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| Open AccessKappa chain maturation helps drive rapid development of an infant HIV-1 broadly neutralizing antibody lineage
Development of broadly neutralizing antibodies (bnAb) against HIV-1 in infected adults is a multi-step process unachievable by current vaccine approaches. Here the authors reconstruct the ontogeny of an infant bnAb, which develops in fewer steps, and identify its unique features that may shorten the path to HIV vaccines.
- Cassandra A. Simonich
- , Laura Doepker
- & Julie Overbaugh
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Article
| Open AccessInnate lymphocyte-induced CXCR3B-mediated melanocyte apoptosis is a potential initiator of T-cell autoreactivity in vitiligo
Tissue signals that prime autoreactive T cells at the onset of autoimmunity remain enigmatic. Here the authors show NK and ILC1 cells are increased in vitiligo patients, and induce melanocyte apoptosis via CXCR3B, which in turn leads to increased priming of T cell responses in cell culture.
- Meri K. Tulic
- , Elisa Cavazza
- & Thierry Passeron
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Article
| Open AccessConcentration and avidity of antibodies to different circumsporozoite epitopes correlate with RTS,S/AS01E malaria vaccine efficacy
RTS,S/AS01E has been tested in a phase 3 malaria vaccine trial and has shown partial efficacy in children and infants. Here, the authors analyze IgG concentration and avidity to CSP in ~1000 participants and show that IgG avidity to the C-terminus of CSP is significantly associated with vaccine-mediated protection.
- Carlota Dobaño
- , Hèctor Sanz
- & Claudia Daubenberger
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Article
| Open AccessJoint sequencing of human and pathogen genomes reveals the genetics of pneumococcal meningitis
Streptococcus pneumoniae is a causative agent of meningitis and bacteremia. In a combined pathogen and host GWAS, Lees et al. find that host genetic variation is associated with both susceptibility and severity of pneumococcal meningitis, and specific bacterial genetic variation associated with susceptibility.
- John A. Lees
- , Bart Ferwerda
- & Diederik van de Beek
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Article
| Open AccessInterferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) shows a striking bias towards higher prevalence in females. Here, the authors perform fine-mapping of an SLE-associated locus at Xp21.2 and characterise a candidate gene, CXorf21, as IFN-responsive in immune cells that shows sexually dimorphic expression.
- Christopher A. Odhams
- , Amy L. Roberts
- & Timothy J. Vyse
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Article
| Open AccessmiR-155 harnesses Phf19 to potentiate cancer immunotherapy through epigenetic reprogramming of CD8+ T cell fate
The inability of T cells to properly mount anti-tumour immunity underlies failed cancer immune surveillance or therapy. Here the authors show that a microRNA, miR-155, suppresses Ship1 phosphatase expression to modulate epigenetic reprogramming of CD8 T cell differentiation via the Phf19/PRC2 axis, thereby implicating a novel aspect of cancer immunity regulation.
- Yun Ji
- , Jessica Fioravanti
- & Luca Gattinoni
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Article
| Open AccessIL-1β, IL-23, and TGF-β drive plasticity of human ILC2s towards IL-17-producing ILCs in nasal inflammation
Innate lymphoid cells (ILCs) play critical immunological roles including immune surveillance at mucosal sites. Here the authors show that during nasal inflammation pathogen-induced cytokine production guides the differentiation of ILCs.
- Korneliusz Golebski
- , Xavier R. Ros
- & Suzanne M. Bal
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Article
| Open AccessSuppression of a broad spectrum of liver autoimmune pathologies by single peptide-MHC-based nanomedicines
Immune response against tissue-specific antigens is a hallmark of autoimmunity. Here the authors show that a single autoantigen-based nanomedicine can ameliorate pathology in a broad range of liver autoimmunity models without impairing host defenses, suggesting organ-wide tolerization.
- Channakeshava Sokke Umeshappa
- , Santiswarup Singha
- & Pere Santamaria
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Article
| Open AccessBacteroides fragilis polysaccharide A induces IL-10 secreting B and T cells that prevent viral encephalitis
The capsular polysaccharide A (PSA) of Bacteroides fragilis is known to have immunomodulatory capability during sterile inflammatory disorders. Here Ramakrishna and colleagues show that PSA administration in a murine model of herpes simplex encephalitis induces IL-10 producing B and T cell populations that confer protection against lethal challenge and brain pathology.
- Chandran Ramakrishna
- , Maciej Kujawski
- & Edouard M. Cantin
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Article
| Open AccessCD200R deletion promotes a neutrophil niche for Francisella tularensis and increases infectious burden and mortality
The authors show that the CD200 receptor (CD200R) promotes effective clearance of pulmonary Francisella tularensis infection in knock out mice. This result is unexpected as CD200R is known to dampen pulmonary immune responses, and these data suggest that the beneficial effect against F. tularensis is due to depletion of a neutrophil niche for the bacterium.
- J. Casulli
- , M. E. Fife
- & M. A Travis
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Review Article
| Open AccessCompetition for nutrients and its role in controlling immune responses
Immune cells adapt distinct metabolic strategies to accommodate specific functions associated with cell types or differentiation stages. Here in this review the authors discuss the nutrients, sensors, and mediators of such a metabolic adaption in nutrient-limiting immune microenvironments such as tumors or infections.
- Nidhi Kedia-Mehta
- & David K. Finlay
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Article
| Open AccessSox17 is required for endothelial regeneration following inflammation-induced vascular injury
Endothelial cell regeneration is essential for blood vessels to recover from inflammation-induced injury. Here Liu et al. show that the transcription factor Sox17 is required for endothelial regeneration following endotoxemia, and that delivery of a transgene expressing Sox17 to lung endothelial cells enhances recovery after injury.
- Menglin Liu
- , Lianghui Zhang
- & Asrar B. Malik
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Article
| Open AccessSynthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response
Supraphysiological T cell activation by chimeric antigen receptor (CAR) contributes to T cell exhaustion and adverse events in CAR T cell therapies. Here the authors engineer a synthetic antigen receptor that integrates into the endogenous TCR complex, preserving natural regulatory circuits and achieving improved performance in mouse tumor models.
- Patrick A. Baeuerle
- , Jian Ding
- & Robert Hofmeister
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Article
| Open AccessCaspase-1 initiates apoptosis in the absence of gasdermin D
In inflammasomes, caspase-1 activation leads to pyroptosis mediated by gasdermin D, but cells lacking gasdermin-D still initiate caspase-dependent cell death. Here, Tsuchiya et al. show that these cells undergo Bid- and caspase-3-dependent apoptosis.
- Kohsuke Tsuchiya
- , Shinsuke Nakajima
- & Takashi Suda
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Article
| Open AccessDNA methylation signatures of monozygotic twins clinically discordant for multiple sclerosis
Monozygotic (MZ) twins are ideal to study the influence of non-genetic factors on complex phenotypes. Here, Souren et al. perform an EWAS in peripheral blood mononuclear cells from 45 MZ twins discordant for multiple sclerosis and identify disease and treatment-associated epigenetic markers.
- Nicole Y. Souren
- , Lisa A. Gerdes
- & Jörn Walter
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Article
| Open AccessSingle-molecule kinetics of pore assembly by the membrane attack complex
The membrane attack complex (MAC) is a hetero-oligomeric protein assembly that kills pathogens by perforating their cell envelopes. Here, the authors use atomic force microscopy to show that MAC proteins oligomerize within the membrane, allowing them to identify the kinetic bottleneck of MAC formation.
- Edward S. Parsons
- , George J. Stanley
- & Bart W. Hoogenboom
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Article
| Open AccessAkt and STAT5 mediate naïve human CD4+ T-cell early metabolic response to TCR stimulation
T-cell subsets differ in metabolic requirements for particular tasks. Here the authors characterize metabolic fluxes in naïve human CD4+ cells upon activation, and identify a role of Stat5 in glutaminolysis linked to IL-2 production.
- Nicholas Jones
- , Emma E. Vincent
- & Catherine A. Thornton
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Article
| Open AccessLoss of TET2 and TET3 in regulatory T cells unleashes effector function
Loss of TET proteins in immune cell populations is known to result in immunopathology. Here the authors show that deficiency of Tet2 and Tet3 proteins, specifically in the CD4+ FoxP3+ Treg lineage, results in a dominant pathology in which ex-Treg cells and bystander T cells gain aberrant effector function.
- Xiaojing Yue
- , Chan-Wang J. Lio
- & Anjana Rao
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Article
| Open AccessCXCL4 assembles DNA into liquid crystalline complexes to amplify TLR9-mediated interferon-α production in systemic sclerosis
CXCL4 is an inflammatory chemokine signaling through CXCR3 receptor. Here the authors show a CXCR3-independent function of CXCL4: it forms liquid crystals with DNA, potentiating mammalian and bacterial DNA recognition by TLR9, thereby amplifying interferon-a production in systemic sclerosis.
- Roberto Lande
- , Ernest Y. Lee
- & Loredana Frasca
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Article
| Open AccessLipopolysaccharide inhalation recruits monocytes and dendritic cell subsets to the alveolar airspace
The diversity of human mononuclear phagocyte subsets remains to be characterized in many tissue-specific and functional contexts, including pulmonary inflammation. Here the authors characterize dendritic cell and monocyte subset recruitment to the bronchoalveolar space in a human LPS inhalation model.
- Laura Jardine
- , Sarah Wiscombe
- & A. John Simpson
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Article
| Open AccessFcγRIIb differentially regulates pre-immune and germinal center B cell tolerance in mouse and human
The inhibitory receptor, FcγRIIb, is reported to limit autoimmune B cell response. Here the authors show that FcγRIIb has a dual role in both human and mouse, with reduced FcγRIIb expression or function associated with enhanced pre-immune B cell tolerance, yet defective control of mature autoreactive B cells in the germinal center.
- Marion Espéli
- , Rachael Bashford-Rogers
- & Kenneth G. C. Smith
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Article
| Open AccessA Mycobacterium tuberculosis surface protein recruits ubiquitin to trigger host xenophagy
Ubiquitin (Ub)-mediated xenophagy is important in defense against Mycobacterium tuberculosis (Mtb). Here, Chai et al. describe autophagy triggering by Ub binding to the Mtb surface protein Rv1468c, and show that its deletion leads to increased bacterial loads and hyperinflammatory responses in mice.
- Qiyao Chai
- , Xudong Wang
- & Cui Hua Liu
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Article
| Open AccessA defined mechanistic correlate of protection against Plasmodium falciparum malaria in non-human primates
Proof of protection against blood-stage P. falciparum malaria by a single immunological mechanism has been elusive. Here, using engineered anti-PfRH5 chimeric monoclonal antibodies in non-human primates, the authors show that high levels of merozoite-neutralizing antibodies can achieve protection.
- Alexander D. Douglas
- , G. Christian Baldeviano
- & Simon J. Draper
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Article
| Open AccessDynamic gene regulation by nuclear colony-stimulating factor 1 receptor in human monocytes and macrophages
Receptor tyrosine kinases localize to the cell surface and have been suggested to also have nuclear function. Here the authors provide evidence that Colony Stimulating Factor-1 Receptor (CSF-1R) migrates to the nucleus upon CSF-1 stimulation in monocytes and that upon differentiation into macrophages, CSF-1R localizes to TSS, co-localizes with H3K4me3, and interacts with ELK and YY1.
- Laura Bencheikh
- , M’Boyba Khadija Diop
- & Nathalie Droin
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Article
| Open AccessDifferential human antibody repertoires following Zika infection and the implications for serodiagnostics and disease outcome
In the current study, the authors profile the IgG and IgM antibody repertoires that develop over 7 days following acute Zika virus infection. Using urine and serum samples from infected human patients the authors identify new biomarkers for serodiagnosis of Zika virus.
- Supriya Ravichandran
- , Megan Hahn
- & Surender Khurana
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Article
| Open AccessSpatial and temporal localization of immune transcripts defines hallmarks and diversity in the tuberculosis granuloma
Granulomas are a hallmark and focus of infective and immunological processes during infection with Mycobacterium tuberculosis. Here, Carow and colleagues show distinct spatial and temporal arrangement of immunological transcripts in tuberculosis granulomas.
- Berit Carow
- , Thomas Hauling
- & Martin E. Rottenberg
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Article
| Open AccessMettl3-mediated mRNA m6A methylation promotes dendritic cell activation
Here the authors examine how m6A modification is involved in innate immunity. They show that RNA methyltransferase Mettl3-mediated mRNA m6A methylation promotes dendritic cell (DC) activation and function, and in promoting DC-based T cells responses.
- Huamin Wang
- , Xiang Hu
- & Xuetao Cao
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Article
| Open AccessCharacterizing pre-transplant and post-transplant kidney rejection risk by B cell immune repertoire sequencing
Adaptive immunity from both B and T cells critically controls the rejection or survival of transplanted organs. Here the authors show, by analyzing human B cell receptor repertoire in longitudinal studies of patients receiving kidney transplants, that repertoire diversity is positively associated with the incidence of kidney rejection.
- Silvia Pineda
- , Tara K. Sigdel
- & Minnie M. Sarwal
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Article
| Open AccessPhysical and functional interaction between A20 and ATG16L1-WD40 domain in the control of intestinal homeostasis
Maintaining the intestinal barrier function requires a balance of multiple signalling pathways. Here the authors show that A20, an anti-inflammatory and anti-apoptotic protein, and Atg1611, an autophagy regulator, cross-regulate their respective protein levels and function to serve compensatory and redundant roles in fine-tuning gut barrier homeostasis.
- Karolina Slowicka
- , Inmaculada Serramito-Gómez
- & Geert van Loo
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Article
| Open AccessAdenosine receptor agonism protects against NETosis and thrombosis in antiphospholipid syndrome
Antiphospholipid syndrome is characterised by increased neutrophil extracellular trap formation (NETosis) and, consequently, increased thrombotic events. Here Ali et al. show that treatment with adenosine receptor agonists suppresses NETosis and venous thrombosis in mouse models of antiphospholipid syndrome.
- Ramadan A. Ali
- , Alex A. Gandhi
- & Jason S. Knight
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Article
| Open AccessMultifunctional CRISPR-Cas9 with engineered immunosilenced human T cell epitopes
Possible immunogenicity of the Cas9 protein raises concerns about therapeutic applications. Here the authors identify pre-existing CD8+T-cell immunity in healthy individuals and in response modify Cas9 to remove the immunodominant epitopes.
- Shayesteh R. Ferdosi
- , Radwa Ewaisha
- & Karen S. Anderson
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Article
| Open AccessA small molecule promotes cartilage extracellular matrix generation and inhibits osteoarthritis development
Loss of cartilage tissue is a hallmark of osteoarthritis. Here the authors show that BNTA, a small molecule identified in a chemical screen, promotes ECM generation in human osteoarthritic chondrocytes and cartilage explants, and suppresses pathology in a rat model of osteoarthritis.
- Yuanyuan Shi
- , Xiaoqing Hu
- & Yingfang Ao
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Article
| Open AccessMajor vault protein suppresses obesity and atherosclerosis through inhibiting IKK–NF-κB signaling mediated inflammation
Metabolic diseases are associated with chronic, low-grade inflammation. Here the authors show that major vault protein (MVP) suppresses NF-κB signalling in macrophages via an IRAK1–TRAF6 axis and that loss of MVP in myeloid cells exacerbates the inflammatory response in mice fed a high fat diet.
- Jingjing Ben
- , Bin Jiang
- & Qi Chen
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Article
| Open AccessThe role of platelets in mediating a response to human influenza infection
Influenza viremia is rare in human blood and not well studied. Here, the authors show that influenza can be found in human platelets and that platelet engulfment of influenza A results in TLR7-dependent C3 release, which in turn promotes neutrophil-DNA release and formation of platelet-DNA aggregates.
- Milka Koupenova
- , Heather A. Corkrey
- & Jane E. Freedman
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Article
| Open AccessSerine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation
RIPK1 kinase activity is known to transduce a death signal, but the molecular mechanisms that normally prevent RIPK1 activation are unclear. Here, the authors report that IKK-mediated phosphorylation on RIPK1 Ser25 directly represses its enzymatic activity and thus RIPK1-dependent cell death.
- Yves Dondelinger
- , Tom Delanghe
- & Mathieu J. M. Bertrand
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Article
| Open AccessOrigin and differentiation trajectories of fibroblastic reticular cells in the splenic white pulp
The white pulp of spleen is an important immune structure dynamically modulated during development and immune responses. Here the authors define, using multi-color lineage tracing and single-cell transcriptome analysis, the subset distribution and differentiation trajectory of fibroblastic reticular cells to serve structural insights for splenic white pulps.
- Hung-Wei Cheng
- , Lucas Onder
- & Burkhard Ludewig
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Article
| Open AccessImpaired cellular energy metabolism in cord blood macrophages contributes to abortive response toward inflammatory threats
Neonatal immune responses are known to differ to those of an adult immune response. Here Dreschers and colleagues, compare macrophage populations derived from cord blood or adult peripheral blood and show a metabolic impairment of glycolysis in macrophages derived from cord blood which may impair response to infective scenarios such as sepsis.
- Stephan Dreschers
- , Kim Ohl
- & Klaus Tenbrock
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Article
| Open AccessGasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation
Gasdermins mediate lytic cell death by forming pores in the plasma membrane. Here the authors show that gasdermins also permeabilize mitochondrial membrane, thereby facilitating intrinsic apoptosis pathway, downstream of apoptotic (Gasdermin E) and inflammatory (Gasdermin D) caspase activation.
- Corey Rogers
- , Dan A. Erkes
- & Emad S. Alnemri
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Article
| Open AccessA CRISPR-Cas9 delivery system for in vivo screening of genes in the immune system
The use of functional genomics in primary immune cells has been limited by inefficient vector delivery and risk of perturbing cell states. Here the authors present CHimeric IMmune Editing (CHIME) for in vivo evaluation of gene function and pooled screening approaches.
- Martin W. LaFleur
- , Thao H. Nguyen
- & Arlene H. Sharpe
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Article
| Open AccessNeutrophil extracellular traps in the central nervous system hinder bacterial clearance during pneumococcal meningitis
Neutrophils play critical roles in the host response to bacteria, including the production neutrophil extracellular traps (NET). Here the authors show that NET formation in the context of pneumococcal meningitis impairs bacterial clearance and targeting NET formation in this context could be a potential therapeutic option.
- Tirthankar Mohanty
- , Jane Fisher
- & Adam Linder
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Article
| Open AccessAge-specific differences in the dynamics of protective immunity to influenza
Protective immunity after influenza virus infection is poorly understood. Here, the authors quantify the dynamics of immunity against influenza A virus infections by fitting individual-level mechanistic models to longitudinal serology, and find that the form and dynamics of protection differ between children and adults.
- Sylvia Ranjeva
- , Rahul Subramanian
- & Sarah Cobey
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Article
| Open AccessMapping vaccination coverage to explore the effects of delivery mechanisms and inform vaccination strategies
The success of vaccination programs depends largely on the mechanisms used in vaccine delivery. Here, the authors evaluate the relative effectiveness of two major vaccine delivery strategies, namely routine immunization and supplementary immunization activities in five study countries.
- C. Edson Utazi
- , Julia Thorley
- & Andrew J. Tatem
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Article
| Open AccessRbpj expression in regulatory T cells is critical for restraining TH2 responses
Transcriptional regulator Rbpj is involved in T-helper subset differentiation. Here the authors show that expression of Rbpj in regulatory T cells is required to both regulate TH2 responses and regulate Treg TH2 differentiation potential.
- Michael Delacher
- , Christian Schmidl
- & Markus Feuerer
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Article
| Open AccessCoordinated host-pathogen transcriptional dynamics revealed using sorted subpopulations and single macrophages infected with Candida albicans
The outcomes of the interactions between individual host cells and pathogens are heterogeneous. Here, the authors assess transcriptional variability in both host and pathogen during infection of macrophages with the fungus Candida albicans, using sorted subpopulations and single macrophages.
- José F. Muñoz
- , Toni Delorey
- & Christina A. Cuomo
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Article
| Open AccessThe parasitic worm product ES-62 normalises the gut microbiota bone marrow axis in inflammatory arthritis
Gastrointestinal infection with parasitic helminths can protect against mucosal diseases via impacting on the microbiome. Here the authors show that ES-62, a product secreted by a tissue-resident helminth modulates the host gut microbiome to protect against inflammatory arthritis in a mouse model.
- James Doonan
- , Anuradha Tarafdar
- & William Harnett
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Article
| Open AccessNKG2A is a NK cell exhaustion checkpoint for HCV persistence
Immune cells may become less responsive, or ‘exhausted’, upon chronic viral infection, but the underlying mechanism and crosstalk are still unclear. Here the authors show that, upon chronic hepatitis C virus (HCV) infection, natural killer cell exhaustion is induced by NKG2A signalling to instruct downstream exhaustion of CD8+ T cells and HCV persistence.
- Chao Zhang
- , Xiao-mei Wang
- & Hong Tang
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Article
| Open AccessThe lncRNA Neat1 promotes activation of inflammasomes in macrophages
The inflammasomes are important mediators of protective immunity by promoting inflammatory cytokine production and cell death. Here the authors show that a lncRNA, Neat1, is mobilized by inflammasome-activating signals to promote the assembly of several inflammasome complexes and cytokine maturation to regulate inflammation.
- Pengfei Zhang
- , Limian Cao
- & Mian Wu
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Article
| Open AccessGut microbiota dependent anti-tumor immunity restricts melanoma growth in Rnf5−/− mice
RNF5 is a ubiquitin ligase regulating ER stress response. Here the authors show that Rnf5 deficiency potentiates immune response against melanoma via altered microbiota, and isolate bacterial strains that confer the same phenotype to wild type mice.
- Yan Li
- , Roberto Tinoco
- & Ze’ev A. Ronai
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Article
| Open AccessCrizotinib-induced immunogenic cell death in non-small cell lung cancer
Certain chemotherapeutic agents can exert their anticancer effect through indirect immune-dependent mechanism. Here, the authors screen a library of tyrosine kinase inhibitors and show that crizotinib is an effective stimulator of immunogenic cell death and can potentiate the efficacy of immune checkpoint blockade.
- Peng Liu
- , Liwei Zhao
- & Guido Kroemer
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