Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of TH17 cell immunity.

Regulatory T cells (Treg cells) are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, in the present study we show that interleukin (IL)-27 is specifically produced by intestinal Treg cells to regulate helper T17 cell (TH17 cell) immunity. Selectively increased intestinal TH17 cell responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83+CD62Llo Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Collectively, our study uncovers a new Treg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue and provides further mechanistic insights into tissue-specific Treg cell-mediated immune regulation.

Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of Th17 immunity.

Regulatory T (Treg) cells are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, here we show that IL-27 is specifically produced by intestinal Treg cells to regulate Th17 immunity. Selectively increased intestinal Th17 responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83+TCF1+ Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Collectively, our study uncovers a novel Treg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue, and provides further mechanistic insights into tissue-specific Treg cell-mediated immune regulation.

Gut epithelial IL-27 confers intestinal immunity through the induction of intraepithelial lymphocytes.

IL-27 controls a diverse range of immune responses in many disease settings. Here, we identify intestinal epithelial cells (IECs) as one of the major IL-27 cellular sources in the gut-associated tissue. Unlike IL-27 secreted by innate immune cells, gut epithelial IL-27 is dispensable for T-bet+ regulatory T cell (T reg cell) differentiation or IL-10 induction. Rather, IEC-derived IL-27 specifically promotes a distinct CD8αα+CD4+ intraepithelial lymphocyte (IEL) population that acquires their functional differentiation at the intestinal epithelium. Loss of IL-27 in IECs leads to a selective defect in CD8αα+CD4+ IELs over time. Consequently, mice with IEC-specific IL-27 ablation exhibited elevated pathogen burden during parasitic infection, and this could be rescued by transfer of exogenous CD8αα+CD4+ IELs. Collectively, our data reveal that in addition to its known regulatory properties in preventing immune hyperactivity, gut epithelial IL-27 confers barrier immunity by inducing a specific IEL subset and further suggest that IL-27 produced by different cell types plays distinct roles in maintaining intestinal homeostasis.

Induction of Airway Hypersensitivity to Ovalbumin and Dust Mite Allergens as Mouse Models of Allergic Asthma.

Mouse models of allergic asthma have been utilized to establish the role of T helper type 2 (Th2) cells in driving lung inflammation, airway hyperresponsiveness, and obstruction. Here, we present the allergic asthma models, in which mice are hypersensitized to ovalbumin (OVA) and house dust mite (HDM). These models mimic the major characteristics of human asthma including the eosinophilic inflammation and hyperactivity of the airway, overproduction of Th2 cytokines in the lung, and elevated total and allergen-specific immunoglobulin E (IgE) in serum.

miR-155 promotes T reg cell development by safeguarding medullary thymic epithelial cell maturation.

During thymocyte development, medullary thymic epithelial cells (mTECs) provide appropriate instructive cues in the thymic microenvironment for not only negative selection but also the generation of regulatory T (T reg) cells. Here, we identify that miR-155, a microRNA whose expression in T reg cells has previously been shown to be crucial for their development and homeostasis, also contributes to thymic T reg (tT reg) cell differentiation by promoting mTEC maturation. Mechanistically, we show that RANKL stimulation induces expression of miR-155 to safeguard the thymic medulla through targeting multiple known and previously uncharacterized molecules within the TGFß signaling pathway, which is recognized for its role in restricting the maturation and expansion of mTECs. Our work uncovers a miR-155-TGFß axis in the thymic medulla to determine mTEC maturity and, consequently, the quantity of tT reg cells and suggests that miR-155 ensures proper tT reg cell development in both cell-intrinsic and -extrinsic manners.

Clinic image surveillance reduces mortality in patients with primary hepato-gastrointestinal cancer who develop second primary lung cancer: A STROBE-compliant retrospective study.

Second primary cancer is prevalent in patients with gastrointestinal (GI) cancer, for which lung cancer is the most common and associated with high lethality. Image screening for lung cancer was proved to be effective in early diagnosis and lower mortality. However, trials of screen for lung cancer generally excluded patients with a previous diagnosis of malignancy. The study aimed to investigate the outcome of second primary lung cancer and the factor that improve survival in patients with hepato-GI cancer.A total of 276 patients with secondary lung cancer were found among 3723 newly-diagnosed lung cancer patients diagnosed in Chang Gung Memorial Hospital, between 2010 and 2014. Patients' clinical characteristics, stages and survival were recorded and analyzed. The patients were separated into 2 groups: Group I was defined as lung cancer detected in original primary cancer clinic and group II patients defined as lung cancer detected in other medical places.Sixty-nine cases with primary GI-hepatic and secondary lung cancer were diagnosed (42 (60.8%) in Group I and 27 (39.1%) in Group II). Although both groups had comparable primary cancer stages and treatment, more patients in Group I than Group II were diagnosed as early stage lung cancer (stage I-II: 40.5% vs 11.1%; P = .023). Group II had larger lung tumor sizes than Group I (4.7 vs 3.5 cm; P = .025). Group I showed better 5-year overall survival than Group II (P = .014, median survival: 27 vs 10 months). Among Group II, only 37% had received image follow up in clinic compared with 67% of Group I cases (P = .025). Patients with chest image follow up in clinics also had better 5-year overall survival (P = .043).GI-hepatic cancer was the most common primary malignancy in the lung cancer cohort. Patients had better survival outcome when secondary lung cancer was diagnosed in original primary cancer clinic. Chest image screening strategy may contribute better survival in secondary lung cancer due to detection at an earlier stage.

Spatial and seasonal distribution of microplastics on sandy beaches along the coast of the Hengchun Peninsula, Taiwan.

Here we present the first report on microplastic pollution on the beaches along the coast of the Hengchun Peninsula, which is one of the major tourist attractions in Taiwan. By using a standard operating procedure, sand samples were collected from eight beaches in June and November in 2017, and the microplastics in the sand samples were quantified and characterized in the laboratory. The average density of microplastics ranged from 80 to 480 particles/kg dry weight sand. There was no apparent seasonal difference but there were significant spatial differences among sampling sites. No significant difference in microplastic levels was observed among the west, south, and east coasts, but microplastic density was higher on beaches with higher tourism activity levels. The most abundant type of microplastics was fiber (>97%) and the most common color was white/transparent (57%). In addition, using a Fourier Transform Infrared (FTIR) spectrophotometer we identified microplastics as polyethylene (PE) and polypropylene (PP). Our results show that microplastics are ubiquitous along the coast of the Hengchun Peninsula, and the major factor associated with the abundance of microplastics is tourism activity.

MiR-23~27~24-mediated control of humoral immunity reveals a TOX-driven regulatory circuit in follicular helper T cell differentiation.

Follicular helper T (TFH) cells are essential for generating protective humoral immunity. To date, microRNAs (miRNAs) have emerged as important players in regulating TFH cell biology. Here, we show that loss of miR-23~27~24 clusters in T cells resulted in elevated TFH cell frequencies upon different immune challenges, whereas overexpression of this miRNA family led to reduced TFH cell responses. Mechanistically, miR-23~27~24 clusters coordinately control TFH cells through targeting a network of genes that are crucial for TFH cell biology. Among them, thymocyte selection-associated HMG-box protein (TOX) was identified as a central transcription regulator in TFH cell development. TOX is highly up-regulated in both mouse and human TFH cells in a BCL6-dependent manner. In turn, TOX promotes the expression of multiple molecules that play critical roles in TFH cell differentiation and function. Collectively, our results establish a key miRNA regulon that maintains optimal TFH cell responses for resultant humoral immunity.

Safety and efficacy of computed tomography-guided dye localization using patent blue V for single lung nodule for video-assisted thoracoscopic surgery: a retrospective study.

BACKGROUND: For invisible or impalpable lung nodules, video-assisted thoracoscopic surgery (VATS) has some limitations; some preoperative localization has been developed to overcome this limitation. This study aimed to assess the safety and efficacy of preoperative computed tomography (CT)-guided localization with patent blue V dye. METHODS: In this retrospective study, we examined patients with solitary pulmonary nodule undergoing preoperative CT-guided patent blue V dye localization from 2013 to 2015. We analyzed patients' demographic data, nodular features, and procedures undergone. RESULTS: We enrolled 282 patients (282 lung nodules; mean age: 56.6±11.6 years, with female preponderance) in this study. The mean size of nodules was 0.9±0.5 cm, and mean time of localization was 24 min. The leading complications after localization were asymptomatic pneumothorax (48 patients, 17%) and localized pulmonary hemorrhage (51 patients, 18%). Other rare complications included subcutaneous emphysema and hematoma. We noted two cases with intraoperative poor or fail dye localization. Most patients underwent wedge resection (221 patients, 78.4%) and segmentectomy (36 patients, 12.8%), whereas 25 patients underwent lobectomy (8.9%) after the intraoperative frozen histopathological study confirmed malignancy. Furthermore, postoperative hospital stay was 4.8±2.0 days. Few patients experienced postoperative complications such as empyema (n=1), air leakage (n=3), and chylothorax (n=1). CONCLUSIONS: This study establishes that CT-guided dye localization is a safe and efficient method with rare severe complications and high success rate.

Differential cell-intrinsic regulations of germinal center B and T cells by miR-146a and miR-146b.

Reciprocal interactions between B and follicular T helper (Tfh) cells orchestrate the germinal center (GC) reaction, a hallmark of humoral immunity. Abnormal GC responses could lead to the production of pathogenic autoantibodies and the development of autoimmunity. Here we show that miR-146a controls GC responses by targeting multiple CD40 signaling pathway components in B cells; by contrast, loss of miR-146a in T cells does not alter humoral responses. However, specific deletion of both miR-146a and its paralog, miR-146b, in T cells increases Tfh cell numbers and enhanced GC reactions. Thus, our data reveal differential cell-intrinsic regulations of GC B and Tfh cells by miR-146a and miR-146b. Together, members of the miR-146 family serve as crucial molecular brakes to coordinately control GC reactions to generate protective humoral responses without eliciting unwanted autoimmunity.

Autophagy-Regulated ROS from Xanthine Oxidase Acts as an Early Effector for Triggering Late Mitochondria-Dependent Apoptosis in Cathepsin S-Targeted Tumor Cells.

Cathepsin S (CTSS), which is highly expressed in various malignant tumor cells, has been proposed to promote tumor progression, migration, and invasion. CTSS inhibition not only blocks tumor cell invasion and endothelial tube formation but also induces cellular cytotoxicity. In our previous studies, we have observed that CTSS inhibition induces autophagy, which is responsible for up-regulating xanthine oxidase for early ROS generation and consequent cell death. However, whether the autophagy-regulated early ROS triggers apoptosis remains unclear. We conducted a long-term follow-up study to investigate the relationship between early autophagy and late mitochondria-dependent apoptosis. We demonstrated that early ROS generation is critical for mitochondria damage and the activation of intrinsic apoptotic pathway. Attenuating the early ROS level diminished later mitochondrial damage and downstream apoptotic signaling. Collectively, mitochondria-dependent apoptosis is regulated by autophagy-regulated early ROS, which serves as an early effector that triggers mitochondrial signaling for late apoptosis. The data emphasize the essential role of autophagy-regulated early ROS in triggering late apoptotic signaling.