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Fucose-specific DC-SIGN signalling directs T helper cell type-2 responses via IKKε- and CYLD-dependent Bcl3 activation
C-type lectin receptor DC-SIGN, expressed on dendritic cells, shapes cytokine production in response to pathogens. Here, the authors show how recognition of fucose-expressing pathogens, Schistosoma mansoni and Helicobacter pylori, by this receptor directs T helper cell type-2 responses via activation of the NF-κB family member Bcl3.
- Sonja I. Gringhuis
- , Tanja M. Kaptein
- & Teunis B. H. Geijtenbeek
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Combinatorial flexibility of cytokine function during human T helper cell differentiation
Type I interferons (IFNs) have pleiotropic functions in the immune system. Here, the authors evaluate transcriptional signatures generated by type I IFN under distinct T helper cell differentiation programmes and show that, depending on the cytokine context, IFN-α differentially modulates the global cytokine profile of each T helper subset.
- Maxime Touzot
- , Maximilien Grandclaudon
- & Vassili Soumelis
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Epidermal cells help coordinate leukocyte migration during inflammation through fatty acid-fuelled matrix metalloproteinase production
Metabolic regulation is emerging as an important component of immune response control and may be implicated in the development of inflammatory diseases. Here, the authors show that inflammatory leukocyte recruitment depends on mitochondrial metabolism in epidermal cells in zebrafish.
- Christopher J. Hall
- , Rachel H. Boyle
- & Philip S. Crosier
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| Open AccessPathogenic potential of interferon αβ in acute influenza infection
Interferon αβ(IFNαβ) is known as a potent anti-viral factor, yet its role in influenza infection remains controversial. Here, the authors show that the IFNαβ response is a critical host factor, which, when excessive, causes strong inflammation and severe disease in a mouse model of acute influenza infection.
- Sophia Davidson
- , Stefania Crotta
- & Andreas Wack
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The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages
The ketone body β-hydroxybutyrate is produced in the liver in response to a ketogenic diet. Here, Rahman et al. show that β-hydroxybutyrate mediates the neuroprotective effect of a ketogenic diet by activating the HCA2receptor on a neuroprotective subset of macrophages.
- Mahbubur Rahman
- , Sajjad Muhammad
- & Markus Schwaninger
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Emergent properties of the interferon-signalling network may underlie the success of hepatitis C treatment
The standard treatment for hepatitis C virus (HCV) infection, combining interferon (IFN) α and ribavirin, fails in a number of patients. Here, the authors use a mathematical model of the IFN signalling network in the presence of HCV to explain the success or failure of hepatitis C treatment.
- Pranesh Padmanabhan
- , Urtzi Garaigorta
- & Narendra M. Dixit
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Parallel T-cell cloning and deep sequencing of human MAIT cells reveal stable oligoclonal TCRβ repertoire
Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells, abundant in mucosal tissues, blood and liver. Here, using T-cell cloning and deep sequencing, Lepore et al. analyse the T-cell receptorβ repertoire of MAIT cells and further characterize function and tissue distribution of two semi-invariant subsets of these cells.
- Marco Lepore
- , Artem Kalinichenko
- & Lucia Mori
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Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance
Mice lacking Toll-like receptor 4 (Tlr4) do not develop diet-induced insulin resistance. Here Jia et al.create two tissue-specific Tlr4 knockouts to demonstrate that hepatic Tlr4, but not Tlr4 expressed in myeloid cells, is driving obesity-induced inflammation and insulin resistance.
- Lin Jia
- , Claudia R. Vianna
- & Joel K. Elmquist
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| Open AccessA high-coverage shRNA screen identifies TMEM129 as an E3 ligase involved in ER-associated protein degradation
The human cytomegalovirus protein US11 downregulates host immune responses by redirecting HLA class I molecules for endoplasmic reticulum-associated protein degradation. Using a high-coverage genome-wide shRNA screen, the authors identify TMEM129 as an E3 ubiquitin ligase essential for this process.
- Michael L. van de Weijer
- , Michael C. Bassik
- & Robert Jan Lebbink
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An ITAM-Syk-CARD9 signalling axis triggers contact hypersensitivity by stimulating IL-1 production in dendritic cells
Contact hypersensitivity is caused by the reaction of T cells to various chemical contact allergens. Here, the authors unveil the signalling pathway induced in dendritic cells in response to contact allergens, which is required for the stimulation of T-cell sensitization in contact hypersensitivity.
- Shinsuke Yasukawa
- , Yoshiyuki Miyazaki
- & Hiromitsu Hara
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IL-27 and IL-12 oppose pro-inflammatory IL-23 in CD4+ T cells by inducing Blimp1
Autoimmune diseases are regulated by the balance between pro- and anti-inflammatory cytokines. Here, the authors show that the transcriptional regulator Blimp1 is induced in inflammatory T helper cells by the cytokines IL-27 and IL-12 to counteract pro-inflammatory IL-23 and promote resolution of tissue inflammation.
- Christina Heinemann
- , Sylvia Heink
- & Thomas Korn
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IL-21 induces IL-22 production in CD4+ T cells
The cytokine interleukin-22 maintains the integrity of the colonic epithelium during inflammation. Here, the authors show that IL-21 regulates the production of IL-22 in T cells and this mechanism plays a protective role in a mouse model of colitis.
- Ada Yeste
- , Ivan D. Mascanfroni
- & Francisco J Quintana
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Annexin A8 controls leukocyte recruitment to activated endothelial cells via cell surface delivery of CD63
The leukocyte receptor P-selectin translocates from Weibel-Palade bodies to the plasma membrane of activated endothelial cells, and is stabilized by CD63. Pöter et al. show that annexin A8 is required for P-selectin-mediated adhesion by regulating the supply of CD63 to the Weibel-Palade bodies.
- Michaela Poeter
- , Ines Brandherm
- & Ursula Rescher
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Oncogenic Ras induces inflammatory cytokine production by upregulating the squamous cell carcinoma antigens SerpinB3/B4
The Ras oncogene has many different roles in cancer including the production of cytokines that can influence the tumour microenvironment. Here, Catanzaro et al.demonstrate that Ras can modulate the expression of SerpinB3/B4, which leads to increased cytokine production and tumour growth.
- Joseph M. Catanzaro
- , Namratha Sheshadri
- & Wei-Xing Zong
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MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration
MHC-I is expressed in neurons where it is implicated in synaptic plasticity and neuron regeneration. Here, Cebrián et al. report an increase in MHC-I expression in brain neurons from Parkinson’s disease patients, which is triggered by microglial activation and circulating dopamine.
- Carolina Cebrián
- , Fabio A. Zucca
- & David Sulzer
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MicroRNA-302b augments host defense to bacteria by regulating inflammatory responses via feedback to TLR/IRAK4 circuits
Bacterial infection stimulates a powerful inflammatory response that must be regulated to prevent tissue damage. Zhou et al.identify microRNA-302b as a feedback suppressor of inflammatory signalling that alleviates lung injury following Pseudomonas infection by targeting the NF-κB activator IRAK4.
- Xikun Zhou
- , Xuefeng Li
- & Min Wu
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Nucleic acid sensing by T cells initiates Th2 cell differentiation
Nucleic acids modulate T cell responses; however, the physiological significance of this property remains unclear. Here, the authors show that self-DNA complexes with antimicrobial peptides or histones, which mediates T cell costimulation to induce Th2 cell differentiation.
- Takayuki Imanishi
- , Chitose Ishihara
- & Takashi Saito
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Receptor mimicry by antibody F045–092 facilitates universal binding to the H3 subtype of influenza virus
Influenza A H3 viruses circulate in humans and bind host cells using the haemagglutinin (HA) glycoprotein. Here, Lee et al.perform a structural analysis of antibody F045–092 with broadly neutralizing activity against the H3 subtype and reveal its interaction with the HA receptor binding site.
- Peter S. Lee
- , Nobuko Ohshima
- & Ian A. Wilson
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Generation of colonic IgA-secreting cells in the caecal patch
Gut-associated Peyer’s patches are lymphoid tissues that generate IgA-secreting cells, however less is known about related caecal patches. Here, Masahata et al.show that caecal patches produce IgA-positive B cells that migrate to the intestines to maintain faecal microbiota homeostasis.
- Kazunori Masahata
- , Eiji Umemoto
- & Kiyoshi Takeda
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The phosphatase JKAP/DUSP22 inhibits T-cell receptor signalling and autoimmunity by inactivating Lck
JNK pathway-associated phosphatase (JKAP) is a dual-specificity phosphatase known to regulate substrates in several signalling cascades. Here, Li et al. demonstrate that JKAP has a key role in negative regulation of proximal T-cell receptor signalling and suppression of T-cell-mediated autoimmunity.
- Ju-Pi Li
- , Chia-Yu Yang
- & Tse-Hua Tan
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| Open AccessImpact of genomic polymorphisms on the repertoire of human MHC class I-associated peptides
Mass spectrometry (MS) has furthered our understanding of MHC class I-associated peptides (MIPs), but the technique is inadequate for studying MIP-associated polymorphisms. Here, the authors combine high-throughput MS with exome and transcriptome sequencing to identify polymorphic MIPs from two female siblings.
- Diana Paola Granados
- , Dev Sriranganadane
- & Claude Perreault
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Bhlhe40 controls cytokine production by T cells and is essential for pathogenicity in autoimmune neuroinflammation
T cells that mediate neuroinflammation in EAE, a mouse model of multiple sclerosis, act through their production of cytokines. Here, the authors show that the transcription factor Bhlhe40 regulates the expression of GM-CSF and IL-10 by autoreactive T cells and is crucial for EAE induction.
- Chih-Chung Lin
- , Tara R. Bradstreet
- & Brian T. Edelson
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| Open AccessThe Menin–Bach2 axis is critical for regulating CD4 T-cell senescence and cytokine homeostasis
Immunosenescence particularly affects the T-cell compartment and is involved in the age-related decline of immune functions. Here, the authors show that the absence of the tumour suppressor Menin results in premature senescence of CD4 T cells.
- Makoto Kuwahara
- , Junpei Suzuki
- & Masakatsu Yamashita
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| Open AccessEpigenetic plasticity of Cd8a locus during CD8+ T-cell development and effector differentiation and reprogramming
CD8 expression levels on peripheral CD8+ T cells are regulated during development and effector differentiation. Here, the authors show that methylation patterns at the Cd8a locus, whose product is essential for surface CD8 expression, can change during T-cell development, activation, cytokine polarization and reprogramming.
- Kim L. Harland
- , E. Bridie Day
- & Anne Kelso
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FoxP3+ regulatory T cells promote influenza-specific Tfh responses by controlling IL-2 availability
Regulatory T cells (Tregs) are mainly known to suppress effector T cell and B-cell responses. Here, the authors demonstrate that Tregs are able to promote T follicular helper and germinal centre B-cell responses to influenza by sequestering IL-2, the negative regulator of T follicular helper cell differentiation.
- Beatriz León
- , John E. Bradley
- & André Ballesteros-Tato
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Microtubule acetylation amplifies p38 kinase signalling and anti-inflammatory IL-10 production
α-tubulin acetylation is an evolutionarily conserved modification but despite its prevalence, the physiological function of this process remains poorly understood. Here, the authors show that α-tubulin acetylation regulates p38 kinase signalling and expression of the anti-inflammatory cytokine IL-10 in macrophages.
- Bin Wang
- , Yan-Hua Rao
- & Tso-Pang Yao
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| Open AccessCell-surface localization of Pellino antagonizes Toll-mediated innate immune signalling by controlling MyD88 turnover in Drosophila
Toll signalling activates the innate immune response; however, it remains unclear how this pathway is suppressed to avoid excessive inflammatory responses. Here, the authors report that Pellino, a RING domain-containing ubiquitin E3 ligase, is a negative regulator of Toll signalling in Drosophila.
- Shanming Ji
- , Ming Sun
- & Qinmiao Sun
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| Open AccessSelf-recognition of the endothelium enables regulatory T-cell trafficking and defines the kinetics of immune regulation
Regulatory T cells (Tregs) are important for the maintenance of self-tolerance and this requires their trafficking to the lymph nodes and target tissues. Here, the authors show that the recognition of self-antigens expressed by endothelial cells in target tissue is instrumental for efficient Treg recruitment in vivo.
- Hongmei Fu
- , Madhav Kishore
- & Federica M. Marelli-Berg
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PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model
PI 3-kinase is a major regulator of inflammatory responses. In this study, the authors show that inhibition of the delta isoform of PI 3-kinase attenuates the release of tumour necrosis factor from microglia as well as the signs and symptoms associated with cerebral stroke in an in vivomouse model.
- Pei Ching Low
- , Silvia Manzanero
- & Frédéric A. Meunier
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| Open AccessMHC-dependent inhibition of uterine NK cells impedes fetal growth and decidual vascular remodelling
NK cells are involved in remodelling of the uterine vasculature during pregnancy and the extent of this process is influenced by the combination of maternal NK cell receptors and MHC-I of the fetus. Here, the authors provide further insights into how the presence of MHC-I from each parent differentially affects NK cell function.
- Jens Kieckbusch
- , Louise M. Gaynor
- & Francesco Colucci
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Inhibition of miR-146a prevents enterovirus-induced death by restoring the production of type I interferon
Enterovirus 71 (EV71) is one of the causative agents of hand-food-mouth disease and to date, effective vaccines or antivirals against the disease have not been developed. Here, the authors show that blocking miR-146a upregulation induced upon EV71 infection can have a positive effect on the resolution of infection.
- Bing-Ching Ho
- , I-Shing Yu
- & Sung-Liang Yu
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Fragile X mental retardation protein stimulates ribonucleoprotein assembly of influenza A virus
To successfully replicate and propagate, viruses hijack different components of the host cell machinery. Here, Zhou et al.identify the RNA-binding protein Fragile X mental retardation protein as a host factor involved in influenza A virus replication in host cells.
- Zhuo Zhou
- , Mengmeng Cao
- & Tao Deng
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| Open AccessActivation of the NLRP1b inflammasome independently of ASC-mediated caspase-1 autoproteolysis and speck formation
The NLRP1b inflammasome activation may lead to pyroptosis and secretion of the inflammatory cytokines IL-1ß and IL-18 but the mechanisms behind these processes are not fully understood. Here, the authors show that they can occur independently of the inflammasome adaptor ASC and without caspase-1 autoprocessing.
- Nina Van Opdenbosch
- , Prajwal Gurung
- & Mohamed Lamkanfi
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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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p85α recruitment by the CD300f phosphatidylserine receptor mediates apoptotic cell clearance required for autoimmunity suppression
Apoptotic cell clearance is important for the maintenance of immune homeostasis. Here, Tian et al. reveal how a phosphatidylserine (PS) receptor participates in the clearance of apoptotic cells, and show that loss of the receptor can lead to autoimmunity.
- Linjie Tian
- , Seung-Chul Choi
- & John E. Coligan
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Two potential therapeutic antibodies bind to a peptide segment of membrane-bound IgE in different conformations
Two antibodies targeting the CεmX domain of membrane-bound IgE on human B lymphocytes are being developed to treat allergy. Here, the authors map the antigenic epitopes of the two antibodies and show that they bind to different conformations of the same peptide region.
- Hsing-Mao Chu
- , Jon Wright
- & Carmay Lim
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| Open AccessAcquisition of innate-like microbial reactivity in mucosal tissues during human fetal MAIT-cell development
Mucosa-associated invariant T (MAIT) cells are a recently described subset of unconventional, innate-like T cells and their development is not well understood. Here, the authors analyse MAIT cells in fetal human tissues and show that, unlike in mice, the commensal microflora is not necessary for their maturation in humans.
- Edwin Leeansyah
- , Liyen Loh
- & Johan K. Sandberg
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PTPN2 attenuates T-cell lymphopenia-induced proliferation
Single nucleotide polymorphisms in the gene encoding the protein phosphatase PTPN2 are associated with autoimmunity in humans. Here, Wiede et al. show that PTPN2 suppresses the proliferative capacity of T cells in lymphopenia and prevents the development of autoimmunity resulting from overt homoeostatic proliferation.
- Florian Wiede
- , Nicole L. La Gruta
- & Tony Tiganis
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MafB promotes atherosclerosis by inhibiting foam-cell apoptosis
In the early stages of atherosclerosis, macrophages in the vessel wall convert into foam cells, which promote the rise of atherosclerotic plaques. Here Hamada et al. show that the macrophage transcription factor MafB inhibits foam-cell apoptosis, and that its absence promotes atherosclerosis development in mice.
- Michito Hamada
- , Megumi Nakamura
- & Satoru Takahashi
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Article
| Open AccessTRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins
Gram-negative bacterial infections can often cause inflammation and pain. Meseguer et al. show that the inflammation and pain result from the direct activation of nociceptor TRPA1 channels by lipopolysaccharide, a major component of the outer membrane of Gram-negative bacteria.
- Victor Meseguer
- , Yeranddy A. Alpizar
- & Félix Viana
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Article
| Open AccessIntegrin CD11b positively regulates TLR4-induced signalling pathways in dendritic cells but not in macrophages
The signalling pathways that confer differences in the responses of dendritic cells and macrophages to LPS remain poorly understood. Here, Ling et al.report that the integrin C11b is required for LPS-induced TLR4 trafficking and signalling in dendritic cells but not in macrophages.
- Guang Sheng Ling
- , Jason Bennett
- & Marina Botto
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slanDCs selectively accumulate in carcinoma-draining lymph nodes and marginate metastatic cells
slanDCs represent a population of dendritic cells whose role in cancer immune surveillance is not known. Here, the authors reveal that in cancer patients, slanDCs accumulate in the metastatic tumour-draining lymph nodes but not primary carcinoma sites, suggesting their involvement in nodal immune responses to cancer cells.
- William Vermi
- , Alessandra Micheletti
- & Marco A. Cassatella
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High efficiency cell-specific targeting of cytokine activity
Despite their clinical potential, cytokines can often be highly toxic in patients, due to their systemic activity. Here, the authors present a strategy to engineer immunocytokines with very high targeting efficacies using mutant cytokines linked to nanobodies that only become active when bound to a specific cell marker.
- Geneviève Garcin
- , Franciane Paul
- & Gilles Uzé
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Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation
Asthma is often characterized by Th2-mediated inflammatory responses, which are initiated by lung dendritic cells. Here, Williams et al.demonstrate that dendritic cell expression of transcription factor IRF4 drives Th2 differentiation through IL-33 and IL-10 activation.
- Jesse W. Williams
- , Melissa Y. Tjota
- & Anne I. Sperling
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Adenosine is required for sustained inflammasome activation via the A2A receptor and the HIF-1α pathway
Inflammasome activation can lead to chronic inflammatory conditions; however, the mechanisms controlling the duration of this activation are not well understood. Here, Ouyang et al.report that adenosine sustains inflammasome activity, which brings insights into the pathology of chronic inflammatory diseases.
- Xinshou Ouyang
- , Ayaz Ghani
- & Wajahat Zafar Mehal
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Transdifferentiation of parathyroid cells into cervical thymi promotes atypical T-cell development
Cervical thymi are secondary sites of T-cell development in mice. Here, the authors investigate previously unknown origin of cervical thymi and show that they develop as a by-product of the normal separation of thymic and parathyroid tissue.
- Jie Li
- , Zhijie Liu
- & Nancy R. Manley
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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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Article
| Open AccessmiRNomes of haematopoietic stem cells and dendritic cells identify miR-30b as a regulator of Notch1
Several microRNAs have been implicated in the differentiation of immune cells. Here the authors analyse the global microRNA expression profiles of mouse haematopoietic stem cells and different stages of dendritic cell development and identify Notch1 as a target of miR-30b in regulatory dendritic cells.
- Xiaoping Su
- , Cheng Qian
- & Xuetao Cao
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Skin thymic stromal lymphopoietin initiates Th2 responses through an orchestrated immune cascade
Thymic stromal lymphopoietin is an important initiator of Th2 responses, but, to date, little is known about how it drives the immune cascade in the tissue microenvironment in vivo. Here, the authors show that skin thymic stromal lymphopoietin orchestrate interactions between immune cells, leading to Th2 priming.
- Juan Manuel Leyva-Castillo
- , Pierre Hener
- & Mei Li
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