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| Open AccessAsh1l and lnc-Smad3 coordinate Smad3 locus accessibility to modulate iTreg polarization and T cell autoimmunity
The transcriptional program activated by Smad2/Smad3 is critical for the induction and function of regulatory T cells. Here the authors show that the expression of Smad3 is modulated by the complementary functions of a methyltransferase Ash1l and an lncRNA lnc-Smad3 on the promoter accessibility of the mouseSmad3locus.
- Meng Xia
- , Juan Liu
- & Xuetao Cao
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Article
| Open AccessHSPs drive dichotomous T-cell immune responses via DNA methylome remodelling in antigen presenting cells
Low dose of the heat shock protein gp96 can drive effector T-cell responses, yet high-dose gp96 is immunosuppressive by expanding the regulatory T-cell population. Here the authors explain this dichotomy by showing that high-dose gp96 can drive plasmacytoid dendritic cell expression of neuropilin-1, thus functionally supporting interaction with Treg cells.
- Lauren B. Kinner-Bibeau
- , Abigail L. Sedlacek
- & Robert J. Binder
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Article
| Open AccessJunB is essential for IL-23-dependent pathogenicity of Th17 cells
T helper 17 (Th17) cells can be pathogenic, but what controls this phenotype is unclear. Here the authors show that the transcription factor JunB promotes proinflammatory Th17 function by regulating the transcription of multiple Th17-related genes.
- Zafrul Hasan
- , Shin-ichi Koizumi
- & Hiroki Ishikawa
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Article
| Open AccessThe long noncoding RNA lnc-EGFR stimulates T-regulatory cells differentiation thus promoting hepatocellular carcinoma immune evasion
The role of long noncoding RNAs in regulating T-cell differentiation within the tumour microenvironment is unclear. Here the authors identify a lncRNA that, through direct interactions with EGFR, promotes T-regulatory cell differentiation within the microenvironment of hepatocellular carcinoma, thus promoting tumour growth via immune suppression.
- Runqiu Jiang
- , Junwei Tang
- & Beicheng Sun
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Article
| Open AccessReciprocal regulation of the Il9 locus by counteracting activities of transcription factors IRF1 and IRF4
IFN-γ signalling inhibits production of IL-9, the defining cytokine of the Th9 cell subset. Here the authors show that IFN-γ does this by driving IRF1 to compete with IRF4 forIl9promoter binding and skewing these cells towards a Th1 phenotype, an effect that reduces asthmatic inflammation in mice.
- Lucia Campos Carrascosa
- , Matthias Klein
- & Magdalena Huber
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Article
| Open AccessElevated levels of Bcl-3 inhibits Treg development and function resulting in spontaneous colitis
Bcl-3 modulates effector T cell responses, but the importance of Bcl-3 in T regulatory cells and autoimmunity is not clear. Here the authors show that Bcl-3 impedes NF-κB DNA binding to alter T regulatory cell development and function, causing spontaneous colitis in mice.
- Sonja Reißig
- , Yilang Tang
- & Nadine Hövelmeyer
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| Open AccessThe role of alternative polyadenylation in the antiviral innate immune response
RNA processing by alternative polyadenylation (APA) can result in 3′UTR diversity and regulation of target RNA function. Here the authors survey APA in viral infection of macrophages.
- Xin Jia
- , Shaochun Yuan
- & Anlong Xu
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Article
| Open AccessArmc5 deletion causes developmental defects and compromises T-cell immune responses
Mutations in ARMC5 are associated with risk of primary macronodular adrenal gland hyperplasia. Here the authors show that mice lacking Armc5 have adrenal gland hyperplasia and defective T-cell proliferation, differentiation, survival andin vivoT-cell-mediated immune responses.
- Yan Hu
- , Linjiang Lao
- & Jiangping Wu
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Article
| Open AccessK48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression
The E3 ligase Mule has been previously reported to be essential for B cell development and function by modulating p53 ubiquitination and degradation. Here Haoet al. identify KLF4 as a novel ubiquitination target of Mule and show it controls T cell proliferation and autoimmunity.
- Zhenyue Hao
- , Yi Sheng
- & Tak W. Mak
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Article
| Open AccessMicroRNA-155 influences B-cell function through PU.1 in rheumatoid arthritis
MiR-155 is thought to inhibit PU.1 and thereby drive antigen-induced B-cell maturation. Here the authors show that patients with rheumatoid arthritis have high B-cell miR-155 expression and that an antagomir can rescue PU.1 expression, suggesting potential therapeutic avenues to treat rheumatoid arthritis.
- Stefano Alivernini
- , Mariola Kurowska-Stolarska
- & Gianfranco Ferraccioli
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| Open AccessmiR-424(322) reverses chemoresistance via T-cell immune response activation by blocking the PD-L1 immune checkpoint
Resistance to chemotherapy occurs in many ovarian cancer cases. Here, the authors show that mir-424(322) expression restores the sensitivity of ovarian cancer cells to chemotherapy by blocking the PD-L1 immune checkpoint, and find that combining immunotherapy and chemotherapy has a synergistic effect.
- Shaohua Xu
- , Zhen Tao
- & Ke Chen
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| Open AccessIntronic regulation of Aire expression by Jmjd6 for self-tolerance induction in the thymus
Jmjd6 is a dioxygenase that catalyses lysyl hydroxylation of splicing regulatory proteins. Here the authors show that Jmjd6 directs splicing of a central tolerance regulator Aire in medullary thymic epithelial cells, and that Jmjd6 deficiency leads to loss of Aire and multi-organ autoimmunity in mice.
- Toyoshi Yanagihara
- , Fumiyuki Sanematsu
- & Fukui Yoshinori
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Article
| Open AccessMesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs
The physiological role of crosstalk between mesenchymal stem cells (MSC) and macrophages is unclear. Here, Phinney et al. show that MSCs transfer mitochondria to macrophages under oxidative stress, and desensitize macrophages to mitochondria by using microvesicles to repress Toll receptor signalling.
- Donald G. Phinney
- , Michelangelo Di Giuseppe
- & Luis A. Ortiz
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| Open AccessMicroRNA-31 negatively regulates peripherally derived regulatory T-cell generation by repressing retinoic acid-inducible protein 3
Peripherally derived regulatory T cells (pTreg) exhibit immunosuppressive capacity. Here, the authors show that microRNA-31 acting through inhibiting its direct target Gprc5a negatively regulates pTreggeneration and promotes the development of experimental autoimmune encephalomyelitis.
- Lingyun Zhang
- , Fang Ke
- & Honglin Wang
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| Open AccessGenomic modulators of gene expression in human neutrophils
Neutrophils are the most abundant subset of leukocyte and central to many diseases. Here by mapping expression quantitative trait loci (eQTL) in the context of epigenetic marks in neutrophils and monocytes of 101 healthy European adults, the authors provide a resource to advance understanding of immune-related trait-associated genetic variants.
- Vivek Naranbhai
- , Benjamin P. Fairfax
- & Julian C. Knight
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Article
| Open AccessNF-κB-induced microRNA-31 promotes epidermal hyperplasia by repressing protein phosphatase 6 in psoriasis
Psoriasis is accompanied by NF-κB activation and hyperplasia. Here the authors show that NF-κB transcriptionally activates miR-31, which downregulates a negative cell cycle regulator protein phosphatase 6, and that this is critical for NF-κB to drive keratinocyte hyperproliferation.
- Sha Yan
- , Zhenyao Xu
- & Honglin Wang
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| Open AccessMonozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naïve-to-memory B-cell transition
Epigenetic changes are thought to contribute to the aetiology of common variable immunodeficiency (CVID), a disease characterized by loss of B-cell function. Here, by comparing DNA methylation profile in B cells from monozygotic twins discordant for CVID, the authors show a gain of DNA methylation in CVID B cells.
- Virginia C. Rodríguez-Cortez
- , Lucia del Pino-Molina
- & Esteban Ballestar
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MiR-125a targets effector programs to stabilize Treg-mediated immune homeostasis
Compromised function of regulatory T cells can lead to autoimmunity. Here the authors show that miR-125a stabilizes regulatory T-cell function and is downregulated in lupus and Crohn’s disease, as well as autoimmune mouse models, and that a chemical miR-125a analogue reverts established disease in a mouse model of multiple sclerosis.
- Wen Pan
- , Shu Zhu
- & Nan Shen
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ERK phosphorylation and miR-181a expression modulate activation of human memory TH17 cells
How the magnitude of the response is regulated in different T-cell memory subsets remains poorly understood. Here the authors show that miR-181 lowers the threshold of Th17 memory activation via sustained Erk phosphorylation, while Erk-dependent induction of ID3 limits Th17 activity at later time.
- Federico Mele
- , Camilla Basso
- & Silvia Monticelli
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| Open AccessMicroRNA-146a regulates ICOS–ICOSL signalling to limit accumulation of T follicular helper cells and germinal centres
Maturation of antibody-producing B cells in germinal centers is orchestrated by T follicular helper cells. Here Pratama et al. show that miR-146a negatively regulates T follicular helper cells by targeting ICOS-ICOS ligand signaling in germinal centers.
- Alvin Pratama
- , Monika Srivastava
- & Carola G. Vinuesa
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Critical role of histone demethylase Jmjd3 in the regulation of CD4+ T-cell differentiation
The histone demethylase Jmjd3 is involved in many biological processes. Here, the authors generate T cell-specific Jmjd3-deficient mice and show that Jmjd3 has a role in T-cell function and in the differentiation and interconversion of T-cell subsets in the intestine.
- Qingtian Li
- , Jia Zou
- & Rong-Fu Wang
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High-throughput detection of miRNAs and gene-specific mRNA at the single-cell level by flow cytometry
Flow cytometry allows high-throughput analysis of multiple proteins in individual cells, but relies on availability of antibodies. Here Porichis et al.report a sensitive method for multi-parameter flow cytometric and imaging detection of proteins together with mRNA or miRNA at the single-cell level.
- Filippos Porichis
- , Meghan G. Hart
- & Daniel E. Kaufmann
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Functional high-throughput screening identifies the miR-15 microRNA family as cellular restriction factors for Salmonella infection
The functional role of microRNAs in the interplay between bacterial pathogens and host cells is not well defined. Here, using an image-based high-throughput screening approach, the authors identify a family of microRNAs that regulates Salmonellainfection and characterize their mechanism of action.
- Claire Maudet
- , Miguel Mano
- & Ana Eulalio
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Article
| Open AccessMiR-9 promotes microglial activation by targeting MCPIP1
MicroRNA-9 (miR-9) is known for its function in neurogenesis and axonal extension but its role in the immune responses in the brain is not fully understood. Here, Yao et al. show that miR-9 is involved in the activation of microglia, cells of the myeloid origin that are involved in immune surveillance in the brain.
- Honghong Yao
- , Rong Ma
- & Shilpa Buch
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RNA-binding proteins regulate the expression of the immune activating ligand MICB
The expression of stress-induced ligands and their recognition by the NKG2D-activating receptor is important for the elimination of virally infected and cancerous cells by cytotoxic lymphocytes. Here, the authors provide insights into the post-transcriptional mechanism regulating the expression of the NKG2D ligand, MICB.
- Daphna Nachmani
- , Tony Gutschner
- & Ofer Mandelboim
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TNF-α blockade induces IL-10 expression in human CD4+ T cells
Th17 cells are involved in the pathogenesis of several inflammatory diseases. Here, the authors show that inhibitors of the pro-inflammatory cytokine TNF, used in patients undergoing anti-inflammatory treatment, might mediate the acquisition of anti-inflammatory properties by these typically pathogenic cells.
- Hayley G. Evans
- , Urmas Roostalu
- & Leonie S. Taams
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A genome-wide regulatory network identifies key transcription factors for memory CD8+ T-cell development
The establishment of a memory phenotype in T cells requires profound changes in their transcriptional profile, but many components of this profile are still not known. Here, the authors perform a systematic study to identify key transcription factors associated with memory CD8+T-cell development.
- Guangan Hu
- & Jianzhu Chen
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| Open AccessInhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CYLD
Phosphodiesterase 4 inhibitors are under development as anti-inflammatory drugs, however, their mechanisms of action remain poorly understood. Komatsu et al. show that Rolipram, a specific inhibitor of PDE4, reduces inflammation in a model of middle ear infection by upregulating the deubiquitinase CYLD.
- Kensei Komatsu
- , Ji-Yun Lee
- & Jian-Dong Li
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| Open AccessT-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements
T-bet and GATA3 regulate differentiation of T cells into Th1 or Th2 cell fates, but little is known about their functional interaction outside of the IFNγ and Il4 /Il5/Il13 loci. Kanhere et al. map these factors across the genome in human T cells, revealing unappreciated breadth of function and interplay between them.
- Aditi Kanhere
- , Arnulf Hertweck
- & Richard G. Jenner
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| Open AccessUnidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells
Exosomes released from cells can transfer RNA to recipient cells. In this study, the authors demonstrate that microRNAs in exosomes from T cells can be transferred to antigen-presenting cells during immune synapsis, and that this can alter gene expression, suggesting a new form of cellular communication.
- María Mittelbrunn
- , Cristina Gutiérrez-Vázquez
- & Francisco Sánchez-Madrid