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Thymus is the important immune organ, responsible for T cell development and differentiation. The lower circulating T counts have been observed in patients who died from COVID-19 compared with survivors. Azvudine, also known as FNC, is a thymus-homing anti-SARS-CoV-2 drug in treating COVID-19 patients. In this study, single-cell transcriptome, proteomics, and parallel reaction monitoring (PRM) were applied to insight into the activation process of FNC in rat and SARS-CoV-2 rhesus monkey thymus. The results indicated that thymic immune cells possess a robust metabolic capacity for cytidine-analogue drugs such as FNC. Key enzymes involved in the FNC phosphorylation process, such as Dck, Cmpk1, and Nme2, were highly expressed in CD4+ T cells, CD8+ T cells, and DP (CD4+ CD8+) cells. Additionally, FNC could upregulate multiple phosphorylated kinases in various cell types while downregulating the phosphatases, phosphoribosyl transferases, and deaminases, respectively. The robust phosphorylation capacity of the thymus for cytidine analogue drug FNC, and the activation effect of FNC on the NAs metabolism system potentially contribute to its enrichment in the thymus and immune protection effect. This suggests that it is crucial to consider the expression level of phosphorylation kinases when evaluating NA drug properties, as an important factor during antiviral drug design. The activation effect of FNC on the nucleoside metabolism system potentially contribute to its enrichment in the thymus and immune protection effect. [Display omitted] [ABSTRACT FROM AUTHOR]

Graves' disease (GD) is an autoimmune disease and the most common cause of hyperthyroidism. While the phosphotyrosine phosphatase non-receptor type 22 (PTPN22) variant is associated with GD susceptibility, its precise role and mechanism in GD remain unclear. To investigate this, we induced GD in mice using Ad-TSHR289 and isolated CD4+ T cells from spleen tissues. We conducted a series of experiments, including hematoxylin-eosin staining, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, flow cytometry, immunofluorescence (IF), reverse transcription quantitative PCR (RT-qPCR), and western blotting. PTPN22 expression was found to be downregulated in GD mice. Overexpression of PTPN22 ameliorated pathological damage and increased serum levels of T4 and thyroid stimulating hormone receptor antibody (TRAb), as well as the ratio of thyroid weight to body weight in GD mice. Furthermore, GD mice exhibited elevated levels of CD4+ and IL-17+ T cells, an increased Th17/Treg ratio, and upregulation of IL-17A mRNA expression. Conversely, there was a decrease in Foxp3+ T cells and transcriptional levels of Foxp3, which were reversed by PTPN22 overexpression. In vitro experiments showed that PTPN22 overexpression in CD4+ T cells from spleen tissues of GD mice enhanced Foxp3 expression while reducing IL-17A expression. Mechanistically, PTPN22 overexpression led to decreased levels of phosphorylated Lck (p-Lck), Lck, phosphorylated Fyn (p-Fyn), Fyn, phosphorylated Zap70 (p-Zap70), and Zap70 in both in vivo and in vitro GD models. In summary, PTPN22 can alleviate thyroid dysfunction in GD by modulating Th17/Treg balance through the downregulation of the Lck/Zap70 signaling axis. • PTPN22 was lowly expressed in GD mice. • Overexpression of PTPN22 alleviated thyroid dysfunction in GD mice. • PTPN22 regulated Th17/Treg balance in GD mice. • PTPN22 regulated CD4+ T cell differentiation in vitro. • Downregulation of PTPN22 activated TCR signaling. [ABSTRACT FROM AUTHOR]

Particulate matter with aerodynamic diameters ≤2.5 µm (PM 2.5) is a major environmental risk factor for acute asthma exacerbation, and the underlying mechanism is not completely understood. Studies have indicated that DNA methylation is a potential mechanism linking PM 2.5 to its health effects. We conducted a panel study involving 24 adult patients with asthma in Beijing,China between 2017 and 2019. PM 2.5 and other atmospheric pollutant exposure data were repeatedly measured. Blood samples were collected for genome-wide DNA methylation analysis. A linear mixed-effects (LME) model was conducted to identify differentially methylated probes (DMPs) associated with PM 2.5 exposure. After filtering out probes that did not meet the criteria through quality control, 811,001 CpG sites were included in the LME model, and 36 DMPs were strongly associated with personal PM 2.5 exposure at false discovery rate (FDR) < 0.05, of which 22 and 14 DMPs negatively and positively correlated with personal PM 2.5 exposure, respectively. Functional analysis revealed that DMPs affected smooth muscle cell contraction and development, extracellular matrix synthesis and secretion, T cell activation and differentiation, and inflammatory factor production. This study provides evidence linking personal PM 2.5 exposure to genome-wide DNA methylation in adult patients with asthma. Identifying enrichment pathways can provide biological insights into the acute health effects of PM 2.5. • Particulate matter with aerodynamic diameters ≤2.5 µm (PM 2.5) exposure was associated with altered DNA methylation in asthma patients. • The linear mixed-effects model identified 36 differentially methylated probes (DMPs) that link PM 2.5 to DNA methylation changes. • These DMPs may be involved in asthma development. • Identifying enrichment pathways can provide insights about the effect of PM 2.5 on asthma. [ABSTRACT FROM AUTHOR]

Background: Neuroimmune communication plays an important role in allergic inflammation, but the neuroimmune regulation of allergic rhinitis remains unclear. Objective: The goal of this study was to investigate the role of CD4-positive T lymphocyte (CD4+ T cells) adhesion to D-U87 neuron-like cells in mediating allergic rhinitis CD4+ T cell differentiation. Methods: D-U87 neuron-like cells were derived from the human glioblastoma U87 cell line. CD4+ T cells were isolated from human peripheral blood using a magnetic separation technique. In vitro coculture of D-U87 neuron-like cells and CD4+ T cells was established. The number of adherent CD4+ T cells was counted using a fluorescence microscope. The percentages of CD4+IFNγ+ and CD4+IL4+ T cells and the levels of IFNγ and IL4 cytokines in the supernatant were measured by flow cytometry. Results: The results showed that the number of adherent CD4+ T cells in patients with allergic rhinitis was significantly higher than that in healthy controls. In allergic rhinitis, the percentage of CD4+IL4+ T cells was significantly increased in the adherent group compared with that in the nonadherent group. Moreover, blocking ICAM1 and E-selectin decreased the number of adherent CD4+ T cells and the percentage of CD4+IL4+ T cells in allergic rhinitis. Conclusion: Adhesion contributes to CD4+IL4+ T cell differentiation in the in vitro coculture system of D-U87 neuron-like cells and allergic rhinitis CD4+ T cells, which may provide new insights into therapeutic strategies for allergic rhinitis. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-6 has anti- and pro-inflammatory functions, controlled by IL-6 classic and trans-signaling, respectively. Differences in the downstream signaling mechanism between IL-6 classic and trans-signaling have not been identified. Here, we report that IL-6 activates glycolysis to regulate the inflammatory response. IL-6 regulates glucose metabolism by forming a complex containing signal-transducing activators of transcription 3 (STAT3), hexokinase 2 (HK2), and voltage-dependent anion channel 1 (VDAC1). The IL-6 classic signaling directs glucose flux to oxidative phosphorylation (OxPhos), while IL-6 trans-signaling directs glucose flux to anaerobic glycolysis. Classic IL-6 signaling promotes STAT3 translocation into mitochondria to interact with pyruvate dehydrogenase kinase-1 (PDK1), leading to pyruvate dehydrogenase α (PDHA) dissociation from PDK1. As a result, PDHA is dephosphorylated, and STAT3 is phosphorylated at Ser727. By contrast, IL-6 trans-signaling promotes the interaction of sirtuin 2 (SIRT2) and lactate dehydrogenase A (LDHA), leading to the dissociation of STAT3 from SIRT2. As a result, LDHA is deacetylated, and STAT3 is acetylated and phosphorylated at Tyr705. IL-6 classic signaling promotes the differentiation of regulatory T cells via the PDK1/STAT3/PDHA axis, whereas IL-6 trans-signaling promotes the differentiation of Th17 cells via the SIRT2/STAT3/LDHA axis. Conclusion: IL-6 classic signaling generates anti-inflammatory functions by shifting energy metabolism to OxPhos, while IL-6 trans-signaling generates pro-inflammatory functions by shifting energy metabolism to anaerobic glycolysis. • IL-6 regulate glucose metabolism via STAT3/VDAC1/HK2IL-6 classic signaling shifts glucose flux to OxPhosIL-6 trans-signaling shifts glucose flux to anaerobic glycolysisIL-6 classic signaling induce STAT3 interacts with PDK1, to destabilize the interaction between PDK1 and PDHA in mitochondriaIL-6 trans-signaling promote LDHA interacts with SIRT2, to destabilize the interaction between SIRT2 and STAT3 in cytoplasm [ABSTRACT FROM AUTHOR]

This study investigated the effects of glycation combined with phosphorylation on the structure and allergenic potential of parvalbumin (PV) in silver carp (Hypophthalmichthy molitrix). The method increased PV's molecular weight and altered its structure. In vivo , this approach significantly reduced the risk of PV allergy, with decreased serum levels of IgE, IgG, histamine, β -hexosaminidase, and interleukin-4 decreased, while interferon-γ levels increased. Spleen tissue demonstrated increased expression of transforming growth factor- β , interleukin-12, and T-bet. Although the relative abundance of allergy-associated gut microbiota (Firmicutes and Bacteroidetes) changed, the diversity and composition of the gut microbiome in mice remained similar to normal mice at the family and genus taxonomic levels. Allergic mice exhibited imbalanced gut microbiota including Firmicutes , Lactobacillaceae , Staphylococcaceae , and Lactobacillus. Norank_f__Muribaculaceae and Bacteroidetes helped alleviate the allergenic potential. Therefore, glycation combined with phosphorylation can significantly reduce the risk of PV allergy through structural changes and regulation of the gut microbiome. • Galactose-phosphate modification changed parvalbumin structure and allergenicity. • Galactose-phosphate modification regulated gut microbiome and T cell differentiation in mice. • Galactose-phosphate conjugation mitigated allergies in BALB/c mice. [ABSTRACT FROM AUTHOR]

Hashimoto's thyroiditis (HT) during pregnancy is usually accompanied by an elevation of thyroid‐stimulating hormone and a reduction of serum‐free thyroxine during gestation, which may lead to abortion, preterm delivery, and reduced intellectual function of the offspring. Epigenetic alterations may provide important insights into genetic–environmental interactions in HT. Here, we examined global DNA methylation patterns in patients with HT during pregnancy. DNA was extracted from 13 women with HT during pregnancy (HTDP) and eight healthy pregnant women as a control group. Genome‐wide methylation was detected with the use of an Illumina Human Methylation 850K Beadchip. A total of 652 differentially methylated positions (DMPs) and 27 differentially methylated regions (DMRs) were identified between the HTDP and control groups. GO analysis revealed that DMPs were significantly enriched in 540 GO terms, which included regulation of the differentiation of keratinocytes, T helper cell differentiation, and alpha‐beta T‐cell differentiation. Moreover, significant enrichment of KEGG pathways of the DMPs included mucin‐type O‐glycan biosynthesis, focal adhesion, and the insulin signaling pathway. The GO items associated with DMRs included muscle cell proliferation, response to biotic stimulus, anatomical structure formation involved in morphogenesis, and genes primarily involved in the FoxO signaling pathway. Finally, the DTNA gene was identified as the seed gene of functional epigenetic modules. In summary, the DNA methylation pattern of the HTDP group was distinct from that of the control group, and thus, changes in DNA methylation may influence the development of HT by regulation of the autoimmunity process. [ABSTRACT FROM AUTHOR]

Different doses of allergen lead to different T lymphocyte responses which partly explain the phenomenon of low or high dose tolerance. Dendritic cells (DC) are responsible for driving the T lymphocyte responses to a variety of exogenous stimuli, but the mechanisms are not completely understood. Elucidate the mechanisms of how DCs drive the differentiation of T lymphocytes in response to different doses of allergen. Groups of male BALB/c mice (n=4-5) were sensitized intraperitoneally with sham or different doses (low: 10 mg, high: 1000 mg) of Der P1 (house dust mite allergen). They were exposed daily to aerosolized Der p1 allergen for 7 consecutive days. Different concentrations of Der p1 solution were nebulized: sham, low dose (15 mg/mL), or high dose (1500 mg/mL). Bronchoalveolar lavage fluid (BALF) was obtained from the lungs. Levels of IL-12 in BALF were measured. Lung tissue sections were then stained to detect the expression of Hsp70 by lung DCs. Lung DCs exposed to a higher sensitizing doses of Der p1 allergen tend to express significantly higher levels of Hsp70 and secrete higher levels of IL-12 in BALF. There was a significant positive correlation between the levels of Hsp70 expression by lung DCs with IL-12 levels in BALF (r=0.581). Higher exposure doses of allergen puts lung DCs under stressed condition thereby induced high expression of 'stress proteins' which may explain the mechanism of DCs drive the T lymphocyte response. [ABSTRACT FROM AUTHOR]

T cell differentiation is a key pathological process of aplastic anemia (AA). Tregs and Th17 must be balanced for efficient immune tolerance. Discorea nipponica saponins (DNS) improves the recovery from hematopoiesis in AA models through its ability to increase the number of T-helper cells whilst decreasing the percentage of T-cytotoxic cells in AA mice. However, the mechanisms by which DNS leads to these therapeutic effects remains largely undefined. Here, we explored the mechanism(s) by which DNS regulates T cell subsets in mouse AA models. BALB/c male mice were used to establish the AA model using 137Cs irradiation and intraperitoneal injection with cyclophosphamides and Chloramphenicol. Mice were administrated DNS/Tripterygium wilfordii polyglycoside tablets (TW)/cyclosporine A (CsA)/distilled water via gavage each day for 14 days. Peripheral blood, spleen and bone marrow were obtained. Bone marrow morphology, Notch/RBPJκ/FOXP3/RORγt signaling and molecules regulating Th17/Treg balance were evaluated. We found that DNS-M attenuated pancytopenia in mouse AA models. DNS-M could not only suppressed Th 17 cell numbers and RORγt expression, but enhanced the prevalence of Treg cells and Foxp3 expression. Moreover, DNS-M modulated the level of Notch1, Jagged1, RBPJκ, FOXP3, RORγt, DLL4 in AA models. These data suggest that the administration of DNS-M exhibits therapeutic effects through restoring the Th17/Treg cell balance in AA mice through its regulation of the Notch/RBPJκ/FOXP3/RORγt pathway. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is caused by an aberrant autoimmune response in the central nervous system (CNS), which results in progressive demyelination. Current therapies, mostly disease-modifying therapies, have limited wide use due to their higher costs, low patient's compliance, and serious side effects. Here, we firstly show that nano-sized gold clusters (GA, molecular formula Au 29 SG 27) can significantly attenuate or reverse clinical symptoms and prevent neuronal demyelination in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS when administered prophylactically or therapeutically. GA reduces the infiltration of Th1 and Th17 cells, and the secretion of associated pro-inflammatory cytokines in the CNS. Notably, GA shows potent direct inhibitory activity on the differentiation of CD4+ T cells into Th1 and Th 17 in vitro with no effect on apoptosis and activation of T cells. Mechanistic studies show that GA inhibit JAK/STAT signaling, which is critical for Th-cell differentiation, through specific Au-binding with JAK protein in cells. Collectively, our results sheds light on GA as a novel nano-drug for MS treatment with low toxicity and high efficiency. [Display omitted] • Ultrasmall gold clusters have excellent performance in preventing and reversing the severity of the disease in experimental autoimmune encephalomyelitis inflicted mice, an animal models of multiple sclerosis. • Gold clusters reduce the infiltration of Th1 and Th17 cells and secretion of pro-inflammatory cytokines in the CNS. • Au clusters suppressed the inflammatory response of CNS in EAE mice by inhibiting the differentiation of CD4+ T-cell. • Mechanistic studies elucidates that gold clusters can inhibit JAK/STAT signaling through specific Au-binding with JAK protein in cells. • Upon entrying into the cells, gold clusters undergo degradation and oxidation, which is analyzed by synchrotron radiation x-ray absorption spectroscopy. [ABSTRACT FROM AUTHOR]

For most solid tumors, surgery is still the most effective treatment. However, postoperative recurrence is the main reason for the failure of surgical treatment of malignant tumors. It is urgent to develop new nanomedicine systems to inhibit postoperative recurrence. Here, we designed a tumor cell membrane fusion liposome loaded AIE photosensitizer and Metformin named TMFL to inhibit postoperative recurrence. First, thanks to the homing effect of tumor cell membranes, TMFL can enter tumor tissues through active targeting. Under light irradiation, TMFL can produce singlet oxygen (1O 2), which promoted immunogenic cell death (ICD) of tumor cells, thereby inducing dendritic cell (DC) maturation and stimulating T cell immunity. Metformin released by TMFL further promoted T cell differentiation into Central Memory T cell (Tcm) and inhibited tumor recurrence. The results of experiments showed that TMFL plus light treatment increased the content of mature DC in lymph nodes. In addition, TMFL can effectively promote the differentiation of T cells into Tcm, increase the content of T cells in recurrent tumor tissue, and inhibit the tumor recurrence. In view of the current major problems such as postoperative tumor recurrence, our TMFL system has a good clinical application potential. [Display omitted] • TMFL can effectively promote the differentiation of T cells into TCM. • TMFL can enter tumor tissues through active targeting. • TMFL can promote ICD and T cell immunity. [ABSTRACT FROM AUTHOR]

CD4 T cells are major immune cell types that mediate effector responses appropriate for diverse incoming threats. These cells have been categorized into different subsets based on how they are induced, expression of specific master transcription factors, and the resulting effector cell phenotypes as defined by expression of signature cytokines. However, recent studies assessing the expression of gene modules in single CD4 T cells, rather than expression of one or a few signature genes, have provided a more complex picture in which the canonical model does not fit as cleanly as proposed. Here, we review the concepts of lineage commitment, plasticity and functional heterogeneity in the context of this greater complexity. We then apply our current understanding of CD4 T cell subsets to discuss outstanding questions regarding follicular helper T cells and follicular regulatory T cells with respect to their shared features with other known CD4 T cell subsets. [ABSTRACT FROM AUTHOR]

Until now, the specific pathogenesis of silicosis is not clear. Exosomal miRNAs, as a newly discovered intercellular communication medium, play an important role in many diseases. Our previous research found that serum exosomal miR125a-5p was increased in silicosis patients by miRNAs high-throughput sequencing. TRAF6, is a target gene of miR125a-5p, which is involved in T-cell differentiation. Furthermore, results from animal study indicate that knockdown of miR-125a-5p can regulate T lymphocyte subsets and significantly reduce pulmonary fibrosis by targeting TRAF6. However, the level of serum exosomal miR125a-5p in silicosis patients has not been reported, the role of macrophages-secreted exosomal miR-125a-5p in regulating T cell differentiation to promote fibroblast transdifferentiation (FMT) remains unknown. In this study, the levels of serum exosomal miR125a-5p and serum TGF-β1, IL-17A, IL-4 cytokines in silicosis patients were elevated, with the progression of silicosis, the level of serum exosomal miR125a-5p and serum IL-4 were increased; thus, the serum level of IFN-γ was negatively correlated with the progression of silicosis. In vitro , the levels of miR125a-5p in macrophages, exosomes, and T cells stimulated by silica were significantly increased. When the mimic was transfected into T cells, which directly suppressed TRAF6 and caused the imbalance of T cells differentiation, induced FMT. To sum up, these results indicate that exosomal miR-125a-5p may by targeting TRAF6 of T cells, induces the activation and apoptosis of T cells and the remodeling of Th1/Th2 and Th17/Tregs distribution, ultimately promotes FMT. Suggesting that exosomal miR-125a-5p may be a potential therapeutic target for silicosis. [Display omitted] • Exosomal miR125a-5p, serum TGF-β1, IL-17A, IL-4 in silicosis patients were elevated. • Exosomal miR125a-5p was positively correlated with the progression of silicosis. • Exosomal miR-125a-5p can reshape CD4+ T cell subtypes distribution, promotes FMT. • Exosomal miR-125a-5p may be a biomarker and therapeutic target for silicosis. [ABSTRACT FROM AUTHOR]

Rapamycin has great potential in the antitumor application, but its therapeutic effect is seriously affected by poor water solubility, targeting ability, and low bioavailability. Here, we constructed a novel composite nanomaterial with PCN-224 as a drug carrier and loaded rapamycin, named R@BP@HA. The nanoplate not only improves targeting, but also synergizes rapamycin with PCN-224 to effectively promote tumor cell apoptosis, which subsequently causes immunogenic cell death (ICD), and shows strong therapeutic effect in 4T1 breast cancer model. The treatment effect depends on three main points:(i)Proapoptotic effect of rapamycin on tumor cells;(ii)ROS production by PCN-224-mediated photodynamic therapy;(iii)ICD induced DC maturation, increased immune response and promoted T cell proliferation and differentiation. This nanoplate offers potential antitumor efficacy in combination with chemotherapy, photodynamic therapy, and immunotherapy. Image: Rapamycin was self-assembled into a water-soluble nanoparticle by BSA, and then loaded onto PCN-224. The R@BP@HA was constructed with HA modification on the surface and then entered the tumor tissue through passive EPR targeting and active HA targeting. Under the action of 660 nm laser, rapamycin was released to the tumor site, and PCN-224 produced ROS. The two synergies effectively killed tumor cells. Dead tumor cells induce ICD, increase the expression level of DAMPs, and further induce DC maturation. DC can effectively present antigens to T cells, promote the proliferation and activation of T cells, and effectively promote the body's immune response. [Display omitted] [ABSTRACT FROM AUTHOR]

CD4+ T cells are critical regulators of the adaptive immune system and have diverse roles in regulating responses to the broad array of microbes encountered. Appropriate execution of their effector function requires precise and coordinated migration of these cells to specific lymphoid niches and peripheral sites. This migration is largely controlled by dynamic expression of chemokine receptors and the discrete functions of distinct subsets of CD4+ T cells can often be determined from their expression of specific chemokine receptors. In this chapter, we discuss recent advances in the subset-specific homing of distinct T helper populations, focusing on new insights stemming from the increased diversity and plasticity now observed among CD4+ T cells as well as how chemokine receptors can govern T cell-fate decisions. We also discuss current understanding of CD4+ memory T cells with reference to their diversification based on chemokine receptor expression. [ABSTRACT FROM AUTHOR]

Korean diesel particulate matter 20 (KDP20) is a pollutant comprising a complex mixture of carbon and chemical irritants. Although particulate matter and nasal inflammation are strongly associated, the underlying molecular mechanism based on systematic transcriptome analysis remains unknown. In this study, genome-wide gene expression profiles of mouse nasal tissues were determined following exposure to KDP20 for 5 and 10 days and compared with those of the control (n = 4/group). We identified 758 significant differentially expressed genes (DEGs) and classified them as 5-day-specific, 10-day-specific, and common among groups based on their expression patterns. The terms "regulation of alpha-beta T cell differentiation," "macrophage differentiation," and "cell adhesion mediated by integrin" were significantly enriched in each group. Receiver operating characteristic analysis revealed six genes as potential predictive biomarkers. The differential expression of these six genes was validated using quantitative RT-PCR (n = 3/group). Furthermore, a possible mechanism for nasal inflammation was suggested through the binding analysis between metal ions and genes. The genes identified in this study may play important roles in regulating the mechanism of nasal inflammation induced by diesel particles, especially immune cell regulation, and may function as markers for diesel particle-induced nasal inflammation. [Display omitted] • KDP20 exposure for 5–10 days causes nasal inflammation in mice. • DEGs between groups are associated with immune cell differentiation & inflammation. • Six genes were identified as biomarkers of KDP20-induced nasal inflammation. [ABSTRACT FROM AUTHOR]

Silicosis caused by long-term inhalation of crystalline silica during occupational activities seriously threatens the health of occupational populations. Imbalances in T helper 1(Th1), Th2, Th17, and regulatory T cells (Tregs) promote the development of pulmonary silicosis. Exosomes and their contents, especially microRNAs (miRNAs), represent a new type of intercellular signal transmission mediator related to various diseases including pulmonary fibrosis. However, whether exosomal miRNAs can affect the progression of silicosis by regulating T cell differentiation remains to be determined. To test this hypothesis, we established a miR-125a-5p antagomir mouse model and examined changes in miR-125a-5p levels and T cell subtypes. We found that miR-125a-5p levels were increased in lung tissues and serum exosomes in the silica group at 7 days and 28 days. Downregulation of miR-125a-5p attenuated α-smooth muscle actin (α-SMA), collagen I, fibronectin, p-p65, and p-inhibitor of nuclear factor kappa B (NF-κB) kinase (IKK) protein expression, while tumor necrosis factor receptor-associated factor 6 (TRAF6) and p-inhibitor of κBα (IKBα) expression were increased. MiR-125a-5p anta-miR treatment contributes to the maintenance of Th1/Th2 balance during the progression of pulmonary fibrosis. Our findings indicated that knockdown miR-125a-5p could regulate T lymphocyte subsets and significantly reduce pulmonary fibrosis by targeting TRAF6. [Display omitted] • miR-125a-5p were increased in fibrotic murine lung tissues and serum exosomes. • Exosomal miR-125a-5p exerts pro-fibrotic effects by regulating T lymphocyte subsets. • miR-125a-5p may be a promising therapeutic target in pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Elevated levels of arsenic may be present in groundwater, and long-term exposure to arsenic increases hepatic fibrosis. T helper 2 (Th2) cells are involved in the fibrotic cascade, and cell metabolism is a regulatory factor participating in CD4+ T cell differentiation and function. However, the mechanism for Th2 cell regulation of arsenite-induced hepatic fibrosis is not fully understood. In present study, for arsenite-fed mice, activated hepatic stellate cells may be involved in the infiltration of CD4+ T cells, accompanied by up-regulation of GATA3, a transcription factor, and IL-13, the major Th2 cytokine. Exposed to arsenite, Jurkat cells had increased aerobic glycolysis to promote the cell cycle and cell proliferation. Further, this process elevated levels of marker molecules, including those of the Th2 paradigm characterized by GATA3, IL-4, and IL-13. LX-2 cells were activated when treated with culture medium from Jurkat cells exposed to arsenite. miR-21 may be a therapeutic target for arsenite-induced hepatic fibrosis. In vitro , miR-21 knock-down caused inhibition of the PTEN/PI3K/AKT pathway induced by arsenite. It also reversed the elevated glycolysis and the accelerated cell cycle and cell proliferation. Indeed, this alteration led to diminished expression of GATA3, IL-4, and IL-13 in T cells differentiated under Th2 conditions, which inhibits activation of LX-2 cells. Consistent with the results in vitro, miR-21 knock-out in mice reversed hepatic fibrosis and attenuated the levels of GATA3 and IL-13 induced by arsenite. These findings indicate that miR-21 regulates the glycolysis of CD4+ T cells through the PTEN/PI3K/AKT pathway to accelerate the cell cycle, thereby facilitating CD4+ T cell polarization toward Th2 and releasing the fibrogenic factor IL-13, which participates in arsenite-associated hepatic fibrosis. Inhibition of Th2 polarization of CD4+T cells or miR-21 could be a therapeutic strategy to combat hepatic fibrosis caused by exposure to arsenic. [Display omitted] • Th2 polarization of CD4+ T cells accelerates arsenite-induced liver fibrosis. • miR-21 regulates Th2 polarization of CD4+ T cells via metabolic reprogramming. • Th2 polarization of CD4+ T cells activates HSCs via releasing IL-13. • Depletion of miR-21 blocks arsenite-induced hepatic fibrosis in mice. [ABSTRACT FROM AUTHOR]

Pathogenic microorganisms that are ubiquitous in the environment threaten human health and food safety. Polyinosinic:polycytidylic acid (Poly (I:C)) is a macromolecule with a double-stranded RNA structure, which is often used to simulate viruses. Our previous study found that Poly (I:C) maternal stimulation could affect the reproduction of laying hens and their offspring, but the underlying mechanism needed to be explored. In the present study, splenic transcriptomes were sequenced and analyzed from two groups (Poly (I:C) treatment as the challenged group and saline treatment as the control) and in three generations (maternal stimulated F0 hens, unchallenged F1 and F2 generations). The results showed that Poly (I:C) maternal stimulation affected gene expression patterns in laying hens and their offspring. A total of 27 differentially expressed genes (DEGs) with the same regulating trend were discovered in the F0 and F1 generations, indicating an influence of the intergenerational transmission effect. Functional enrichment analysis of Gene Ontology (GO) showed that lymphocyte differentiation, positive regulation of leukocyte differentiation, positive regulation of MAPK cascade, and T cell differentiation were the common biological processes between F0 and F1 generations, revealing Poly (I:C) could affect the immunity of the treated F0 hens and the unchallenged subsequent generations. Further study showed that pathways associated with growth, development, biosynthesis, and metabolism of F2 chicks were also affected by Poly (I:C) maternal stimulation. Correlation analysis between DEGs and reproductive traits revealed that PHLDA2 (pleckstrin homology-like domain family A member 2) and PODN (podocan) with inheritable effect were highly correlated with egg-laying rate and egg weight in F1 hens, suggesting their potential long-term role in regulating reproductive traits. ARHGAP40 , FGB , HRH4 , PHLDA2 , PODN , NTSR1, and NMU were supposed to play important roles in regulating chickens' immunity and reproductive traits. This study reveals the far-reaching effect on transcriptome induced by Poly (I:C), reflecting the influence of the mother's living environment on the offspring. It is an important reference for future research into the multi-generational transmission of maternal stimulation and harmful environmental factors. [Display omitted] • Environment that female exposed may affect transcriptome of their offspring. • Poly(I:C) affects the immunity of the challenged animals and their subsequent offspring. • Poly(I:C) stimulus affects development, biosynthesis and metabolism of grandchildren. • PHLDA2 and PODN with transgenerational effects were correlated with reproduction. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a common total joint disorder associated with regulatory T cell (Treg)/IL-17-producing T helper (Th17) cell imbalance. This study elucidated the mechanism underlying Th17/Treg imbalance during OA progression. CD4+ T cells were isolated and induced to differentiate and obtain Th17 and Treg cells, and an OA mouse model was established by anterior cruciate ligament transection surgery, followed by loss- and gain-of-function assays. Max interacting protein 1 (MXI1), tectonic family member 2 (TCTN2), Forkhead Box Protein P3 (Foxp3), signal transducer and activator of transcription 3 (STAT3), and retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt) expression was determined in cells and mice, accompanied by the measurement of the proportion of Th17 and Treg cells and the levels of interleukin (IL)− 1β, tumor necrosis factor (TNF)-α, and interferon (INF)-γ. Articular cartilage histopathology was observed by hematoxylin and eosin staining and Safranin O-Fast Green staining. Relationship between MXI1 and TCTN2 was assessed. Bioinformatics analysis identified MXI1 and TCTN2 upregulation in OA patients. Mechanistically, MXI1 bound to TCTN2 promoter to promote its transcription. Upregulated MXI1 boosted INF-γ, STAT3, IL-1β, TNF-α, and RORγt levels and Th17 cell differentiation, but restricted Foxp3 expression and Treg cell differentiation in CD4+ T cells. Effects caused by overexpressed MXI1 were negated by silenced TCTN2. Also, the impacts of MXI1 overexpression on Th17/Treg imbalance and IL-1β, STAT3, TNF-α, Foxp3, INF-γ, and RORγt expression were further validated in OA mice, accompanied by aggravated articular cartilage degeneration. Conclusively, MXI1 facilitated Th17/Treg imbalance to accelerate OA progression. • MXI1 and TCTN2 are highly expressed in OA. • MXI1 promotes differentiation of Th17 cells. • MXI1 increases transcription of TCTN2. • MXI1 induces Th17/Treg imbalance in OA by upregulating TCTN2. • This study provides a novel consideration for OA treatment. [ABSTRACT FROM AUTHOR]

Background Human induced pluripotent stem cells (iPSCs) morphologically and functionally resemble human embryonic stem cells, which presents the opportunity to use patient-specific somatic cells for disease modeling and drug screening. In order to take one step closer to clinical applications, it is important to generate iPSCs through a less invasive approach and from any accessible tissue, including peripheral blood. Meanwhile, how to differentiate blood cell-derived iPSCs into neuron-like cells is still unclear. Methods We utilized Epstein–Barr nuclear antigen-1-based episomal vectors, a nonviral system that can reprogram somatic cells into iPSCs in both feeder-dependent and feeder-free conditions, to generate iPSCs from T cells via electroporation and then induce them into neuronal cells. Results We successfully isolated sufficient T cells from 20 mL peripheral blood of the donors and reprogrammed these T cells into iPSCs within 4 weeks. These iPSCs could be stably passaged to at least 50 passages, and exhibited the abilities of pluripotency and multiple-lineage differentiation. Notably, under the medium induction for 21 days, these T-cell-derived iPSCs could be differentiated into Nestin (neural progenitor marker)-, GFAP (glial cell marker)-, and MAP2 (neuron cell marker)-positive cells detected by immunofluorescence methods. Conclusion We have developed a safer method to generate integration-free and nonviral human iPSCs from adult somatic cells. This induction method will be useful for the derivation of human integration-free iPSCs and will also be applicable to the generation of iPSCs-derived neuronal cells for drug screening or therapeutics in the near future. [ABSTRACT FROM AUTHOR]

Memory T cells are usually considered to be a feature of a successful immune response against a foreign antigen, and such cells can mediate potent immunity. However, in mice, alternative pathways have been described, through which naïve T cells can acquire the characteristics and functions of memory T cells without encountering specific foreign antigen or the typical signals required for conventional T cell differentiation. Such cells reflect a response to the internal rather the external environment, and hence such cells are called innate memory T cells. In this review, we describe how innate memory subsets were identified, the signals that induce their generation and their functional properties and potential role in the normal immune response. The existence of innate memory T cells in mice raises questions about whether parallel populations exist in humans, and we discuss the evidence for such populations during human T cell development and differentiation. [ABSTRACT FROM AUTHOR]

Benzotriazole UV stabilizers (BUVSs) are widely used as additives in various materials, including plastics, to prevent damage from UV-irradiation. However, despite the extensive usage of BUVSs, information on their toxicological properties is limited. In this study, we investigated the effect of BUVSs on the immune regulatory system via the aryl hydrocarbon receptor (AhR). A cell-based transactivation assay using DR-EcoScreen cells revealed that, among 13 BUVSs tested, UV-P, UV-PS, UV-9, and UV-090 activated AhR in a dose-dependent manner. In particular, the AhR agonistic activity of UV-PS was about 10-fold more potent than those of UV-P, UV-090, and UV-9, and UV-PS acted as a full agonist against AhR. In order to investigate the immune regulatory effects of these BUVSs, we orally treated C57BL/6 mice with UV-PS or UV-P (10, 30, and 100 mg/kg) and studied the differentiation of regulatory T cells (Tregs) in spleen cells. Flow-cytometry analysis revealed that the administration of UV-PS (30 and 100 mg/kg) or UV-P (100 mg/kg) significantly increased the population of CD4+-/CD25+-/Foxp3+ Tregs in the spleen. In addition, we found that the in vitro exposure of mouse splenocytes to UV-PS (10 and 30 μM) or UV-P (30 μM) as well as to TCDD (0.1 nM) significantly induced Tregs. Notably, the induction of Tregs was eliminated by co-treatment with an AhR antagonist, CH-223191, in each case. Taken together, these findings suggest that some BUVSs might induce Tregs through direct AhR activation and act as immunosuppressive modulators. [Display omitted] • UV-P, UV-PS, UV-9, and UV-090 activated AhR. • UV-PS showed 10-fold more potent AhR activity than did UV-P, UV-9, and UV-090. • Oral treatment of mice with UV-PS or UV-P significantly induced splenic Treg. • In vitro treatment of mouse splenocytes with UV-PS or UV-P significantly induced Treg. • Treg induction by UV-PS or UV-P was eliminated by co-treatment with an AhR antagonist. [ABSTRACT FROM AUTHOR]

Background: The pathogenesis of nasal polyposis has not been fully understood. Recent studies indicate that there is a subset of CD4+CD25highFoxP3+T cells (regulatory T cells [Tregs]) that express retinoic acid receptor related orphan receptor C (RORC) or IL-17, and these cells might be new proinflammatory cells because of the expression of IL-17 with loss of their suppressive function. The goals of this study were to localize Th17-like Tregs (Th17-like Tregs or RORC+Tregs) in nasal polyps and to investigate the role of staphylococcal enterotoxin B (SEB) on the differentiation of Tregs to RORC+Tregs in vitro. Methods: A total of 60 patients were enrolled in this study. Of the 60 patients, 40 had chronic rhinosinusitis with nasal polyps (CRSwNPs), and 20 subjects who were undergoing septoplasty were enrolled as control subjects. The nasal polyps of CRSwNP patients were subclassified as either eosinophilic polyp (EP) and noneosinophilic polyp (NEP) according to the result of hematoxylin and eosin stain. Tissues and whole blood were collected from all subjects. Double immunofluorescent staining and reverse-transcription polymerase chain reaction for RORC and FOXP3 were conducted on the tissues. RORC expressions of Tregs were measured in the tissue using flow cytometry. The proportions of RORC+Tregs subsets and cytokines profiles from the supernatant were measured using flow cytometry after stimulation with SEB. Results: The cells that express both RORC and FOXP3 and RORC+Tregs were significantly higher in the nasal polyps, especially in EPs compared with NEPs, and control mucosa. RORC+Tregs in peripheral blood mononuclear cells significantly increased in patients with EPs 24 hours after SEB stimulation in vitro. Conclusion: The results indicate that SEB may be involved in the differentiation of Tregs to RORC+Tregs, and these cells may be involved in the pathogenesis of eosinophilic nasal polyposis. [ABSTRACT FROM AUTHOR]

Abstract: Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a rare tumor usually localized in the thyroid gland and perithyroid tissues. It is considered to arise from ectopic thymic tissue or branchial pouch remnants. It occurs more frequently in children and adolescents. We report 2 cases of spindle epithelial tumor with thymus-like differentiation localized in the thyroid gland, and 1 of them was associated with a parathyroid adenoma. We emphasize the need for a close and long-term follow-up in these patients. [Copyright &y& Elsevier]

Abstract: Despite advances in the treatment of ALL, in most patients long-term survival rates remain unsatisfactory. The objective of the present study was to investigate the anti-cancer effects of Prostaglandin E2 (PGE2) in two different ALL cell lines (CCRF-CEM (T-ALL) and Nalm-6 (B-ALL)). The anti-leukemic effects of PGE2 were also compared with two epigenetic compounds (trichostatin A and 5-aza-2´-deoxycytidine). MTT assay was used to assess growth inhibition by anti-cancer drugs in these cells. All three compounds were shown to induce apoptosis in both ALL cell lines using flow cytometry and Western blotting. To evaluate the differentiation induction by these agents, the expressions of CD19 and CD38 markers on Nalm-6 cell line and CD7 marker on CCRF-CEM cell line were assayed. Surprisingly, the flow cytometric analysis showed a significant increase in CD markers expression in response to PGE2 treatments. We, for the first time, provide evidences that PGE2 has anti-leukemic effects and induces differentiation at micromolar ranges in both T- and B-cell derived ALL cell lines. Since T-ALL cells are insensitive to current chemotherapies, these findings may help the designing of new protocols for T-ALL differentiation therapy in the future. [Copyright &y& Elsevier]

The differentiation of naive T cells into distinct subsets of effector T cells is critical for effective immunity against a wide variety of infectious agents in the environment. Activation of innate immune responses by Candida species through pattern-recognition receptors directs the subsequent development of naive T cells into TH17 cells, which are essential for effective mucosal immunity against fungi. Thorough analyses of cohorts of patients with unusual susceptibility to chronic mucocutaneous candidiasis resulting from TH17 deficiency have confirmed the role of TH17 cells and TH17 cytokines in human host defense against Candida species and have provided valuable insights into the complex process of TH17 cell development. [ABSTRACT FROM AUTHOR]

The mechanisms underlying the pathogenesis of autoimmune hepatitis are not fully understood, though there is growing evidence that genetic predisposition, molecular mimicry and/or impairment of regulatory T-cells are involved in the initiation and perpetuation of the autoimmune liver attack. The histological picture of interface hepatitis, characterized by a dense portal mononuclear cell infiltrate, was the first to suggest an autoaggressive cellular immune attack in the pathogenesis of this condition. Liver damage is likely to be orchestrated by CD4pos T-cells recognizing an autoantigenic liver peptide. For autoimmunity to arise, the peptide must be presented by antigen-presenting cells to naïve CD4pos T-helper (Th0) cells. Once activated, Th0-cells can differentiate into Th1-, Th2-, or Th17-cells, initiating a cascade of immune reactions that are determined by the cytokines they produce. Autoantigen recognition and the above effector mechanisms are opposed by regulatory T-cells, a cell subset numerically and functionally impaired in autoimmune hepatitis. [Copyright &y& Elsevier]

The article presents a study on the activation of activin receptor type-2A (Acvr2a) as a T helper cell (Th17 cell)-specific gene induced during Th17 differentiation. It states that the expression of Acvr2a was inhibited when Th17 cell differentiation was inhibited by all tarans retinoic acid (ATRA) that induces regulatory T cell (Treg) differentiation. Results show that Acvr2a is a Th17 specific gene making Th17 cells.

Summary: Segmented filamentous bacteria (SFB) are noncultivable commensals inhabiting the gut of various vertebrate species and have been shown to induce Th17 cells in mice. We present the complete genome sequences of both rat and mouse SFB isolated from SFB-monocolonized hosts. The rat and mouse SFB genomes each harbor a single circular chromosome of 1.52 and 1.59 Mb encoding 1346 and 1420 protein-coding genes, respectively. The overall nucleotide identity between the two genomes is 86%, and the substitution rate was estimated to be similar to that of the free-living E. coli. SFB genomes encode typical genes for anaerobic fermentation and spore and flagella formation, but lack most of the amino acid biosynthesis enzymes, reminiscent of pathogenic Clostridia, exhibiting large dependency on the host. However, SFB lack most of the clostridial virulence-related genes. Comparative analysis with clostridial genomes suggested possible mechanisms for host responses and specific adaptations in the intestine. [Copyright &y& Elsevier]

Background & Aims: Although T-helper (Th) 17 and Th1 cells are involved in pathogenesis of intestinal inflammation, their developmental pathways and sufficiency to promote disease are not known; nor are the roles of CD4+CD25+ regulatory T (TR) cells in their development. Methods: We performed adoptive transfer experiments to investigate the induction and suppression of colitis using naïve CD4+CD45RBhigh T cells and/or CD4+CD25+ TR cells that were obtained from retinoid-related orphan receptor gamma t (RORγt) gfp/ + or Ly5.1/Ly5.2 congenic mice. Results: We observed 3 types of colitogenic CD4+ Th1 cells (interleukin [IL]-17A−interferon [IFN]-γ+): RORγt– classical Th1 cells that differentiated directly from naïve T cells; RORγt+ Th1-like cells; and RORγt– alternative Th1 cells that were terminally differentiated from RORγt+ cells via Th17 (IL-17A+IFN-γ–), Th17/Th1 (IL-17A+IFN-γ+), or Th1-like (IL-17A–IFN-γ+) cells. In this pathway, CD4+CD25+ TR cells suppress the development of not only classical Th1 cells, but also alternative Th1 cells at the transition of Th17/Th1 into alternative Th1 cells, resulting in accumulation of Th17 and Th17/Th1 cells in mice in which the development of colitis was suppressed. Furthermore, TR cells regulated the established balance of Th17 and Th1 cells under colitic conditions to yield a high ratio of Th17 and Th17/Th1 cells to Th1 cells in noncolitic conditions. Conclusions: Th17 and Th17/Th1 cells become colitogenic alternative Th1 cells via Th17, Th17/Th1, and Th1-like cells, independently of classical Th1 cells. TR cells suppress this pathway, resulting in accumulation of Th17 and Th17/Th1 cells. [Copyright &y& Elsevier]

Summary: Objectives: Diagnosing abdominal tuberculosis (TB) remains a challenge. A recently developed RD-1 gene-based assay for diagnosing tuberculosis infection shows promising results. We evaluated the diagnostic usefulness of this assay compared with conventional tests in patients with suspected abdominal TB in clinical practice. Methods: All patients with suspected abdominal TB were prospectively enrolled in a tertiary hospital during a 1-year period. In addition to the conventional tests for diagnosing TB, the IFN-γ-producing T-cell response to ESAT-6 and CFP-10 by ELISPOT assay using peripheral blood mononuclear cells (PBMC) and peritoneal fluid mononuclear cells (PF-MC) were performed. Results: Forty eight patients with suspected abdominal TB were enrolled. Of these patients, 30 (63%) were classified as abdominal TB including 14 TB peritonitis (12 confirmed+1 probable+1 possible), 6 abdominal TB lymphadenitis (3 confirmed+3 probable), 4 hepatic TB (3 confirmed+1 possible), 2 intestinal TB (1 confirmed+1 probable), 3 renal TB (1 confirmed+2 probable), and 1 pancreatic TB (1 confirmed). Eighteen (38%) were classified as not TB. ELISPOT assay using PBMC was performed on samples from all 48 subjects. The sensitivity and specificity of the PBMC ELISPOT assay were 89% (95% CI, 71–98%) and 78% (95% CI, 52–94%), respectively. In the 11 patients in whom PF-MC ELISPOT assay was performed, it was positive in 5 of 6 patients with TB peritonitis, and negative in all 5 patients with not TB. Conclusions: The ELISPOT assay using PBMC and PF-MC is a useful adjunct to the current tests for diagnosing abdominal TB. [Copyright &y& Elsevier]

Abstract: Human leukocyte antigen (HLA) matching between donor and recipient for all six major histocompatibility antigens will minimize the immune activation of the recipient after solid-organ transplantation. Corticosteroids, the antiproliferative agents azathioprine and mycophenolate, calcineurin inhibitors cyclosporine and tacrolimus, antilymphocyte sera and rapamycin suppress different pathways of immune activation, although they have potential side-effects. Donor antigen-pretreatment of the recipient to induce graft acceptance and tolerance is difficult in renal transplantation, and impracticable for cardiothoracic transplantation. The stages leading to chronic obliterative bronchiolitis after lung transplantation are described. The role of cluster of differentiation-4+ (CD4+) T-cells, antigen-presenting cells and CD8+ T-cells in chronic rejection are also discussed. Different types of antigen are recognized through direct and indirect pathways. [Copyright &y& Elsevier]

Abstract: Graft injury following solid-organ transplantation and leading to rejection is mediated by innate (early and non-specific) and acquired (rapid response to antigen) immunological mechanisms. Hyperacute rejection is rare and minimized by applying a leukocyte crossmatch test at harvest. Acute rejection occurs within days to weeks of transplant. Major histocompatibility complex (MHC) molecules have a role in activating T-cells against foreign antigen which is presented on leukocytes called professional antigen-presenting cells (APCs). Co-stimulatory molecules are also required. The role of cluster of differentiation-4+ (CD4+) T-cells in allorecognition is discussed. CD8+ T-cells probably contribute to graft damage. [Copyright &y& Elsevier]

After activation by unique cytokines, CD4+ naive T cells differentiate into lineages of helper/effector (TH) and regulatory T (Treg) cells that are characterized by distinct developmental pathways and unique biologic functions. The trusted binary system of TH1 and TH2 has been expanded to include the IL-17–producing TH17 cell lineage, which plays a role in immune responses to infectious agents and maintenance of autoimmune diseases. Acting as counterbalance, Treg cells maintain peripheral tolerance and protect the host from autoaggressive lymphocytes. TH1 cells produce IFN-γ and are involved in cell-mediated immunity, TH2 cells produce IL-4 and contribute to humoral immunity, TH17 cells generate IL-17 and play an important role in immune responses to fungi and extracellular pathogens, and forkhead box protein 3–positive (FOXP3+) Treg cells secrete TGF-β and IL-10 and downregulate effector T cells. Autosomal dominant hyper-IgE syndrome, a rare primary immunodeficiency disorder, is caused by hypomorphic heterozygous mutations of signal transducer and activator of transcription 3 (STAT3), preventing TH17 lineage differentiation and increasing susceptibility to Staphylococcus and Candida species infections. Mutations in the FOXP3 gene interfere with Treg cell development and cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Other single-gene defects resulting in reduced Treg cell function include CD25, signal transducer and activator of transcription 5b, autoimmune regulator, and Wiskott-Aldrich syndrome protein. These observations emphasize the importance of functionally distinct T-cell lineages in maintaining a balanced innate and cognate immune system. [Copyright &y& Elsevier]

Background: TH17 cells are of pathologic relevance in autoimmune disorders and presumably also in allergy and asthma. Regulatory T (Treg) cells, in contrast, suppress inflammatory and allergen-driven responses. Despite these disparate functions, both T-cell subsets have been shown to be dependent on TGF-β for their development. Objective: The aim of the study was to analyze the differentiation and function of human TH17 cells in comparison with other TH cell subsets. Methods: Naive human CD4+ T cells were differentiated in vitro, and gene expression was analyzed by means of quantitative real-time PCR, ELISA, and immunofluorescence. The function of TH cell subsets was assessed by monitoring the response of primary bronchial epithelial cells in coculture experiments. Results: In vitro differentiated TH17 cells differ from Treg and other TH cells in their potency to induce IL-6 and IL-1β expression in primary bronchial epithelial cells. TGF-β, IL-1β, IL-6, and IL-23 are necessary during TH17 cell differentiation to acquire these functions, including IL-17 production. In contrast, TGF-β alone is necessary and sufficient to induce the transcription factor RORC2. This transcription factor, previously thought to be specific for TH17 cells, is also expressed in Treg cells, CD25+ cells, cytotoxic T cells, and natural killer T cells. Conclusion: This study demonstrates mechanisms of differentiation to human TH17 cells, a subset that effectively and uniquely modulates the function of primary bronchial epithelial cells. [Copyright &y& Elsevier]

Background: Chronic eosinophilic pneumonia (CEP) with asthma precedes the onset of Churg-Strauss syndrome (CSS) in half of all patients with CSS. It is not known what determines whether patients with CEP after asthma will have CSS. Objective: We examined whether activation of regulatory T cells in patients with CEP inhibits CSS development and is otherwise involved in the mechanism of CSS disease. Methods: In patients with CSS (n = 38), CEP with asthma (n = 20), and general adult asthma (n = 108), we examined the number of CD4+CD25+ T cells in peripheral blood, as well as levels of expression of the cytokines IL-2, IL-5, IL-10, and TGF-β by CD4+CD25+ T cells, CD4+CD25− T cells, or both. Results: At disease onset, patients with CSS, unlike patients with CEP, had significantly fewer CD4+CD25+ T cells than patients with any step of asthma. CD4+CD25+ T cells producing IL-10 were rarely detected in patients with CSS at disease onset or relapse, whereas the numbers of IL-10–producing T cells in patients with CEP were high at disease onset. There were fewer CD4+CD25− T cells producing IL-2 in patients with CSS before treatment than in patients with CEP at disease onset. The proportions of CD4+CD25+ T cells producing IL-10 and CD4+CD25− T cells producing IL-2 in patients with CSS increased at remission. Conclusions: Maintenance of the numbers of regulatory T cells in patients with CEP with asthma might inhibit CSS development through the action of cytokines, such as IL-10 and IL-2, produced by CD4+CD25+ or CD4+CD25− T cells. This might be part of a mechanism that influences progression and prognosis in these diseases. [Copyright &y& Elsevier]

Background: Studies of human asthma and of animal models of allergic inflammation/asthma highlight a crucial role for TH2 cells in the pathogenesis of allergic asthma. Repressor of GATA (ROG) is a POZ (BTB) domain–containing Kruppel-type zinc finger family (or POK family) repressor. A repressive function to GATA3, a master transcription factor for TH2 cell differentiation, is indicated. Objective: The aim of this study was to clarify the regulatory roles of ROG in the pathogenesis of TH2-driven allergic diseases, such as allergic asthma. Methods: We examined allergic airway inflammation and airway hyperresponsiveness (AHR) in 3 different mouse models, which use either ROG-deficient (ROG −/−) mice, ROG transgenic mice, or adoptive transfer of cells. Results: In ROG −/− mice TH2 cell differentiation, TH2 responses, eosinophilic airway inflammation, and AHR were enhanced. In ROG transgenic mice the levels of eosinophilic airway inflammation and AHR were dramatically reduced. Furthermore, adoptive transfer of TH2 cells with increased or decreased levels of ROG expression into the asthmatic mice resulted in reduced or enhanced airway inflammation, respectively. Conclusion: These results indicate that ROG regulates allergic airway inflammation and AHR in a negative manner, and thus ROG might represent another potential therapeutic target for the treatment of asthmatic patients. [Copyright &y& Elsevier]

It is proposed that cell proliferation with reduced individual cell growth (total protein accumulation) is necessary. hut not sufficient, for cell differentiation. These conditions may facilitate transcription and accumulation of histones HI and/or H1° relative to the core histones. This may have a critical role in cell differentiation. [ABSTRACT FROM AUTHOR]

Based on the fact that mycotoxins and the food-borne bacteria coexist in the natural environment and pose a significant health hazard to humans and animals, it is important to investigate the immunosuppressive mechanism of ZEA (zearalenone), DON (deoxynivalenol), and their combination in bacterial infections. In this study, we established a mouse model of mycotoxin low-dose exposure combined with Listeria monocytogenes infection and investigated the effects of ZEA, DON and their combination on Th1-mediated anti-intracellular bacterial infection based on CD4+ T cell activation and differentiation using both in vitro and in vivo analyses. The present study showed that both ZEA and DON aggravated Listeria monocytogenes infection in mice and affected the activation of CD4+ T cells and Th1 differentiation, including the effects on costimulatory molecules CD28 and CD152 and on cross-linking of IL-12 and IL-12R, by inhibiting T cell receptor (TCR) signaling. When compared with ZEA, DON was found to have a greater impact on many related indicators. Surprisingly, the combined effects of ZEA and DON did not appear to enhance toxicity compared to treatment with the individual mycotoxins. Our findings more clearly revealed that exposure to low-dose ZEA and DON caused immunosuppression in the body by mechanisms including inhibition of CD4+ T cells activation and reduction of Th1 cell differentiation, thus exacerbating infection of animals by Listeria monocytogenes. [Display omitted] • ZEA,DON aggravated Listeria monocytogenes infection in mice. • ZEA,DON inhibited the activation of naive CD4+ T cells in vitro and in vivo. • ZEA,DON inhibited the differentiation of naive CD4+ T cells into Th1 subtype. • The key cause of these negative effects of ZEA, DON is reduced TCR signaling. [ABSTRACT FROM AUTHOR]

Summary: Colorectal cancer is the third most common malignant cancer worldwide and molecular mechanisms of cancer metastasis are poorly understood. Researches suggested that the canonical Wnt/β-catenin signaling pathway plays a critical role in development and cancer. β-catenin acts as a component of the Wnt signaling in addition to being an integral component of adherens junctions. The traditional notion that β-catenin dysregulation caused by inactivating mutation of APC cannot completely elucidate the role of β-catenin in invasion and metastasis. Recently, the important roles of SATB1in T-cell development and differentiation and in promotion of breast tumor growth and metastasis were reported. The hypothesis we proposed is that SATB1 may be involved in the development and progression of colorectal cancer in a Wnt/β-catenin signaling-dependent manner. [ABSTRACT FROM AUTHOR]

Thymus, as a primary site of appropriate adaptive immunity formation, is an essential organ in face of a self-tolerance as well as a potential menace from impairment of body integrity. Due to vital selection processes during differentiation and maturation of T lymphocytes, control over cell survival and programmed cell death must be orchestrated in detail. Indeed, thymus is highly sensitive to wide spectrum of stressors that initiate acute structural changes. Hypoxia, one of the most common complications in congenital heart defects (CHDs) patients, provokes stress-induced thymus involution. Disrupted embryolonic development of thymus in association with congenital heart defects, may negatively affect physiological immune mechanisms. We propose that detailed analysis of thymic morphology could critically contribute to unveil the pathophysiology of diseases associated with disrupted adaptive immunity in children with heterogeneous congenital heart diseases. [ABSTRACT FROM AUTHOR]

Summary HIV persists in long-lived infected cells that are not affected by antiretroviral treatment. These HIV reservoirs are mainly located in CD4+ T cells, but their distribution is variable in the different subsets. Susceptibility to HIV-1 increases with CD4+ T cell differentiation. We evaluated whether the metabolic programming that supports the differentiation and function of CD4+ T cells affected their susceptibility to HIV-1. We found that differences in HIV-1 susceptibility between naive and more differentiated subsets were associated with the metabolic activity of the cells. Indeed, HIV-1 selectively infected CD4+ T cells with high oxidative phosphorylation and glycolysis, independent of their activation phenotype. Moreover, partial inhibition of glycolysis (1) impaired HIV-1 infection in vitro in all CD4+ T cell subsets, (2) decreased the viability of preinfected cells, and (3) precluded HIV-1 amplification in cells from HIV-infected individuals. Our results elucidate the link between cell metabolism and HIV-1 infection and identify a vulnerability in tackling HIV reservoirs. Graphical Abstract Highlights • The susceptibility of CD4+ T cell subsets to HIV-1 matches their metabolic activity • HIV-1 selectively infects CD4+ T cells with enhanced glycolysis and OXPHOS • Inhibition of metabolic activities blocks HIV-1 replication • Suboptimal inhibition of glycolysis impairs amplification of HIV-1 reservoirs Targeting HIV reservoirs remains a challenge. Valle-Casuso et al. found that HIV-1 selectively infects highly metabolic CD4+ T cells, independent of their activation phenotype. Inhibition of metabolic pathways blocks the early steps of HIV-1 replication and induces death of infected cells, highlighting a metabolic vulnerability that can be therapeutically exploited. [ABSTRACT FROM AUTHOR]

Summary CD4 T cells are critical for protective immunity against Mycobacterium tuberculosis (Mtb), the cause of tuberculosis (TB). Yet to date, TB vaccine candidates that boost antigen-specific CD4 T cells have conferred little or no protection. Here we examined CD4 T cell responses to two leading TB vaccine antigens, ESAT-6 and Ag85B, in Mtb-infected mice and in vaccinated humans with and without underlying Mtb infection. In both species, Mtb infection drove ESAT-6-specific T cells to be more differentiated than Ag85B-specific T cells. The ability of each T cell population to control Mtb in the lungs of mice was restricted for opposite reasons: Ag85B-specific T cells were limited by reduced antigen expression during persistent infection, whereas ESAT-6-specific T cells became functionally exhausted due to chronic antigenic stimulation. Our findings suggest that different vaccination strategies will be required to optimize protection mediated by T cells recognizing antigens expressed at distinct stages of Mtb infection. [ABSTRACT FROM AUTHOR]

In this issue of Cell Stem Cell, Zheng et al. (2011) report that HSCs expressing PD-Li display enhanced engraftment in irradiated allogeneic recipients. Independently in Nature, Fujisaki et al. (2011) observe allogeneic HSCs persisting in proximity to regulatory T cells in nonirradiated recipients, further connecting HSCs and immune tolerance. [ABSTRACT FROM AUTHOR]

Background: T lymphocytes are prevalent in sinus mucosa and are implicated in chronic rhinosinusitis (CRS) pathogenesis. However, the major T-cell subpopulations, helper (CD4+) and cytotoxic (CD8+), have not been adequately examined in CRS. This study was designed to characterize human sinus mucosa and peripheral blood (PB) CD4+ and CD8+ T cells and their level of differentiation in CRS with nasal polyps (NPs), CRS without NPs, and control patients. Methods: A prospective study was performed. Percentages of CD4+ and CD8+ T cells and their levels of differentiation were analyzed in sinus mucosa and PB by flow cytometry. Cell populations were defined as naive, central memory, effector memory, and effector T cells using cell surface markers CD45RA, CD62L, and CD27. The influence of coexisting allergy, sinus eosinophilic mucus (EM), and culture results were examined. Results: In all patients, sinus mucosa had a lower percentage of CD4+ and a higher percentage of CD8+ T cells compared with PB. However, CRS with NPs (n = 86) had a significantly higher percentage of mucosal CD8+ T cells compared with CRS without NPs (n = 40) in control (n = 13) patients (p < 0.0001). Effector memory T cells were increased in sinuses compared with PB in all patients; however, the percentage of effector memory CD8+ T cells was greatest in CRS with NP mucosa (p = 0.002). Surprisingly coexisting allergy or culture results did not influence the mucosal T-cell phenotype. CRS with NP patients with sinus EM had a significantly higher percentage of mucosal CD8+ T cells. Conclusion: Sinus mucosa in CRS with NPs is characterized by a significant enrichment of CD8+ T cells and a relative deficiency of CD4+ T cells. The majority of NP CD8+ T cells had a terminally differentiated, mature, effector memory phenotype, which raises the question, whether these cells are pathogenic or appear as a consequence of inflammation, independent of the presence of allergy or positive microbial culture. [ABSTRACT FROM AUTHOR]

Background: IL-17 is an important cytokine signature of the TH differentiation pathway TH17. This T-cell subset is crucial in mediating autoimmune disease or antimicrobial immunity in animal models, but its presence and role in human disease remain to be completely characterized. Objective: We set out to determine the frequency of TH17 cells in patients with cystic fibrosis (CF), a disease in which there is recurrent infection with known pathogens. Methods: Explanted lungs from patients undergoing transplantation or organ donors (CF samples = 18; non-CF, nonbronchiectatic samples = 10) were collected. Hilar nodes and parenchymal lung tissue were processed and examined for TH17 signature by using immunofluorescence and quantitative real-time PCR. T cells were isolated and stimulated with antigens from Pseudomonas aeruginosa and Aspergillus species. Cytokine profiles and staining with flow cytometry were used to assess the reactivity of these cells to antigen stimulation. Results: We found a strong IL-17 phenotype in patients with CF compared with that seen in control subjects without CF. Within this tissue, we found pathogenic antigen–responsive CD4+IL-17+ cells. There were double-positive IL-17+IL-22+ cells [TH17(22)], and the IL-22+ population had a higher proportion of memory characteristics. Antigen-specific TH17 responses were stronger in the draining lymph nodes compared with those seen in matched parenchymal lungs. Conclusion: Inducible proliferation of TH17(22) with memory cell characteristics is seen in the lungs of patients with CF. The function of these individual subpopulations will require further study regarding their development. T cells are likely not the exclusive producers of IL-17 and IL-22, and this will require further characterization. [Copyright &y& Elsevier]

Background: Asthma is defined as a chronic inflammatory disease of the airways; however, the underlying physiologic and immunologic processes are not fully understood. Objective: The aim of this study was to determine whether TH9 cells develop in vivo in a model of chronic airway hyperreactivity (AHR) and what factors control this development. Method: We have developed a novel chronic allergen exposure model using the clinically relevant antigen Aspergillus fumigatus to determine the time kinetics of TH9 development in vivo. Results: TH9 cells were detectable in the lungs after chronic allergen exposure. The number of TH9 cells directly correlated with the severity of AHR, and anti–IL-9 treatment decreased airway inflammation. Moreover, we have identified programmed cell death ligand (PD-L) 2 as a negative regulator of TH9 cell differentiation. Lack of PD-L2 was associated with significantly increased TGF-β and IL-1α levels in the lungs, enhanced pulmonary TH9 differentiation, and higher morbidity in the sensitized mice. Conclusion: Our findings suggest that PD-L2 plays a pivotal role in the regulation of TH9 cell development in chronic AHR, providing novel strategies for modulating adaptive immunity during chronic allergic responses. [Copyright &y& Elsevier]

Background: IL-4 and signal transducer and activator of transcription 6 (STAT6) play an important role in the progression of allergic airway disease (AAD) or asthma. IL-4 and STAT6 mediate TH2 responses in T cells and immunoglobulin class-switching to IgE in B cells. Both TH2 responses and IgE promote the asthmatic condition. We have previously demonstrated that poly (ADP-ribose) polymerase (PARP) 14, a member of the PARP family of proteins, regulates the transcription function of STAT6. However, the role of PARP-14 in AAD is not known. Objective: Here we investigate the role of PARP-14 and the enzyme activity associated with it in a model of AAD dependent on airway hyperresponsiveness and lung inflammation. We also elucidate the mechanism by which PARP-14 regulates AAD. Methods: The role of PARP-14 and its enzyme activity in AAD and TH2 differentiation were examined by using a murine model of AAD and in vitro TH cell differentiation. Results: PARP-14–deficient animals show reduced lung pathology and IgE levels when compared with control animals. Treating mice with a pharmacologic inhibitor for PARP activity reduced the severity of airway hyperresponsiveness and lung inflammation. Mechanistically, our data indicate that PARP-14 and its enzyme activity aid in the differentiation of T cells toward a TH2 phenotype by regulating the binding of STAT6 to the Gata3 promoter. Conclusion: PARP-14 and the catalytic activity associated with it promote TH2 differentiation and AAD in a murine model, and targeting PARP-14 might be a potential new therapy for allergic asthma. [Copyright &y& Elsevier]