Garam Choi

Enhancing p-Type Thermoelectric Performances of Polycrystalline SnSe via Tuning Phase Transition Temperature

SnSe emerges as a new class of thermoelectric materials since the recent discovery of an ultrahigh thermoelectric figure of merit in its single crystals. Achieving such performance in the polycrystalline counterpart is still challenging and requires fundamental understandings of its electrical and thermal transport properties as well as structural chemistry. Here we demonstrate a new strategy of improving conversion efficiency of bulk polycrystalline SnSe thermoelectrics. We show that PbSe alloying decreases the transition temperature between Pnma and Cmcm phases and thereby can serve as a means of controlling its onset temperature. Along with 1% Na doping, delicate control of the alloying fraction markedly enhances electrical conductivity by earlier initiation of bipolar conduction while reducing lattice thermal conductivity by alloy and point defect scattering simultaneously. As a result, a remarkably high peak ZT of ∼1.2 at 773 K as well as average ZT of ∼0.5 from RT to 773 K is achieved for Na0.01(Sn1-xPbx)0.99Se. Surprisingly, spherical-aberration corrected scanning transmission electron microscopic studies reveal that NaySn1-xPbxSe (0 < x ≤ 0.2; y = 0, 0.01) alloys spontaneously form nanoscale particles with a typical size of ∼5-10 nm embedded inside the bulk matrix, rather than solid solutions as previously believed. This unexpected feature results in further reduction in their lattice thermal conductivity.

Dynamic control of Th2 cell responses by STAT3 during allergic lung inflammation in mice.

Signal transducer and activator of transcription (STAT) family molecules play essential roles during the differentiation of helper T cells from naïve precursors. Although the role of STAT3 in driving Th17 cell polarization has been well established, its role on Th2 responses to allergens remains incompletely understood. By employing T cell-specific STAT3 deficient mice, we demonstrate that STAT3 in T cells plays diverse role on Th2 cells depending on their locations in an animal model of allergic asthma. In the bronchial lymph nodes, STAT3-deficient T cells produced significantly reduced levels of Th2 cytokines. The frequencies of Th2 cells among CD4(+) T cells in the lung were comparable between STAT3-sufficient and STAT3-deficient T cells. By contrast, STAT3-deficient T cells in the airway exhibited significantly enhanced production of Th2 cell cytokines compared to STAT3-sufficient T cells. Interestingly, a major population of IL-4/5 producers among STAT3-deficient T cells in the airway co-produced IFNγ. The frequency of Th17 cells was significantly diminished whereas that of Th1 cells was increased in all the lung-associated tissues. Our results demonstrate the dynamic and opposing roles of STAT3 during the development of Th2 cells from bronchial lymph nodes to the airway and propose the need of careful consideration on STAT3-targeting approaches for the treatment of lung diseases.

Fibrinogen cleavage products and Toll-like receptor 4 promote the generation of programmed cell death 1 ligand 2–positive dendritic cells in allergic asthma

Background: Inhaled protease allergens preferentially trigger TH2‐mediated inflammation in allergic asthma. The role of dendritic cells (DCs) on induction of TH2 cell responses in allergic asthma has been well documented; however, the mechanism by which protease allergens induce TH2‐favorable DCs in the airway remains unclear. Objective: We sought to determine a subset of DCs responsible for TH2 cell responses in allergic asthma and the mechanism by which protease allergens induce the DC subset in the airway. Methods: Mice were challenged intranasally with protease allergens or fibrinogen cleavage products (FCPs) to induce allergic airway inflammation. DCs isolated from mediastinal lymph nodes were analyzed for surface phenotype and T‐cell stimulatory function. Anti‐Thy1.2 and Mas‐TRECK mice were used to deplete innate lymphoid cells and mast cells, respectively. Adoptive cell transfer, bone marrow DC culture, anti–IL‐13, and Toll‐like receptor (TLR) 4–deficient mice were used for further mechanistic studies. Results: Protease allergens induced a remarkable accumulation of TH2‐favorable programmed cell death 1 ligand 2 (PD‐L2)+ DCs in mediastinal lymph nodes, which was significantly abolished in mice depleted of mast cells and, to a lesser extent, innate lymphoid cells. Mechanistically, FCPs generated by protease allergens triggered IL‐13 production from wild‐type mast cells but not from TLR4‐deficient mast cells, which resulted in an increase in the number of PD‐L2+ DCs. Intranasal administration of FCPs induced an increase in numbers of PD‐L2+ DCs in the airway, which was significantly abolished in TLR4‐ and mast cell–deficient mice. Injection of IL‐13 restored the PD‐L2+ DC population in mice lacking mast cells. Conclusion: Our findings unveil the “protease–FCP–TLR4–mast cell–IL‐13” axis as a molecular mechanism for generation of TH2‐favorable PD‐L2+ DCs in allergic asthma and suggest that targeting the PD‐L2+ DC pathway might be effective in suppressing allergic T‐cell responses in the airway. Graphical abstract: Figure. No caption available.

Atherogenic dyslipidemia promotes autoimmune follicular helper T cell responses via IL-27.

The incidence of atherosclerosis is higher among patients with systemic lupus erythematosus (SLE); however, the mechanism by which an atherogenic environment affects autoimmunity remains unclear. We found that reconstitution of atherosclerosis-prone Apoe–/– and Ldlr–/– mice with bone marrow from lupus-prone BXD2 mice resulted in increased autoantibody production and glomerulonephritis. This enhanced disease was associated with an increase in CXCR3+ follicular helper T cells (TFH cells). TFH cells isolated from Apoe–/– mice had higher expression of genes associated with inflammatory responses and SLE and were more potent in inducing production of the immunoglobulin IgG2c. Mechanistically, the atherogenic environment induced the cytokine IL-27 from dendritic cells in a Toll-like receptor 4 (TLR4)-dependent manner, which in turn triggered the differentiation of CXCR3+ TFH cells while inhibiting the differentiation of follicular regulatory T cells. Blockade of IL-27 signals diminished the increased TFH cell responses in atherogenic mice. Thus, atherogenic dyslipidemia augments autoimmune TFH cell responses and subsequent IgG2c production in a TLR4- and IL-27-dependent manner.Dyslipidemia and autoimmune disease are often associated. Chung and colleagues demonstrate a mechanistic pathway by which dyslipidemia leads to the induction of pathogenic autoantibodies.

Concomitant suppression of TH2 and TH17 cell responses in allergic asthma by targeting retinoic acid receptor-related orphan receptor γt

Background: Allergic asthma is a heterogeneous chronic inflammatory disease of the airways with a massive infiltration of eosinophils or neutrophils mediated by allergen‐specific TH2 and TH17 cells, respectively. Therefore successful treatment of allergic asthma will require suppression of both TH2 and TH17 cells. Objective: We sought to investigate the role of the TH17 cell pathway in regulating TH2 cell responses in allergic asthma. Methods: Allergic asthma was induced by intranasal challenge with proteinase allergens in C57BL/6, Il17a−/−Il17f−/−, and retinoic acid receptor–related orphan receptor &ggr;t (ROR&ggr;t)gfp/gfp mice. A pharmacologic ROR&ggr;t inhibitor was used to evaluate its preventive and therapeutic effects in allergic asthma. Characteristics of allergic airway inflammation were analyzed by using flow cytometry, histology, quantitative real‐time PCR, and ELISA. Mixed bone marrow chimeric mice, fate mapping analysis, short hairpin RNA transduction, and in vitro T‐cell differentiation were used for mechanistic studies. Results: Mice deficient in IL‐17A and IL‐17F, as well as ROR&ggr;t, exhibited a significant reduction not only in TH17 cell responses but also in TH2 cell responses in an animal model of allergic asthma. Similarly, mice treated with an ROR&ggr;t inhibitor had significantly diminished TH17 and TH2 cell responses, leading to reduced neutrophil and eosinophil numbers in the airway. ROR&ggr;t‐deficient T cells were intrinsically defective in differentiating into TH2 cells and expressed increased levels of B‐cell lymphoma 6 (Bcl6). Bcl6 knockdown resulted in a remarkable restoration of TH2 cell differentiation in ROR&ggr;t‐deficient T cells. Blockade of ROR&ggr;t also significantly hampered the differentiation of human TH2 and TH17 cells from naive CD4+ T cells. Conclusion: ROR&ggr;t in T cells is required for optimal TH2 cell differentiation by suppressing Bcl6 expression; this finding suggests that targeting ROR&ggr;t might be a promising approach for the treatment of allergic asthma by concomitantly suppressing TH17 and TH2 cell responses in the airway.

Blockade of STAT3 in T Cells Inhibits Germinal Center Reactions against Intranasal Allergens.

Understanding the developmental mechanisms of humoral immunity against intranasal antigens is essential for the development of therapeutic approaches against air-borne pathogens as well as allergen-induced pulmonary inflammation. Follicular helper T (Tfh) cells expressing CXCR5 are required for humoral immunity by providing IL-21 and ICOS costimulation to activated B cells. However, the regulation of Tfh cell responses against intranasal antigens remains unclear. Here, we found that the generation of Tfh cells and germinal center B cells in the bronchial lymph node against intranasal proteinase antigens was independent of TGF-β. In contrast, administration of STAT3 inhibitor STA-21 suppressed the generation of Tfh cells and germinal center B cells. Compared with wild-type OT-II T cells, STAT3-deficient OT-II T cells transferred into recipients lacking T cells not only showed significantly reduced frequency Tfh cells, but also induced diminished IgG as well as IgE specific for the intranasal antigens. Co-transfer study of wild-type OT-II and STAT3-deficient OT-II T cells revealed that the latter failed to differentiate into Tfh cells. These findings demonstrate that T cell-intrinsic STAT3 is required for the generation of Tfh cells to intranasal antigens and that targeting STAT3 might be an effective approach to ameliorate antibody-mediated pathology in the lung.

Clonal Expansion of Allergen-specific CD4+ T Cell in the Lung in the Absence of Lymph Nodes

The expansion of allergen-specific CD4+ T cells is a critical step in inducing airway inflammation during allergic asthma. Such clonal expansion of T cells is initiated through the interaction between allergen-bearing dendritic cells and allergen-specific naïve T cells in the draining lymph nodes. Whether such T cell clonal expansion also occurs in the lung, the primary organ encountering inhaled allergens, remains unclear. Compared with wild-type mice, we found similar frequencies of CD4+ T cells in the lung of lymph node-deficient Rorgtgfp/gfp mice after repeated exposure to inhaled allergens. In addition, we observed an evident population of CD4+ T cells that underwent clonal expansion in the lung of allergen-challenged mice treated with an S1P antagonist FTY720 in an in vivo proliferation study with CFSE-labeled OT-II T cells. Moreover, the expansion of allergen-specific CD4+ T cells was significantly enhanced in the lungs of Rorgtgfp/gfp mice in comparison to that of wild-type mice. These results together demonstrate that the clonal expansion of allergen-specific CD4+ T cells occurs in the absence of the lymph nodes, indicating that the lung can act as a primary site of the clonal expansion of CD4+ T cells in response to inhaled allergens.

Enhanced Rg3 negatively regulates Th1 cell responses

Background Korean Red Ginseng (KRG; Panax ginseng Meyer) is a widely used medicinal herb known to exert various immune modulatory functions. KRG and one of its purified components, ginsenoside Rg3, are known to possess anti-inflammatory activities. How they impact helper T cell-mediated responses is not fully explored. In this study, we attempted to evaluate the effect of KRG extract (KRGE) and ginsenoside Rg3 on Th1 cell responses. Methods Using well-characterized T cell in vitro differentiation systems, we examined the effects of KRGE or enhanced Rg3 on the Th1-inducing cytokine production from dendritic cells (DC) and the naïve CD4+ T cells differentiation to Th1 cells. Furthermore, we examined the change of Th1 cell population in the intestine after treatment of enhanced Rg3. The influence of KRGE or enhanced Rg3 on Th1 cell differentiation was evaluated by fluorescence-activated cell sorting, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction. Results KRGE significantly inhibited the production level of IL-12 from DCs and subsequent Th1 cell differentiation. Similarly, enhanced Rg3 significantly suppressed the expression of interferon gamma (IFNγ) and T-bet in T cells under Th1-skewing condition. Consistent with these effects in vitro, oral administration of enhanced Rg3 suppressed the frequency of Th1 cells in the Peyers patch and lamina propria cells in vivo. Conclusion Enhanced Rg3 negatively regulates the differentiation of Th1 cell in vitro and Th1 cell responses in the gut in vivo, providing fundamental basis for the use of this agent to treat Th1-related diseases.