Featured
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Article
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Notch2 controls developmental fate choices between germinal center and marginal zone B cells upon immunization
Sustained exogenous Notch2 signaling prompts Follicular B cells to trans-differentiate into Marginal Zone B cells. This study reveals that under physiological conditions, Notch2 signalling regulates a fate choice in antigen activated Follicular B cells, dictating whether they develop into Germinal Center B cells or Marginal Zone B cells.
- Tea Babushku
- , Markus Lechner
- & Lothar J. Strobl
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Article
| Open Access
The phosphatase DUSP22 inhibits UBR2-mediated K63-ubiquitination and activation of Lck downstream of TCR signalling
The T cell receptor signalosome integrates multiple positive and negative regulatory elements to finetune the response and limit harmful inflammation. Here authors show a regulatory cascade of T cell activation, in which DUSP22 negatively regulates UBR2, which is an activator of the kinase Lck via K63 ubiquitination.
- Ying-Chun Shih
- , Hsueh-Fen Chen
- & Tse-Hua Tan
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Article
| Open Access
Inflammasome activity is controlled by ZBTB16-dependent SUMOylation of ASC
Inflammasomes are multiprotein complexes, including the protein ASC, that assemble in response to inflammatory stimulation. Here the authors characterise the regulation of ASC during inflammasome formation and show the involvement of SUMOylation and zinc-finger and BTB domain-containing protein 16 (ZBTB16).
- Danfeng Dong
- , Yuzhang Du
- & Dakang Xu
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Review Article
| Open Access
Molecular and metabolic orchestration of the lymphatic vasculature in physiology and pathology
- Nieves Montenegro-Navarro
- , Claudia García-Báez
- & Melissa García-Caballero
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Article
| Open Access
Cryo-electron tomography of NLRP3-activated ASC complexes reveals organelle co-localization
The authors characterized puncta in the ASC complex by correlative light microscopy and cryo-ET in cells and propose an ultrastructure of the ASC filament network.
- Yangci Liu
- , Haoming Zhai
- & Yorgo Modis
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Article
| Open Access
Determining zebrafish dorsal organizer size by a negative feedback loop between canonical/non-canonical Wnts and Tlr4/NFκB
Dorsal organizer initiates the dorsal-ventral axis formation in vertebrates. Here, the authors demonstrate that Tlr4/NFκB-mediated negative feedback regulation of Wnt/β-catenin signaling determines the precise size of the zebrafish dorsal organizer.
- Juqi Zou
- , Satoshi Anai
- & Tohru Ishitani
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Article
| Open Access
Themis2 regulates natural killer cell memory function and formation
Innate immunity represents the first line of defence against pathogens, but certain innate cells are capable of memory formation, albeit with different and lesser-known mechanisms than adoptive immune cells. Here authors show that Themis2 regulates both memory NK cell development and function, via distinct downstream pathways.
- Tsukasa Nabekura
- , Elfira Amalia Deborah
- & Akira Shibuya
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Article
| Open Access
Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling
Three structures of human SLC15A4 are presented in the outward-facing apo monomeric and dimeric states and the inward-facing TASL-bound state, revealing the molecular mechanism of SLC15A4-mediated TASL recruitment in human endolysosomal TLRs signalling.
- Xudong Chen
- , Min Xie
- & Maojun Yang
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Article
| Open Access
MAVS integrates glucose metabolism and RIG-I-like receptor signaling
MAVS is an adapter protein involved in RIG-I-like receptor (RLR) signaling. Here, the authors show how MAVS link RLR-mediated signaling and glucose metabolism, employing distinct mechanisms in different organelles.
- Qiao-qiao He
- , Yu Huang
- & Shi Liu
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Article
| Open Access
Toll-like receptor mediated inflammation directs B cells towards protective antiviral extrafollicular responses
Compared to germinal centres, extrafollicular plasmablast responses are thought to produce lower affinity antibodies, offering little protection from infection. Here authors show in an influenza infection and immunization mouse model that extrafollicular responses could yield protective antibodies, and that their development depends on signals provided via Toll-like receptor stimulation.
- Jonathan H. Lam
- & Nicole Baumgarth
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Article
| Open Access
Growth hormone releasing hormone signaling promotes Th17 cell differentiation and autoimmune inflammation
Endocrine factors have been shown to alter functions of pathogenic Th17 cells that are involved in autoimmunity. Here the authors study the influence of growth hormone releasing hormone receptor and show that this receptor is found on Th17 cells and promotes ocular autoimmunity.
- Lin Du
- , Bo Man Ho
- & Wai Kit Chu
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Article
| Open Access
Cisplatin toxicity is counteracted by the activation of the p38/ATF-7 signaling pathway in post-mitotic C. elegans
In contrast to mammalian cells, C. elegans models can be useful because of cells being post-mitotic in adults. Here the authors show activation of the p38 pathway in cisplatin resistant adult animals and characterise the proteins upstream and downstream of the p38 MAPK signalling pathway that are involved in the cisplatin response.
- Dorota Raj
- , Bashar Kraish
- & Peter Naredi
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Article
| Open Access
Catch bond models may explain how force amplifies TCR signaling and antigen discrimination
Catch bonds where lifetime increases with force applied can form when T cell receptors (TCR) interact with agonist peptide-MHC (pMHC) complexes. Here the authors use a modelling and experimental approach to analyse 55 TCR–pMHC bond lifetime curves measured under force to further characterise the structural bases and functional relevance of catch bonds.
- Hyun-Kyu Choi
- , Peiwen Cong
- & Cheng Zhu
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Article
| Open Access
Discrete LAT condensates encode antigen information from single pMHC:TCR binding events
The linker for activation of T cells (LAT) protein is involved in the activation of T cells. Here the authors discover micron scale LAT condensation events downstream of singly bound T-cell receptors during T cell activation and characterise how LAT condensation timing affects downstream T cell signalling.
- Darren B. McAffee
- , Mark K. O’Dair
- & Jay T. Groves
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Article
| Open Access
Structure of the human NK cell NKR-P1:LLT1 receptor:ligand complex reveals clustering in the immune synapse
NKR-P1 is an inhibitory receptor on the surface of natural killer cells, and its engagement with the ligand LLT1 on activated monocytes and B cells triggers NK cell self-tolerance and other immunological processes. Here authors set up a comprehensive, structure-based model of NKR-P1-LLT1 interaction that involves NKR-P1 homodimer formation and subsequent bridging of two LLT1 molecules.
- Jan Bláha
- , Tereza Skálová
- & Ondřej Vaněk
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Article
| Open Access
Covalent TCR-peptide-MHC interactions induce T cell activation and redirect T cell fate in the thymus
Differentiation and activation of T cells are normally modulated by non-covalent interactions between T cell receptor (TCR) and antigenic peptides. Here the authors use step-wise mutations, biochemical characterization and structural insights to describe the contributions of natural covalent bonds between TCR and antigenic peptides during these processes.
- Christopher Szeto
- , Pirooz Zareie
- & Stephen R. Daley
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Article
| Open Access
The intrinsically disordered protein TgIST from Toxoplasma gondii inhibits STAT1 signaling by blocking cofactor recruitment
Intrinsically disordered proteins (IDP) are pleotropic proteins with diverse functions. Here the authors show that an IDP, TgIST, from T. gondii blocks interferon-induced gene expression by binding to the STAT1 dimer interface and preventing the recruitment of co-transcriptional activators, CBP/p300, to STAT1 to inhibit expression of immunity genes.
- Zhou Huang
- , Hejun Liu
- & L. David Sibley
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Article
| Open Access
CXCL4 synergizes with TLR8 for TBK1-IRF5 activation, epigenomic remodeling and inflammatory response in human monocytes
The chemokine, CXCL4, is proposed to enhance Toll-like receptor (TLR) signaling by facilitating TLR ligand import. Here the authors show that CXCL4 also synergizes with TLR8 to promote the activation of TBK1 and IKKε and induce epigenetic remodeling of relevance inflammatory genes to enhance inflammatory responses in human monocytes.
- Chao Yang
- , Mahesh Bachu
- & Lionel B. Ivashkiv
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Article
| Open Access
Mechanically active integrins target lytic secretion at the immune synapse to facilitate cellular cytotoxicity
Cytotoxic response is mediated by delivery of lytic molecules at the effector cell/target cell junction site, termed the immunological synapse. Here the authors find, using single cell biophysical measurements, that the during this process the αLβ2 integrin, LFA-1, helps focus lytic granule release via talin-dependent, pulling force-mediated spatial guidance.
- Mitchell S. Wang
- , Yuesong Hu
- & Morgan Huse
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Article
| Open Access
Discovery of a signaling feedback circuit that defines interferon responses in myeloproliferative neoplasms
Interferon alpha (IFNalpha) therapy is showing promising results to treat myeloproliferative neoplasms (MPNs). Here, the authors show that IFNalpha response requires ULK1 phosphorylation to induce p38-MAPK signalling but it is counteracted by ROCK1-2 activation suggesting combination therapy of IFNalpha-ROCK1-2 inhibition may improve MPNs treatment.
- Diana Saleiro
- , Jeremy Q. Wen
- & Leonidas C. Platanias
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Article
| Open Access
PCBP2 maintains antiviral signaling homeostasis by regulating cGAS enzymatic activity via antagonizing its condensation
cGAS senses viral DNA and forms cytosolic cGAS-DNA granules to mediate anti-DNA viral signaling pathway. Here the authors show that PCBP2 interacts with cGAS and antagonizes condensation of cGAS-DNA granules, thus maintaining host immune homeostasis.
- Haiyan Gu
- , Jing Yang
- & Qinmiao Sun
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Article
| Open Access
Molecular recognition of formylpeptides and diverse agonists by the formylpeptide receptors FPR1 and FPR2
Zhuang et al. report four cryo-EM structures of formylpeptide receptors FPR1 and FPR2 coupled with Gi protein and diverse agonists, revealing how FPRs as pattern recognition receptors recognize formylpeptides and synthetic agonists and a distinctive receptor activation mechanism.
- Youwen Zhuang
- , Lei Wang
- & Cheng Zhang
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Article
| Open Access
Myeloid 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 Access
Intraperitoneal microbial contamination drives post-surgical peritoneal adhesions by mesothelial EGFR-signaling
Abdominal surgery can often lead to complications including the formation of peritoneal adhesions and the molecular mechanisms underlying this process are still unknown. Here, the authors suggest that bacterial contamination drives adhesion formation through mesothelial EGFR signalling.
- Joel Zindel
- , Jonas Mittner
- & Daniel Candinas
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Article
| Open Access
G-protein-coupled receptor P2Y10 facilitates chemokine-induced CD4 T cell migration through autocrine/paracrine mediators
P2Y10 is a G-protein-coupled receptor that is expressed in CD4 T cells. Here authors show that its ligands, lysophosphatidylserine and ATP, are induced in T cells upon chemokine stimulation and regulate RhoA activation and migration through an autocrine/paracrine loop.
- Malarvizhi Gurusamy
- , Denise Tischner
- & Nina Wettschureck
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Article
| Open Access
Defactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation
The transcription factor, IRF5, has been implicated in the regulation of inflammation, but how IRF5 protein is activated is still unclear. Here the authors use inhibitor library screening, biochemical analyses and in vivo/ex vivo data to show that a protein tyrosine kinase, Pyk2, may be key for the activation of IRF5 in macrophages and inflammatory responses in the gut.
- Grigory Ryzhakov
- , Hannah Almuttaqi
- & Irina A. Udalova
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Article
| Open Access
Transient mTOR inhibition rescues 4-1BB CAR-Tregs from tonic signal-induced dysfunction
Chimeric antigen receptor engineering in T cells has been shown to be of great potential therapeutic benefit in a range of immune pathologies, although the functionality of such cell therapies can be limited due to tonic signalling and the induction of dysfunction. Here the authors show transient inhibition of mTOR can rescue their 41-BB-CAR-Tregs from tonic signalling-induced dysfunction.
- Baptiste Lamarthée
- , Armance Marchal
- & Julien Zuber
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Article
| Open Access
Optineurin modulates the maturation of dendritic cells to regulate autoimmunity through JAK2-STAT3 signaling
Optineurin (OPTN) has been implicated in various biological processes, but its function in dendritic cells (DC) maturation is still unclear. Here the authors show, by characterizing Optn-conditional knockout mice, that the loss of OPTN induces Jak2/Stat3 activation and IL-10 production to suppress DC maturation and function, thereby ameliorating autoimmune responses in mice.
- Jiajia Wang
- , Jiaying Wang
- & Qinjie Weng
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Article
| Open Access
NLRP3 phosphorylation in its LRR domain critically regulates inflammasome assembly
Nlrp3 inflammasome activation requires Nek7 recruitment to drive ASC speck formation. Here the authors show how Nlrp3 phosphorylation events control this Nek7 recruitment.
- Tingting Niu
- , Charlotte De Rosny
- & Bénédicte F. Py
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Article
| Open Access
Targeting the actin nucleation promoting factor WASp provides a therapeutic approach for hematopoietic malignancies
Cancer cells proliferate and invade via cytoskeletal proteins such as WASp, exclusively expressed in hematopoietic cells. Here the authors show a specific small molecule compound inhibiting cancer cell activity by WASp degradation and demonstrating its therapeutic potential in vitro and in vivo.
- Guy Biber
- , Aviad Ben-Shmuel
- & Mira Barda-Saad
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Article
| Open Access
Metabolic requirements of NK cells during the acute response against retroviral infection
Metabolic alterations control the fate and function of immune cells in response to infections, but the function of NK cell metabolism in the context of acute viral infections is unclear. Here the authors show that acute NK cell responses to Friend retrovirus involve increased glycolysis and mitochondrial metabolism and require amino acid transport as well as iron sufficiency.
- Elisabeth Littwitz-Salomon
- , Diana Moreira
- & David K. Finlay
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Article
| Open Access
Infection-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 Access
Structure of the human marker of self 5-transmembrane receptor CD47
CD47 is a transmembrane receptor involved in the regulation of various signalling pathways and a promising target for immuno-oncology therapeutics. Here, the authors present the crystal structure of full-length human CD47 and provide insights into the molecular mechanism of CD47-mediated signalling.
- Gustavo Fenalti
- , Nicolas Villanueva
- & Kandasamy Hariharan
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Article
| Open Access
CD45 pre-exclusion from the tips of T cell microvilli prior to antigen recognition
CD45 limits T cell activation, so its exclusion from the T cell immunological synapse is thought to occur as a means to enable TCR signalling. Here the authors use a variety of cellular imaging methods to show that CD45 is indeed excluded from the tips of the T cell microvilli and that this occurs prior to contact with antigen, indicating this exclusion is one of the initiating factors for antigen presentation and T cell activation.
- Yunmin Jung
- , Lai Wen
- & Klaus Ley
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Article
| Open Access
N4BP1 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 Access
Quantifying information accumulation encoded in the dynamics of biochemical signaling
Understanding how cells discriminate between stimuli is an ongoing challenge. Here, the authors propose a mathematical framework for inferring the mutual information encoded in temporal signaling dynamics and use it to study how information is transmitted over time in response to different stimuli in NFκB, MAPK and p53 signaling pathways.
- Ying Tang
- , Adewunmi Adelaja
- & Alexander Hoffmann
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Article
| Open Access
Notch2-mediated plasticity between marginal zone and follicular B cells
Notch signalling is central to marginal zone B cell development, but it is unclear what path this development takes in vivo. Here the authors use a mouse that lacks these cells to show that transgenic induction of Notch2 is sufficient for development of marginal zone B cells via transdifferentiation from follicular B cells and that this mechanism can occur in wildtype mice.
- Markus Lechner
- , Thomas Engleitner
- & Ursula Zimber-Strobl
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Article
| Open Access
The order and logic of CD4 versus CD8 lineage choice and differentiation in mouse thymus
Developing T cells commit to either CD4/helper or CD8/cytotoxic lineage in the thymus, but how CD4 and CD8 coreceptors and TCR signaling dictate this selection process is still unclear. Here the authors use single cell RNA sequencing of mouse thymocytes to show that, in selection intermediates, TCR signaling strength informs coreceptor expression timing.
- Mohammad M. Karimi
- , Ya Guo
- & Matthias Merkenschlager
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Article
| Open Access
B7-CD28 co-stimulation modulates central tolerance via thymic clonal deletion and Treg generation through distinct mechanisms
B7-CD28 co-stimulation is important for T cell activation and clonal expansion in the periphery. Here the authors show that, in mouse thymus, B7-CD28 differentially controls thymocyte clonal deletion and Treg induction, with distinct CD28 signaling domains and B7-expressing antigen presenting cells mediating these two processes.
- Masashi Watanabe
- , Ying Lu
- & Richard J. Hodes
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Article
| Open Access
RNF115 plays dual roles in innate antiviral responses by catalyzing distinct ubiquitination of MAVS and MITA
MAVS and MITA are adapter proteins that play distinct roles in the context of the host response to RNA and DNA viruses, respectively. Here the authors implicate RNF115 in dual temporal and spatial mechanisms of interacting and catalyzing distinct ubiquitination of MAVS and MITA to modulate RNA and DNA antiviral immune responses.
- Zhi-Dong Zhang
- , Tian-Chen Xiong
- & Bo Zhong
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Article
| Open Access
T cell-intrinsic role for Nod2 in protection against Th17-mediated uveitis
How mutations in the microbial receptor NOD2 induce Blau syndrome in humans and related uveitis is unclear. Here the authors show, using Nod2-deficient mice and experimental uveitis, that Nod2 negatively regulates T cell activation and transcription of autoimmunity-related genes to suppress Th17 responses and uveitis.
- Ruth J. Napier
- , Ellen J. Lee
- & Holly L. Rosenzweig
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Article
| Open Access
A versatile soluble siglec scaffold for sensitive and quantitative detection of glycan ligands
Sialic acid-binding immunoglobulin-type lectins (Siglecs) are a family of immunomodulatory receptors expressed on cells of the hematopoietic lineage. Here the authors demonstrate an approach for the identification of the glycan ligands of Siglecs, which is also applicable to other families of glycan-binding proteins.
- Emily Rodrigues
- , Jaesoo Jung
- & Matthew S. Macauley
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Article
| Open Access
MFSD7C switches mitochondrial ATP synthesis to thermogenesis in response to heme
Mitochondria maintain a balance between thermogenesis and ATP synthesis, but how this is coordinated is largely unknown. Here, the authors show that MFSD7C coordinates ATP synthesis and thermogenesis in response to heme by directly binding to electron transport chain complexes and SERCA2b.
- Yingzhong Li
- , Nikola A. Ivica
- & Jianzhu Chen
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Article
| Open Access
Preferential inhibition of adaptive immune system dynamics by glucocorticoids in patients after acute surgical trauma
Glucocorticoids (GC) are commonly used to suppress undesirable inflammatory responses. Here the authors show, using hi-dimensional flow cytometry data, that GC treatment following major surgeries alters adaptive immunity without significant modulation of innate immune responses or pain/functional impairment.
- Edward A. Ganio
- , Natalie Stanley
- & Brice Gaudilliere
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Article
| Open Access
MAPK-dependent hormonal signaling plasticity contributes to overcoming Bacillus thuringiensis toxin action in an insect host
Bacillus thuringiensis (Bt) is an important bioinsecticide, but high-level resistance has been rapidly evolving in agricultural pests. Here, Guo et al. show that the MAPK cascade can be activated by enhanced upstream insect hormone signals to counter Bt virulence in the diamondback moth.
- Zhaojiang Guo
- , Shi Kang
- & Youjun Zhang
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Article
| Open Access
IRAP-dependent endosomal T cell receptor signalling is essential for T cell responses
T cell receptors (TCR) are internalized when activated by their ligands. Here the authors show that the internalized TCRs are localized to endosomes expressing IRAP and Syntaxin 6 to maintain intracellular signalling capacity, whose importance is shown by the absence of efficient polyclonal anti-tumour response in mice with T-specific conditional deletion of IRAP.
- Irini Evnouchidou
- , Pascal Chappert
- & Loredana Saveanu
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Article
| Open Access
Distinct fate, dynamics and niches of renal macrophages of bone marrow or embryonic origins
Renal macrophages (RMs) can be of bone marrow or embryonic origin, but their abundance, fate and metabolic profiles in physiological and pathogenic settings are still unclear. Here the authors show, by characterizing these two RMs in multiple transgenic mouse lines, that they exhibit distinct dynamics, homeostasis, immune activity, and metabolic properties.
- Fengming Liu
- , Shen Dai
- & Xuebin Qin
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Article
| Open Access
TAGAP instructs Th17 differentiation by bridging Dectin activation to EPHB2 signaling in innate antifungal response
TAGAP gene variants are linked to human autoimmunity. Here the authors identify TAGAP as a Dectin-1 and EphB2-binding protein mediating antifungal innate immune signaling and cytokine production, and demonstrate TAGAP in non-T cells promotes Th17 response in mouse models of infection and autoimmunity.
- Jianwen Chen
- , Ruirui He
- & Chenhui Wang
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Article
| Open Access
TNIK signaling imprints CD8+ T cell memory formation early after priming
Coordinate expression of multiple factors play critical roles in the regulation between effector and memory CD8+ T cell differentiation. Here the authors show upon acute viral infection TNIK is critically required as a regulator of effector and memory T cell differentiation.
- Carla A. Jaeger-Ruckstuhl
- , Magdalena Hinterbrandner
- & Adrian F. Ochsenbein
Expression of USP25 associates with fibrosis, inflammation and metabolism changes in IgG4-related disease