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| Open AccessEndothelial cell-specific expression of serine/threonine kinase 11 modulates dendritic cell differentiation
In the bone marrow, dendritic cell development is governed by supporting cells, such as endothelial cells. Here authors show that expression of serine/threonine kinase 11 in endothelial cells regulates differentiation of dendritic cell precursors via modulating secretion of stem cell factor.
- Qiang Zhao
- , Young-Min Han
- & Ming-Hui Zou
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Article
| Open AccessTNF antagonist sensitizes synovial fibroblasts to ferroptotic cell death in collagen-induced arthritis mouse models
Expansion of synovial fibroblast is associated with rheumatoid arthritis (RA) progression, but how this expansion is regulated is still not clear. Here the authors use a mouse RA model, single cell RNA sequencing and in vitro analyses to show that inducing ferroptosis and suppressing TNF signaling reduce fibroblast numbers and ameliorate experimental arthritis.
- Jiao Wu
- , Zhuan Feng
- & Ping Zhu
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Article
| Open AccessAn instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia
Activating mutations in Interleukin-7 receptor alpha (IL7Ra) have been reported in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) but its role in leukaemogenesis is not clear. Here, the authors show that activation of IL7Ra in primary human hematopoietic progenitors initiates preleukaemia and cooperates with CDKN2A silencing to develop BCP-ALL.
- Ifat Geron
- , Angela Maria Savino
- & Shai Izraeli
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| Open AccessMyeloid cell nuclear differentiation antigen controls the pathogen-stimulated type I interferon cascade in human monocytes by transcriptional regulation of IRF7
The interferon response is a critical component of the innate immune response. Here the authors implicate MNDA in the regulation of type I interferon responses to pathogen infection.
- Lili Gu
- , David Casserly
- & Andrew G. Bowie
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Article
| Open AccessProteomic profiling of MIS-C patients indicates heterogeneity relating to interferon gamma dysregulation and vascular endothelial dysfunction
Multi-inflammatory syndrome in children (MIS-C) can be associated with SARS-CoV-2 infection but can also be similar to other inflammatory syndromes. Here the authors characterise the plasma proteome phenotype in MIS-C and compare to other SARS-CoV-2 related syndromes and find disproportionately high IFN-γ responses in MIS-C patients.
- Caroline Diorio
- , Rawan Shraim
- & Edward M. Behrens
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Article
| Open AccessThe concerted change in the distribution of cell cycle phases and zone composition in germinal centers is regulated by IL-21
How IL-21 functions during development of high affinity antibody in germinal centres (GC) is not fully known. Here using a cell cycle reporter mouse, the authors show that IL-21 promotes cell cycle progression within the GC light zone and enables release from the G1 cell cycle stage.
- Dimitra Zotos
- , Isaak Quast
- & David M. Tarlinton
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Article
| Open AccessDelayed induction of type I and III interferons mediates nasal epithelial cell permissiveness to SARS-CoV-2
The innate immune response in epithelial cells after SARS-CoV-2 infection is not fully understood. Here the authors use human air-liquid interface culture and show single cell transcription changes and delayed type I Interferon responses after SARS-CoV-2 infection compared with other respiratory viruses.
- Catherine F. Hatton
- , Rachel A. Botting
- & Christopher J. A. Duncan
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Article
| Open AccessCross-species analysis of viral nucleic acid interacting proteins identifies TAOKs as innate immune regulators
Whether there are conserved nucleic acid (NA) binding proteins across species is not fully known. Using data from human, mouse and fly, the authors identify common binders, implicate TAOKs and show that these kinases bind NAs across species and promote virus defence in mammalian cells.
- Friederike L. Pennemann
- , Assel Mussabekova
- & Andreas Pichlmair
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Article
| Open AccessMicroenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy
Cytotoxic chemotherapy rarely generates durable anti-tumor immune responses. Here the authors show that tumor microenvironment-derived IL-6 promotes resistance to doxorubicin by suppressing CD8 T cell anti-tumor immune responses in a preclinical model of B-cell acute lymphoblastic leukemia.
- Eric H. Bent
- , Luis R. Millán-Barea
- & Michael T. Hemann
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Article
| Open AccessA non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling
Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) is normally induced by innate immunity sensing for protection from pathogens. Here the authors show that cGAMP is also upstream of DNA damage signaling by activating ATM-CHK2-mediated repair pathway, while simultaneously suppressing the homology-directed repair.
- Daipayan Banerjee
- , Kurt Langberg
- & Nagaraj Kerur
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Article
| Open AccessAsthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region
Susceptibility to asthma and severity of symptoms are regulated by a number of different genomic regions. Here the authors characterise a 5kb regulatory region and demonstrate genetic and topological regulation of IL33 and association with disease in different human cohorts.
- Ivy Aneas
- , Donna C. Decker
- & Marcelo A. Nóbrega
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Article
| Open AccessStructural and functional analysis of target recognition by the lymphocyte adaptor protein LNK
LNK is a potent negative regulator of cytokine signaling implicated in blood cells proliferation. Here the authors present structures of the substrate recognition (SH2) domain of LNK in complex with phosphorylated motifs from JAK2 and EPOR; providing insight into its binding specificity and mode of action.
- Rhiannon Morris
- , Yaoyuan Zhang
- & Jeffrey J. Babon
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Article
| Open AccessPhosphoproteome profiling uncovers a key role for CDKs in TNF signaling
Tumor necrosis factor (TNF) has various effects on phosphorylation-mediated cellular signaling. Combining phosphoproteomics, subcellular localization analyses and kinase inhibitor assays, the authors provide systems level insights into TNF signaling and identify modulators of TNF-induced cell death.
- Maria C. Tanzer
- , Isabell Bludau
- & Matthias Mann
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| Open AccessSelf-reactivity controls functional diversity of naive CD8+ T cells by co-opting tonic type I interferon
There is heterogeneity in the response to self-ligands within the naïve CD8+ T cell pool and the consequences of this are unclear. Here the authors show subsets of naïve CD8+ T cells which differ in expression of Ly6C and CD5 and response to viral infection through regulation by type I IFN signalling.
- Young-Jun Ju
- , Sung-Woo Lee
- & Jae-Ho Cho
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Article
| Open AccessInterleukin-31 promotes fibrosis and T helper 2 polarization in systemic sclerosis
Systemic sclerosis (SSc) disease involves multisystem fibrosis and autoimmunity with limited treatment options. Here the authors demonstrate that IL-31 and IL-31RA are overexpressed in dermal fibroblasts from SSc patients and show that fibrosis and cytokine release can be reduced upon blocking of IL-31/IL-31RA.
- Ai Kuzumi
- , Ayumi Yoshizaki
- & Shinichi Sato
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Article
| Open AccessCleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors
Loss of function polymorphisms of phospholipase D3 and D4 are associated with inflammatory diseases and their function is unclear. Here the authors show that PLD3/4 function as RNAses and deletion of these proteins in mice leads to accumulation of ssRNA which exacerbates inflammation through TLR signalling.
- Amanda L. Gavin
- , Deli Huang
- & David Nemazee
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Article
| Open AccessMETTL3-mediated m6A RNA methylation promotes the anti-tumour immunity of natural killer cells
Post transcriptional modifications to RNA may be important in the function of NK cells but this is not fully known. Here the authors show that m6A-methyltransferase METTL3 deletion in NK cells leads to reduced function and protection against tumour challenge through suppressing response to IL-15.
- Hao Song
- , Jiaxi Song
- & Zhigang Tian
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Article
| Open AccessInfection-induced type I interferons critically modulate the homeostasis and function of CD8+ naïve T cells
Infections induce activation of naïve T cells for protective immunity, but insights for this host-pathogen crosstalk are still missing. Here the authors show that infection-induced type I interferon (IFN-I) signaling promote the differentiation, expansion and functional maturation of naïve CD8 T cells, particularly for low affinity clones, to enhance anti-microbial immunity.
- Mladen Jergović
- , Christopher P. Coplen
- & Janko Nikolich-Žugich
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Article
| Open AccessListeria exploits IFITM3 to suppress antibacterial activity in phagocytes
Interferon (IFN) is an important component of antiviral immunity, but can also be exploited by bacteria for immune evasion. Here the authors show that Listeria monocytogenes (Lm) induces type I IFN to suppress the degradation of Lm virulence proteins, ActA and LLO, and promote Lm infection in an IFITM3-dependent manner, thereby hinting at a potential target for antimicrobial therapy.
- Joel M. J. Tan
- , Monica E. Garner
- & John H. Brumell
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Article
| Open AccessInterferon lambda 4 impairs hepatitis C viral antigen presentation and attenuates T cell responses
A genetic variant in the IFN-lambda 4 gene has been associated with poor hepatitis C virus prognosis but it is not clear how this functions. Here the authors show that IFN-lambda 4 promotes ER stress and inhibits presentation of HCV epitopes to CD8+ T cells.
- Qian Chen
- , Mairene Coto-Llerena
- & Markus H. Heim
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Article
| Open AccessGut microbiome-mediated metabolism effects on immunity in rural and urban African populations
The authors profile stool metagenomics and plasma metabolomics in Tanzanian individuals and uncover a gradient of gut microbial profiles, from rural through urban Tanzania towards Western populations. Integration with ex vivo blood microbial stimulations reveals immune responses associated with histidine and arginine pathways, mediated by Bifidobacterium longum and Akkermansia muciniphila.
- Martin Stražar
- , Godfrey S. Temba
- & Ramnik J. Xavier
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| Open AccessThe cytokines HGF and CXCL13 predict the severity and the mortality in COVID-19 patients
Infection with SARS CoV2 results in the induction of multiple cytokine and inflammatory pathways. Here the authors demonstrate the association of HGF and CXCL13 production with increased severity and mortality in COVID-19 patients.
- Matthieu Perreau
- , Madeleine Suffiotti
- & Giuseppe Pantaleo
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| Open AccessIL-15 and PIM kinases direct the metabolic programming of intestinal intraepithelial lymphocytes
Intraepithelial lymphocytes (IEL) respond to IL-15 complexed with IL-15Ra but how this intrinsically affects IEL is unclear. Here the authors use proteomics analyses of the main mouse IEL subsets and identify PIM kinases as essential for IEL proliferation, metabolism and effector function downstream of IL-15.
- Olivia J. James
- , Maud Vandereyken
- & Mahima Swamy
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| Open AccessFractional response analysis reveals logarithmic cytokine responses in cellular populations
Our ability to interpret single-cell multivariate signaling responses is still limited. Here the authors introduce fractional response analysis (FRA), involving fractional cell counting, capable of deconvoluting heterogeneous multivariate responses of cellular populations.
- Karol Nienałtowski
- , Rachel E. Rigby
- & Michał Komorowski
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Article
| Open AccessThe RNase MCPIP3 promotes skin inflammation by orchestrating myeloid cytokine response
Zinc finger proteins are involved in the resolution of immune responses and function by degrading mRNA of inflammatory cytokines. Here the authors show MCPIP3 promotes skin inflammation via modification of cytokine profiles in pDCs and macrophages.
- Bo Liu
- , Jiancheng Huang
- & Cliff Y. Yang
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Article
| Open AccessTerminal uridyltransferase 7 regulates TLR4-triggered inflammation by controlling Regnase-1 mRNA uridylation and degradation
Terminal uridyltransferase 7 (TUT7) adds U-tails on diverse RNAs to promote degradation. Here the authors show that TUT7 is induced upon LPS treatment in macrophages and promotes decay of Regnase-1, thereby regulating the expression of a subset of cytokines, including IL-6.
- Chia-Ching Lin
- , Yi-Ru Shen
- & Li-Chung Hsu
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Article
| Open AccessInfluenza virus infection expands the breadth of antibody responses through IL-4 signalling in B cells
The reasons why influenza infection promotes a broader antibody response compared with vaccines are not fully understood. Here the authors show that unmasking of haemagglutinin epitopes and IL-4 signals in the germinal centre contribute to broader antibody responses after infection.
- Kosuke Miyauchi
- , Yu Adachi
- & Masato Kubo
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Article
| Open AccessTumor microenvironmental cytokines bound to cancer exosomes determine uptake by cytokine receptor-expressing cells and biodistribution
Cancer derived exosomes are reported to promote metastatic dissemination. Here the authors show that cytokines in the tumor microenvironment bind to exosomes via glycosaminoglycan side chains of proteoglycans, and these exosomes are preferentially taken up by specific cell lineages and organs to promote metastasis.
- Luize G. Lima
- , Sunyoung Ham
- & Andreas Möller
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Article
| Open AccessClinical and molecular characteristics of COVID-19 patients with persistent SARS-CoV-2 infection
Some patients with COVID-19 fail to clear the viral infection quickly, yet our understanding for the underlying immune characteristics is still lacking. Here the authors use single-cell RNA sequencing and other data form such patients to show that persistent infection is associated with immune suppression and reduced expression of ribosomal protein genes.
- Bin Yang
- , Junpeng Fan
- & Chaoyang Sun
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Article
| Open AccessPeripheral and lung resident memory T cell responses against SARS-CoV-2
Lung resident memory T (TRM) cells are important for protection from viral infection in the lungs. Here the authors use paired lung biopsy material and blood to characterize T cell responses in patients with COVID-19 over time and find persistence of antiviral lung TRM cells that might be important to limit reinfection.
- Judith Grau-Expósito
- , Nerea Sánchez-Gaona
- & Meritxell Genescà
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| Open AccessTNF controls a speed-accuracy tradeoff in the cell death decision to restrict viral spread
Controlled cell death can be an efficient anti-viral strategy, but also leads to tissue damage and needs to be balanced. Oyler-Yaniv et al. combine mathematical modelling and microscopy to show that exposure to TNF in response to viral infection causes cells to tune their speed-vs-accuracy trade-off in cell death decision to limit HSV-1 spread.
- Jennifer Oyler-Yaniv
- , Alon Oyler-Yaniv
- & Roy Wollman
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Article
| Open AccessA BAFF/APRIL axis regulates obesogenic diet-driven weight gain
Interactions between the immune system and adipose tissue contribute to the regulation of body weight, however, the underlying mechanisms remain incompletely understood. Here the authors dissect the role of two structurally and functionally similar immune mediators, BAFF and APRIL, in modifying diet-induced weight gain and adipocyte lipid handling.
- Calvin C. Chan
- , Isaac T. W. Harley
- & Senad Divanovic
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| Open AccessDual vaccination against IL-4 and IL-13 protects against chronic allergic asthma in mice
Asthma is caused by hyperreactivity to benign antigens, with humoral immunity orchestrated by interleukin-4 (IL-4) and IL-13 being the key etiological factor. Here the authors show, in humanized mouse models, that dual vaccination against IL-4 and IL-13 induces their durable suppression ameliorate experimental asthma, and to hint clinical translation.
- Eva Conde
- , Romain Bertrand
- & Laurent L. Reber
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Article
| Open AccessThe ubiquitylation of IL-1β limits its cleavage by caspase-1 and targets it for proteasomal degradation
Hyperactivation of inflammasome-induced IL-1β can cause immunopathology and is a feature of autoinflammatory diseases. Here, the authors show how ubiquitination of IL-1β limits its activity by targeting it for proteasomal degradation and preventing its cleavage by caspase-1.
- Swarna L. Vijayaraj
- , Rebecca Feltham
- & James E. Vince
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| Open AccessCritical role of interferons in gastrointestinal injury repair
Despite being prevalent yet well studied, ulcerative colitis still has poorly characterized pathophysiology. Here the authors use mouse colitis models to find that type I and III interferon (IFN) both contribute to ameliorating the disease, with IFN signaling in either the epithelial or hematopoietic compartment sufficient for this protective effect.
- Constance McElrath
- , Vanessa Espinosa
- & Sergei V. Kotenko
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Article
| Open AccessPPARɣ drives IL-33-dependent ILC2 pro-tumoral functions
Group 2 innate lymphoid cells (ILC2s) are a component of type 2 immune response recently described to be involved in the regulation of anti-tumor immune responses. Here, the authors show that the expression of the peroxisome proliferator-activated receptor γ (PPAPγ) in human and mouse ILC2 sustains type-2 cytokines secretion and support their pro-tumorigenic role in preclinical cancer models.
- Giuseppe Ercolano
- , Alejandra Gomez-Cadena
- & Camilla Jandus
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Article
| Open AccessCD200–CD200R immune checkpoint engagement regulates ILC2 effector function and ameliorates lung inflammation in asthma
The role of the CD200–CD200R axis in regulating pulmonary inflammation is not completely understood. Here the authors show CD200R is expressed on type 2 innate lymphoid cells (ILC2s), and its engagement by CD200 ameliorates airway hyperreactivity and allergic asthma via inhibition of NF-κB signaling.
- Pedram Shafiei-Jahani
- , Doumet Georges Helou
- & Omid Akbari
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Article
| Open AccessIL-33 expression in response to SARS-CoV-2 correlates with seropositivity in COVID-19 convalescent individuals
Our understanding of the immune response to SARS-CoV-2 infection is still incomplete. Here, the authors find that IL-33, produced during immune recall potentially by CD14+ monocytes, correlates with CD4+ T cell activation, anti-SARS-CoV-2 antibody titer, and disease severity in a cohort of convalescent individuals professionally exposed to the virus.
- Michal A. Stanczak
- , David E. Sanin
- & Erika L. Pearce
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Article
| Open AccessDifferential controls of MAIT cell effector polarization by mTORC1/mTORC2 via integrating cytokine and costimulatory signals
Mucosal-associated invariant T (MAIT) cells are key in immunity and diseases, but how their effector polarization is controlled is still unclear. Here, the authors show that an IL-1β/IL-23/mTORC2 axis is essential for the induction of IL-17-producing MAIT17, while an IL-2/IL-15/mTORC1 axis is important for the homeostasis of IFN-γ-producing MAIT1.
- Huishan Tao
- , Yun Pan
- & Xiao-Ping Zhong
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Article
| Open AccessType I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus
Lupus pathogenesis is associated with high type 1 interferon stimulated gene (ISG) expression. Here, the authors correlate ISG expression in CD8+ T cells from lupus nephritis patients with abnormal mitochondrial function, implicating increased NAD consumption and reduced cell viability in the pathogenesis.
- Norzawani Buang
- , Lunnathaya Tapeng
- & Marina Botto
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Article
| Open AccessHost-derived lipids orchestrate pulmonary γδ T cell response to provide early protection against influenza virus infection
Influenza A infection results in γδ T cell influx and production of IL-17 in the lungs. Here, the authors show that this effect is primed by CD1-restricted ligands that are released by infected cells and presented by B1a cells in the lungs.
- Xiaohui Wang
- , Xiang Lin
- & Liwei Lu
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Article
| Open AccessThe survival and function of IL-10-producing regulatory B cells are negatively controlled by SLAMF5
Regulatory B (Breg) cells suppress excessive inflammation primary via the production of interleukin 10 (IL-10). Here the authors show that the function and homeostasis of mouse and human IL-10+ Breg cells are negatively regulated by the cell surface receptor, SLAMF5, to impact experimental autoimmunity, thereby hinting SLAMF5 as a potential target for immunotherapy.
- Lihi Radomir
- , Matthias P. Kramer
- & Idit Shachar
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Article
| Open AccessIntegrated cytokine and metabolite analysis reveals immunometabolic reprogramming in COVID-19 patients with therapeutic implications
Metabolism changes can modulate immune responses in many contexts, and vice versa. Here the authors associate metabolomic, as well as cytokine and chemokine, data from stratified COVID-19 patients to find that arginine, tryptophan and purine metabolic pathways correlate with hyperproliferation, thus hinting at potential therapeutic targets for severe COVID-19 patients.
- Nan Xiao
- , Meng Nie
- & Zeping Hu
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Article
| Open AccessN4BP1 negatively regulates NF-κB by binding and inhibiting NEMO oligomerization
NF-κB signalling is critical to TLR mediated cytokine release in various immune responses. Here the authors show how N4BP1 inhibits NEMO signalling and subsequent NF-κB activation and how this pathway is negatively regulated by caspase-8 cleavage of N4BP1.
- Hexin Shi
- , Lei Sun
- & Bruce Beutler
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Article
| Open AccessThe neutrophil antimicrobial peptide cathelicidin promotes Th17 differentiation
Neutrophils secrete numerous immune effector molecules including cathelicidin which is associated with antimicrobial properties. Here the authors implicate neutrophil derived cathelicidin in modulation of CD4 T cell homoeostasis and the promotion of Th17 CD4 T cells.
- Danielle Minns
- , Katie J. Smith
- & Emily Gwyer Findlay
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Article
| Open AccessSprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33
Dynamic regulation of colonic secretory cell numbers is a critical component of the response to intestinal injury and inflammation. Here, the authors show that loss of the intracellular signalling regulator Sprouty2 in the intestinal epithelial cells is a protective response to injury that leads to increased secretory cell numbers, thus limiting colitis severity.
- Michael A. Schumacher
- , Jonathan J. Hsieh
- & Mark R. Frey
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Article
| Open AccessA conformation-selective monoclonal antibody against a small molecule-stabilised signalling-deficient form of TNF
TNF can be inhibited by small molecules that stabilize the TNF trimer in an asymmetric conformation. Here, the authors develop a monoclonal antibody that selectively binds this inactive form of TNF, enabling both target engagement assessment and structural characterization of TNF binding to TNF receptor 1.
- Daniel J. Lightwood
- , Rebecca J. Munro
- & Alastair D. G. Lawson
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Article
| Open AccessStructural insights into the disruption of TNF-TNFR1 signalling by small molecules stabilising a distorted TNF
Small molecules stabilising a distorted TNF trimer can inhibit TNF signaling, but the underlying mechanism is unclear. Here, the authors characterize the inhibitor-bound TNF-receptor complex structurally and biochemically, showing that the inhibitors alter TNF-receptor binding stoichiometry and cluster formation.
- David McMillan
- , Carlos Martinez-Fleites
- & James O’Connell
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Article
| Open AccessIntratumoral IL-12 delivery empowers CAR-T cell immunotherapy in a pre-clinical model of glioblastoma
Glioblastoma multiform (GBM) is a common and aggressive type of primary brain cancer that currently has no effective therapy. Here, the authors show, using a mouse GBM model and EGFRvIII-targeting chimeric antigen receptor (CAR)-T cells, that Intratumoral injection of interleukin-12 helps condition the microenvironment and promote anti-tumor immunity.
- Giulia Agliardi
- , Anna Rita Liuzzi
- & Burkhard Becher