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| Open AccessRapid expansion of Treg cells protects from collateral colitis following a viral trigger
Viral infection transiently depletes T regulatory cells (Treg). Here the authors identify a compensatory induced Treg population, which is required to rapidly replenish the Treg niche and suppress microbiota-driven, virus-induced colitis.
- Michelle Schorer
- , Katharina Lambert
- & Nicole Joller
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Article
| Open AccessMass cytometry reveals cellular fingerprint associated with IgE+ peanut tolerance and allergy in early life
Food allergy is triggered by IgE, but some individuals are not allergic to peanuts despite making peanut-specific IgE, and are considered peanut-tolerant. Here, the authors identify differences in blood immune cell composition of peanut-allergic and tolerant infants using mass cytometry, which may help uncover the mechanism of allergic tolerance.
- Melanie R. Neeland
- , Sandra Andorf
- & Kari C. Nadeau
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Article
| Open Accessc-FLIP is crucial for IL-7/IL-15-dependent NKp46+ ILC development and protection from intestinal inflammation in mice
Innate lymphoid cells (ILC) are important immune cells for maintaining the gut homeostasis. Here the authors show that c-FLIP, an anti-apoptotic molecule, is important for the development of NKP46+ ILC1, including conventional natural killer (cNK) cells, and ILC3, with cNK being more critical for ameliorating intestinal inflammation.
- Ute Bank
- , Katrin Deiser
- & Thomas Schüler
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Article
| Open AccessSomatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease
Adult forms of inflammatory bowel disease (IBD) are of a polygenic nature, but paediatric and very early onset (VEO) IBD also occur as monogenic forms. Here, using whole exome sequencing, the authors explore both the monogenic and polygenic contribution to VEO-IBD and characterize a rare somatic mosaic VEO-IBD patient.
- Eva Gonçalves Serra
- , Tobias Schwerd
- & Carl A. Anderson
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Article
| Open AccessPrenatal dietary supplements influence the infant airway microbiota in a randomized factorial clinical trial
Here, the authors present the results of a mother–child cohort randomized clinical trial of n-3 LCPUFA and vitamin D maternal supplementation, finding an association between supplement-induced microbiota changes in infant airways at age 1-month but not the infant fecal or maternal vaginal microbiome.
- Mathis H. Hjelmsø
- , Shiraz A. Shah
- & Hans Bisgaard
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Article
| Open AccessCold-induced urticarial autoinflammatory syndrome related to factor XII activation
Systemic autoinflammatory syndromes such as cryopyrin-associated periodic syndrome (CAPS) are rare and often involve genes related to the inflammasome. Here, the authors report a syndrome characterised by systemic inflammation and cold-induced urticarial rash associated with a Factor XII-activating mutation.
- Jörg Scheffel
- , Niklas A. Mahnke
- & Karoline Krause
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Article
| Open AccessThe mechanistic and functional profile of the therapeutic anti-IgE antibody ligelizumab differs from omalizumab
Immunoglobulin E (IgE) plays a central role in allergic responses, yet therapeutic targeting of IgE with antibodies such as omalizumab is met with various limitations. Here the authors characterize the molecular properties and crystal structure of a new anti-IgE antibody, ligelizumab, for mechanistic insights related to its enhanced suppression activity.
- Pascal Gasser
- , Svetlana S. Tarchevskaya
- & Alexander Eggel
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Article
| Open AccessMissing self triggers NK cell-mediated chronic vascular rejection of solid organ transplants
‘Missing self’ is a mode of natural killer (NK) cell activation aimed to detect the lack of HLA-I molecules on infected or neoplastic cells. Here, the authors show that mismatch between donor HLA-I and cognate receptors on recipient NK cells mediates microvascular inflammation-associated graft rejection, a pathology that is preventable by mTOR inhibition.
- Alice Koenig
- , Chien-Chia Chen
- & Olivier Thaunat
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Article
| Open AccessDouble negative T cells mediate Lag3-dependent antigen-specific protection in allergic asthma
Allergic asthma symptoms may be controlled, but currently no effective therapy exist to address the underlying pathology. Here the authors show, using mouse model of adoptive cell transfer, that CD4-CD8- T cells can suppress the function of dendritic cells and T follicular helper cells via Lag3 to provide allergen-specific protection from asthma.
- Dan Tian
- , Lu Yang
- & Dong Zhang
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Article
| Open AccessSerum FHR1 binding to necrotic-type cells activates monocytic inflammasome and marks necrotic sites in vasculopathies
FHR1 is a serum protein implicated in complement regulation. Here the authors show that human FHR1 binds to necrotic cells, triggering inflammasome activation in monocytes in culture, localizes to necrotic tissue and correlates with inflammatory cytokine levels in vasculopathies.
- Sarah Irmscher
- , Silke R. Brix
- & Christine Skerka
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Article
| Open AccessNeutrophils promote the development of reparative macrophages mediated by ROS to orchestrate liver repair
Neutrophils and macrophages are both involved in the initiation of inflammation, but whether and how they may participate in inflammation resolution is unclear. Here the authors show that neutrophils may mediate the conversion of macrophage into a pro-resolution phenotype via reactive oxygen species production to promote liver repair.
- Wenting Yang
- , Yuandong Tao
- & Li Tang
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Article
| Open AccessSTAT1 signaling shields T cells from NK cell-mediated cytotoxicity
The JAK-STAT signaling pathway is important for cytokine responses and CD4 T-cell differentiation. Here the authors show that Stat1 also serves to protect CD4 T cells from natural killer cell-mediated killing, potentially by promoting the expression of Nlrc5 and MHC-I, to preserve the induction of experimental colitis via the adoptive transfer of CD4 T cells.
- Yu Hui Kang
- , Amlan Biswas
- & Scott B. Snapper
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Article
| Open AccessCationic nanoparticle as an inhibitor of cell-free DNA-induced inflammation
Cell-free DNA (cfDNA) released from damaged or dead cells can activate DNA sensors that exacerbate the pathogenesis of rheumatoid arthritis (RA). Here the authors use ~40 nm cationic nanoparticles to scavenge cfDNA, and demonstrate the potential for nanomedicine to relieve debilitating RA symptoms.
- Huiyi Liang
- , Bo Peng
- & Yongming Chen
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Article
| Open AccessTargeting of NLRP3 inflammasome with gene editing for the amelioration of inflammatory diseases
Activation of the NLRP3 inflammasome triggers the production of inflammatory cytokines. Here, the authors inactivate NLRP3 in macrophages using CRISPR/Cas9 encapsulated in nanoparticles, and show that administration in mice is effective in preventing septic shock and peritonitis, and in improving diabetes-associated inflammation and insulin resistance.
- Congfei Xu
- , Zidong Lu
- & Jun Wang
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Article
| Open AccessEosinophil recruitment is dynamically regulated by interplay among lung dendritic cell subsets after allergen challenge
Eosinophils are important mediators of allergic responses, but how they are recruited to the inflamed site is still unclear. Here the authors show that CD103+ cDC1 cells secrete CCL17 and CCL22 for eosinophil recruitment, with this process promoted by CD24−CD11b+ DC2s in the early phase but suppressed by CD24+ cDC2s in the late phase.
- Shuying Yi
- , Jing Zhai
- & Hua Tang
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Article
| Open AccessEndogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase
Vitamin E metabolites are proposed to have signalling capacity, but how they may regulate immune responses is still unclear. Here the authors show that a vitamin E metabolite, α-T-13′-COOH, can inhibit 5-lipoxygenase and thereby suppress the synthesis of lipid mediators of immune activation and inflammatory responses.
- Helmut Pein
- , Alexia Ville
- & Andreas Koeberle
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Article
| Open AccessNrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming
Understanding how regulators of inflammation affect nucleic acid sensing is important for targeting research against inflammatory diseases and conditions. Here, the authors identify Nrf2 as an important negative regulator of STING and suggest a link between metabolic reprogramming and antiviral cytosolic DNA sensing in human cells.
- David Olagnier
- , Aske M. Brandtoft
- & Christian K. Holm
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Article
| Open AccessStatin as a novel pharmacotherapy of pulmonary alveolar proteinosis
Pulmonary alveolar proteinosis (PAP) is associated with defective macrophage clearance of surfactant. Here, the authors show that patients with PAP have altered cholesterol-to-phospholipid ratio in their surfactant, and that more importantly, statin therapy and reduction of cholesterol accumulation in macrophages can ameliorate PAP in both humans and mice.
- Cormac McCarthy
- , Elinor Lee
- & Bruce C. Trapnell
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Article
| Open AccessRegulation of T cell afferent lymphatic migration by targeting LTβR-mediated non-classical NFκB signaling
Lymphotoxin beta receptor (LTβR) signalling regulates leukocyte migration through the lymphatic endothelial layers. Here, the authors show that treatment of an LTβR-derived decoy peptide can target the non-classical NFκB pathway to inhibit T cell and dendritic cell migration and ameliorate contact hypersensitivity in mouse models.
- Wenji Piao
- , Yanbao Xiong
- & Jonathan S. Bromberg
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Article
| Open AccessThe IL-33-PIN1-IRAK-M axis is critical for type 2 immunity in IL-33-induced allergic airway inflammation
IL-33 orchestrates type 2 immunity in allergic asthma. Here the authors show, using biochemical, structural and patient data, that upon IL-33 or allergic challenge, the isomerase Pin1 modifies IRAK-M to control the production of pro-inflammatory cytokines in the setting of airway inflammation.
- Morris Nechama
- , Jeahoo Kwon
- & Kun Ping Lu
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Article
| Open AccessTreating cat allergy with monoclonal IgG antibodies that bind allergen and prevent IgE engagement
Allergen-specific immunotherapy is used to treat patients affected by acute immunoglobulin E (IgE) responses, but the function mechanism is unclear. Here the authors show that the administration of two cat allergen-specific IgGs reduces allergic responses in mouse models and helps ameliorate clinical symptoms in a phase 1b clinical trial.
- J. M. Orengo
- , A. R. Radin
- & G. D. Yancopoulos
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Article
| Open AccessMT4-MMP deficiency increases patrolling monocyte recruitment to early lesions and accelerates atherosclerosis
Matrix metalloproteinases (MMP) are involved in vascular remodeling associated with plaque progression. Little is known about their immune regulatory role in vascular disorders. Here, the authors report that MT4-MMP-deficiency increases the recruitment of patrolling monocytes to early atherosclerotic lesions, which accelerates atherosclerosis.
- Cristina Clemente
- , Cristina Rius
- & Alicia G. Arroyo
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Article
| Open AccessBone marrow lympho-myeloid malfunction in obesity requires precursor cell-autonomous TLR4
Obesity can affect bone marrow cell differentiation and the generation of myeloid and lymphoid cells. Here, the authors show that diet and obesity, as well as low-dose lipopolysaccharide, can alter Toll-like receptor 4 signaling bone marrow cells to skew the myeloid-lymphoid homeostasis in mice.
- Ailing Liu
- , Minhui Chen
- & Lisa Borghesi
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Article
| Open AccessMaturation of the gut microbiome and risk of asthma in childhood
Colonization of commensal bacteria is thought to impact immune development, especially in the earliest years of life. Here, the authors show, by analyzing the development of the gut microbiome of 690 children, that microbial composition at the age of 1 year is associated with asthma diagnosed in the first 5 years of life.
- Jakob Stokholm
- , Martin J. Blaser
- & Hans Bisgaard
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Article
| Open AccessTNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis
The pathogenesis of paradoxical psoriasis in patients receiving anti-TNF treatments for classical psoriasis is unclear. Here, the authors show that anti-TNF drugs enhance the production of type I interferon by plasmacytoid dendritic cells, causing skin lesions that, unlike classical psoriasis, lack T- cell autoimmunity.
- Curdin Conrad
- , Jeremy Di Domizio
- & Michel Gilliet
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Article
| Open AccessTrapping IgE in a closed conformation by mimicking CD23 binding prevents and disrupts FcεRI interaction
IgE is linked to allergic diseases and there is a great interest in developing anti-IgE therapeutics. Here the authors characterize the binding of human IgE Fc to a single domain antibody (sdab) and show that the sdab induces a closed conformation, which prevents and disrupts IgE binding to its receptor FcεRI and abrogates allergen mediated activation.
- Frederic Jabs
- , Melanie Plum
- & Edzard Spillner
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Article
| Open AccessType I interferon-mediated autoinflammation due to DNase II deficiency
Nucleic acid sensing is important to ensure that an innate immune response is only mounted against microbial nucleic acid. Here, the authors identify loss-of-function mutations in the DNASE2 gene that cause type I interferon-mediated autoinflammation due to enhanced systemic interferon signaling.
- Mathieu P. Rodero
- , Alessandra Tesser
- & Yanick J. Crow
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Article
| Open AccessTyrosine phosphatase SHP2 negatively regulates NLRP3 inflammasome activation via ANT1-dependent mitochondrial homeostasis
The NLRP3 inflammasome is central to a variety of inflammatory diseases, but how it is regulated to prevent excessive inflammation is not clear. Here the authors show that NLRP3 activation causes SHP2 translocation to the mitochondria to interact with and dephosphorylate ANT1, thus stabilizing the mitochondria and preventing release of proinflammatory mitochondrial DNA and ROS.
- Wenjie Guo
- , Wen Liu
- & Qiang Xu
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Article
| Open AccessIntegrative transcriptomic analysis reveals key drivers of acute peanut allergic reactions
Rising rates of peanut allergy pose a public health problem. Here, the authors profile blood transcriptomes during double-blind, placebo-controlled oral challenge in peanut-allergic children to identify gene and cell composition changes, and construct causal networks to detect key allergic reaction drivers.
- C. T. Watson
- , A. T. Cohain
- & S. Bunyavanich
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Article
| Open AccessGenome-wide association study identifies the SERPINB gene cluster as a susceptibility locus for food allergy
Food allergy is an increasing public health problem. In a genome-wide scan of children diagnosed by oral food challenge, Marenholz et al. find new genetic associations underlying food allergy, implicating the immune system and the epithelial barrier.
- Ingo Marenholz
- , Sarah Grosche
- & Young-Ae Lee
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Article
| Open AccessRegulation of endothelial intracellular adenosine via adenosine kinase epigenetically modulates vascular inflammation
The molecular mechanisms underlying vascular inflammation are unclear. Here the authors show that pro-inflammatory stimuli lead to endothelial inflammation by increasing adenosine kinase expression, and that its knockdown in endothelial cells inhibits atherosclerosis and cerebral ischemic injury in mice.
- Yiming Xu
- , Yong Wang
- & Yuqing Huo
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Article
| Open AccessIgG1 memory B cells keep the memory of IgE responses
IgE is an important mediator of protective immunity as well as allergic reaction, but how high affinity IgE antibodies are produced in memory responses is not clear. Here the authors show that IgE can be generated via class-switch recombination in IgG1 memory B cells without additional somatic hypermutation.
- Jin-Shu He
- , Sharrada Subramaniam
- & Maria A. Curotto de Lafaille
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Article
| Open AccessCre/lox-assisted non-invasive in vivo tracking of specific cell populations by positron emission tomography
Non-invasive cell tracking is a powerful method to visualize cells in vivo under physiological and pathophysiological conditions. Here Thunemann et al. generate a mouse model for in vivo tracking and quantification of specific cell types by combining a PET reporter gene with Cre-dependent activation that can be exploited for any cell population for which a Cre mouse line is available.
- Martin Thunemann
- , Barbara F. Schörg
- & Robert Feil
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Article
| Open AccessInhibition of gelatinase B/MMP-9 does not attenuate colitis in murine models of inflammatory bowel disease
Metalloproteinase-9 has been suggested as therapeutic target to treat inflammatory bowel disease. Here de Bruynet al. show that genetic and pharmacological inhibition of metalloproteinase-9 does not ameliorate inflammation and fibrosis in mice challenged with acute and chronic colitis protocols.
- Magali de Bruyn
- , Christine Breynaert
- & Ghislain Opdenakker
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Article
| Open AccessTWEAK mediates inflammation in experimental atopic dermatitis and psoriasis
TWEAK is a TNF family member that binds the NFκB signalling receptor Fn14. Here the authors show that TWEAK is central to skin inflammation in mouse models of atopic dermatitis and psoriasis and causes similar pathology when injected subcutaneously into mice.
- Daniel Sidler
- , Ping Wu
- & Michael Croft
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Article
| Open AccessLoss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease
ARPC1B is a component of the actin-related protein 2/3 complex (Arp2/3), which is required for actin filament branching. Kahret al. show that ARPC1B deficiency in humans is associated with severe multisystem disease that includes platelet abnormalities, eosinophilia, eczema and other indicators of immune disease.
- Walter H. A. Kahr
- , Fred G. Pluthero
- & Aleixo M Muise
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Article
| Open AccessThe transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction
DOCK8-deficiency can cause atopic dermatitis but the mechanism is unclear. Here the authors use mice and human samples to show ARNT-independent DOCK8 inhibition of EPAS1 increases transcription of IL-31 in CD4+T cells, thus driving skin inflammation.
- Kazuhiko Yamamura
- , Takehito Uruno
- & Yoshinori Fukui
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Article
| Open AccessIL-12 protects from psoriasiform skin inflammation
IL-12 and IL-23 share the common p40 subunit yet have distinct immunological functions with IL-12 typically contributing to Th1 responses and IL-23 to Th17 responses. Here the authors show that current p40 based therapies for psoriasis are counterproductive owing to an IFN-γ-independent tissue protective function of IL-12 in skin.
- Paulina Kulig
- , Stephanie Musiol
- & Burkhard Becher
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Article
| Open AccessANGPTL4 deficiency in haematopoietic cells promotes monocyte expansion and atherosclerosis progression
Angiopoietin-like 4 protein (ANGPTL4) is a regulator of lipoprotein metabolism whose role in atherosclerosis has been controversial. Here the authors show that ANGPTL4 deficiency in haematopoietic cells increases atherogenesis by promoting myeloid progenitor cell expansion and differentiation, foam cell formation and vascular inflammation.
- Binod Aryal
- , Noemi Rotllan
- & Carlos Fernández-Hernando
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Article
| Open AccessEndothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability
Endothelial to mesenchymal transition (EndMT) is a crucial developmental process that also plays a role in the pathogenesis of some diseases. Here the authors show that EndMT contributes to the development of atherosclerosis in mice and humans, and is associated with complex human plaques that may be prone to rupture.
- Solene M. Evrard
- , Laura Lecce
- & Jason C. Kovacic
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Article
| Open AccessActivation of STING requires palmitoylation at the Golgi
STING is essential for the type I interferon immune response to foreign DNA. Here, the authors show that palmitoylation of STING at the Golgi is required for activating downstream signalling, and increased Golgi localization of certain STING variants may cause autoimmune disease in some cases.
- Kojiro Mukai
- , Hiroyasu Konno
- & Tomohiko Taguchi
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Article
| Open AccessTumour suppressor death-associated protein kinase targets cytoplasmic HIF-1α for Th17 suppression
HIF-1α is critical for Th17 differentiation. Here the authors show that DAPK (Death-Associated Protein Kinase) inhibits Th17 differentiation and immunopathology in a mouse model of multiple sclerosis by promoting HIF1-α binding to its negative regulator PHD2.
- Ting-Fang Chou
- , Ya-Ting Chuang
- & Ming-Zong Lai
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Article
| Open AccessT-bet is a key modulator of IL-23-driven pathogenic CD4+ T cell responses in the intestine
How transcription factor T-bet and Th17 cells contribute to colitis remains incompletely understood. Here the authors identify T-bet as a negative regulator of IL-23R pathway activation and show that T-bet deficient T cells drive colitogenic Th17 responses dependent on the cytokines IL-17A and IL-22.
- Thomas Krausgruber
- , Chris Schiering
- & Fiona Powrie
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Article
| Open AccessIL-15-dependent balance between Foxp3 and RORγt expression impacts inflammatory bowel disease
Transcription factors directing T cell fate are induced by instructive signals such as cytokines. Here the authors show that IL-15 promotes Foxp3 and inhibits RORγt expression in CD4 T cells, and that IL-15 is critical to suppress colitis by maintaining the Treg to Th1/Th17 ratio in a mouse model.
- Milena J. Tosiek
- , Laurence Fiette
- & Antonio A. Freitas
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Article
| Open Access1,25D3 prevents CD8+Tc2 skewing and asthma development through VDR binding changes to the Cyp11a1 promoter
Type 2 CD8+ T cells (Tc2) play a role in the development of experimental asthma. Here the authors show that 1,25D3, the active form of vitamin D3, can prevent conversion of CD8+T cells to a Tc2 phenotype, reducing asthma susceptibility.
- Michaela Schedel
- , Yi Jia
- & Erwin W. Gelfand
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Article
| Open AccessEndothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis
Atherosclerosis is an inflammatory disease with limited therapeutic options. Here, the authors show that protein kinase MAP4K4 regulates vascular inflammation underlying atherosclerotic plaque development and that its inhibition prevents the disease and promotes lesion regression in mice, proposing a new atherosclerosis treatment.
- Rachel J. Roth Flach
- , Athanasia Skoura
- & Michael P. Czech
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Article
| Open AccessAKAP9 regulates activation-induced retention of T lymphocytes at sites of inflammation
A-kinase anchoring protein 9 (AKAP9) is a scaffold protein that binds signalling proteins and regulates microtubules. Here the authors show that during inflammation AKAP9 in T cells is required for their reactivation and retention at the inflammation site and that its deletion protects from inflammation-induced organ damage.
- Jan M. Herter
- , Nir Grabie
- & Tanya N. Mayadas
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Article
| Open AccessNADH oxidase-dependent CD39 expression by CD8+ T cells modulates interferon gamma responses via generation of adenosine
The ectonucleotidase CD39 ultimately generates extracellular adenosine, modulating paracrine purinergic signaling. Here the authors show that IFNγ induction in CD8+ T cells is accompanied by NADH oxidase-dependent CD39 expression, which then inhibits IFNγ production in CD39-CD8+ T cells.
- Aiping Bai
- , Alan Moss
- & Simon C. Robson
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Article
| Open AccessMeta-analysis identifies seven susceptibility loci involved in the atopic march
The development of asthma following eczema is known as the atopic march. Here the authors conduct a GWAS on affected children and identify two novel loci associated with the disease phenotype.
- Ingo Marenholz
- , Jorge Esparza-Gordillo
- & Young Ae Lee