chitosan, some functional resins, etc., are still produced through the PPM strategy. However, traditional modification reactions normally have low efficiency and are easily hampered by the steric hindrance of giant polymer chains, leading to polymers with undefined structure and properties. PPM has therefore been overshadowed by other strategies to synthesize clearly structured polymers. 8−11With the recent development of modern efficient modular reactions, such as the click reactions 12−19 and highly efficient multicomponent reactions (MCRs), 20−34 functional groups can be effectively introduced into the polymer chain once the polymer precursor containing corresponding reactive modules are obtained. 1,35,36 Thus, the PPM strategy has regained attention, and a series of elegant polymers with clear structure have been successfully prepared through this "old" method. 35−39 By now, how to synthesize highly reactive polymer precursors and how to choose e...

Ugi reaction has been recognized as a multicomponent click reaction to construct a hexa-component one-pot system with π–π stacking and RAFT polymerization for the simple (co)polymer modification of CNT surfaces.

T cells play a critical role in coronavirus diseases. How they do so in COVID-19 may be revealed by analyzing the epigenetic chromatin accessibility of cis- and trans-regulatory elements and creating transcriptomic immune profiles. We performed single-cell assay for transposase-accessible chromatin (scATAC) and single-cell RNA (scRNA) sequencing (seq) on the peripheral blood mononuclear cells (PBMCs) of severely ill/critical patients (SCPs) infected with COVID-19, moderate patients (MPs), and healthy volunteer controls (HCs). About 76,570 and 107,862 single cells were used, respectively, for analyzing the characteristics of chromatin accessibility and transcriptomic immune profiles by the application of scATAC-seq (nine cases) and scRNA-seq (15 cases). The scATAC-seq detected 28,535 different peaks in the three groups; among these peaks, 41.6 and 10.7% were located in the promoter and enhancer regions, respectively. Compared to HCs, among the peak-located genes in the total T cells and its subsets, CD4+ T and CD8+ T cells, from SCPs and MPs were enriched with inflammatory pathways, such as mitogen-activated protein kinase (MAPK) signaling pathway and tumor necrosis factor (TNF) signaling pathway. The motifs of TBX21 were less accessible in the CD4+ T cells of SCPs compared with those in MPs. Furthermore, the scRNA-seq showed that the proportion of T cells, especially the CD4+ T cells, was decreased in SCPs and MPs compared with those in HCs. Transcriptomic results revealed that histone-related genes, and inflammatory genes, such as NFKBIA, S100A9, and PIK3R1, were highly expressed in the total T cells, CD4+ T and CD8+ T cells, both in the cases of SCPs and MPs. In the CD4+ T cells, decreased T helper-1 (Th1) cells were observed in SCPs and MPs. In the CD8+T cells, activation markers, such as CD69 and HLA class II genes (HLA-DRA, HLA-DRB1, and HLA-DRB5), were significantly upregulated in SCPs. An integrated analysis of the data from scATAC-seq and scRNA-seq showed some consistency between the approaches. Cumulatively, we have generated a landscape of chromatin epigenetic status and transcriptomic immune profiles of T cells in patients with COVID-19. This has provided a deeper dissection of the characteristics of the T cells involved at a higher resolution than from previously obtained data merely by the scRNA-seq analysis. Our data led us to suggest that the T-cell inflammatory states accompanied with defective functions in the CD4+ T cells of SCPs may be the key factors for determining the pathogenesis of and recovery from COVID-19.