Signal transduction articles within Nature Communications

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  • Article
    | Open Access

    Aging is associated with immune attrition that may impact the effectiveness of the immune system to protect the host from pathogens. Here the authors show that immune aging is associated with alterations in the Wnt/β-catenin signaling and reduced stem cell memory T lymphocytes, hinting the Wnt/β-catenin pathway as a potential therapy target.

    • Hassen Kared
    • , Shu Wen Tan
    •  & Anis Larbi

  • Article
    | Open Access

    B cell receptors (BCR) capture antigen and initiate downstream antibody responses, but whether and how BCR signaling is regulated by BCR mobility is still unclear. Here the authors show, using single molecule imaging and machine learning analyses, that BCR and CD19 mobility is modulated by the actin nucleation regulators Arp2/3 and N-WASP to control BCR signaling.

    • Ivan Rey-Suarez
    • , Brittany A. Wheatley
    •  & Arpita Upadhyaya

  • Article
    | Open Access

    Dimethyl fumarate (DMF) is a therapy for multiple sclerosis (MS) with undetermined mechanism of action. Here the authors find that clinical response to DMF associates with decrease in IL-17-producing CD8+ T cells (Tc17), delineate molecular pathways involved, and show that DMF suppresses Tc17 pathogenicity in a mouse model of MS.

    • Christina Lückel
    • , Felix Picard
    •  & Magdalena Huber

  • Article
    | Open Access

    Activation of T cells in the tumor microenvironment can be inhibited through a variety of mechanisms. Here, the authors show that Rasal1, a GTPase-activating protein, binds and inhibits signaling downstream of the T Cell Receptor complex and that consistently, its reduced expression enhances anti-tumor T-cell responses in two syngeneic cancer mouse models.

    • Youg Raj Thaker
    • , Monika Raab
    •  & Christopher E. Rudd

  • Article
    | Open Access

    The master transcription factor RORγt, encoded by the RORC gene, controls the polarization of CD4+ T cells expressing interleukin-17 (Th17). Here the authors describe several regulatory elements at the RORC locus that are recognized by NFAT and NFkB to induce a permissive epigenetic configuration of the RORC gene for RORγt expression and Th17 differentiation.

    • Hanane Yahia-Cherbal
    • , Magda Rybczynska
    •  & Elisabetta Bianchi

  • Article
    | Open Access

    Causally linking a mutation to clinical phenotypes in rare hereditary diseases is both challenging and illuminating. Here the authors identify PI3Kɣ mutations in a patient with immune dysregulation, and recapitulate the phenotypes in PI3Kɣ-deficient mice by exposing them to natural microbiota from pet-shop mice.

    • Andrew J. Takeda
    • , Timothy J. Maher
    •  & Carrie L. Lucas

  • Article
    | Open Access

    The enzyme nicotinate phosphoribosyltransferase (NAPRT) mediates the rate-limiting step in NAD salvage pathway starting from nicotinic acid. Here the authors show that NAPRT can be detected extracellularly, binds to Toll like receptor 4, and activates NF-kB signaling and cytokine production in macrophage via NAD synthesis-independent pathways.

    • Antonella Managò
    • , Valentina Audrito
    •  & Silvia Deaglio

  • Article
    | Open Access

    Macrophage specific deletion of GGTase-I, a prenylation enzyme, in mice induces inflammatory response and rheumatoid arthritis. Here the authors show that GGTase-I deficiency and the resulting reduction of RAC1 prenylation increase RAC1 interaction with the adaptor protein IQGAP1, leading to GTP-loading of RAC1 and enhanced proinflammatory cytokine production.

    • Murali K. Akula
    • , Mohamed X. Ibrahim
    •  & Martin O. Bergo

  • Article
    | Open Access

    Here, Zimmer et al. analyze the natural killer (NK) cell response in a patient cohort with acute dengue virus infection showing early NK cell activation and proliferation, and the data suggest that NK cell proliferation depends on IL-18 signaling, and that responding NK cells have a skin-homing phenotype.

    • Christine L. Zimmer
    • , Martin Cornillet
    •  & Niklas K. Björkström

  • Article
    | Open Access

    BTLA is established as a negative regulator of natural killer T (NKT) cell function, and share its ligand HVEM with CD160. Here the authors show, by analyzing NKT activation in CD160-deficient mice or with BTLA blockade, that CD160 synergizes with BTLA to negatively regulate NKT cells during hepatic injury.

    • Tae-Jin Kim
    • , Gayoung Park
    •  & Kyung-Mi Lee

  • Article
    | Open Access

    The Nemo-like kinase (NLK) plays a regulatory role in immune responses. Here, the authors show that NLK inhibits antiviral IFN responses by phosphorylating the mitochondrial antiviral-signaling protein MAVS and describe a MAVS-derived peptide that exhibits antiviral effects both in vitro and in mice.

    • Shang-Ze Li
    • , Qi-Peng Shu
    •  & Xiao-Dong Zhang

  • Article
    | Open Access

    Fas signalling induces apoptosis of activated T cells to maintain immune homeostasis. Here the authors show that Fas also induces PKC-β activation to promote NF-κB-mediated TH9 cell differentiation, while p38 activation by PKC-β antagonizes this effect, thereby supporting a synergy between p38 inhibitor and Fas for TH9 differentiation.

    • Yingying Shen
    • , Zhengbo Song
    •  & Jianli Wang

  • Article
    | Open Access

    The differentiation and function of regulatory T (Treg) cells are critically controlled by T cell receptor (TCR) signaling. Here the authors show that CARD11-BCL10-MALT1 (CBM) complexes are dispensable for effector Treg conversion under inflammatory conditions but are critical for mediating Treg suppressive activity in a MALT1 paracaspase-dependent manner.

    • Marc Rosenbaum
    • , Andreas Gewies
    •  & Jürgen Ruland

  • Review Article
    | Open Access

    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

  • Article
    | Open Access

    The phosphatase Shp-2 was implicated in NK cell education due to its reported association with inhibitory receptors, but its function in this context is unclear. Here the authors show that Shp-2 is not required for NK cell function, but is necessary for IL-15-induced metabolic burst and expansion.

    • Charlène Niogret
    • , S. M. Shahjahan Miah
    •  & Greta Guarda

  • Article
    | Open Access

    CD4+ helper T cells producing IL-9 (Th9) have been implicated in anti-tumor immunity, with Th9 differentiation inducible in vitro via IL-4 and TGFβ treatment. Here the authors show that replacing TGFβ with IL-1β induces a distinct IL-9+ CD4+ population that have strong cytotoxic and anti-tumor activity in preclinical mouse models.

    • Gang Xue
    • , Guangxu Jin
    •  & Yong Lu

  • Article
    | Open Access

    Regulatory T (Treg) cells are important for maintaining immune homeostasis. Here the authors show that STIM1 and STIM2, which activate the Ca2+ channel ORAI1, are essential for the differentiation of peripheral Treg cells into tissue-resident and follicular Treg cells and their ability to limit autoimmunity in mice.

    • Martin Vaeth
    • , Yin-Hu Wang
    •  & Stefan Feske

  • Article
    | Open Access

    Ubiquitination may control protein stability or function. Here the authors show that an ubiquitination enzyme, Hectd3, ubiquitinates Stat3 and Malt1 to modulate their function but not degradation in T cells, and thereby promoting the differentiation of pathogenic Th17 cells and susceptibility to a mouse model of multiple sclerosis.

    • Jonathan J. Cho
    • , Zhiwei Xu
    •  & Dorina Avram

  • Article
    | Open Access

    Microfold cells (M-cell) are specialized cells of the intestine that sample luminal microbiota and dietary antigens. Here the authors show that epithelial non-canonical NFκB signalling, as induced by NIK, is important for M-cells maintenance, yet constitutive NIK activation is associated with gut inflammation and inflammatory bowel disease.

    • Sadeesh K. Ramakrishnan
    • , Huabing Zhang
    •  & Yatrik M. Shah

  • Article
    | Open Access

    Engagement of T cell receptors (TCRs) induces the formation of microclusters that mediate the downstream signalling events. Here the authors show, using high resolution TIRF-SIM and live cell imaging, that ZAP70 and LAT are recruited to TCR with distinct kinetics, with the delayed ZAP70-TCR association modulated by TCR-induced calcium flux.

    • Jason Yi
    • , Lakshmi Balagopalan
    •  & Lawrence E. Samelson

  • Article
    | Open Access

    RIG-I is a critical receptor in the induction of innate immune responses, but mutations in RIG-I can be associated with hyperactive signalling and autoimmune disease. Here Zheng et al. apply HDX-MS approaches to reveal dysregulated checkpoints that result in recognition of self-derived RNA during RIG-I mediated autoimmunity.

    • Jie Zheng
    • , Chen Wang
    •  & Patrick R. Griffin

  • Article
    | Open Access

    Regulatory T (Treg) cells are important for maintaining immune homeostasis by suppressing immune cell activation, but how the Treg cell pool is maintained is still unclear. Here the authors show that a kinase, Lkb1, operates in dendritic cells (DC) to inhibit Treg cell expansion and immunosuppression via mechanisms involving NF-kB/OX40L signalling.

    • Song Chen
    • , Lijun Fang
    •  & Xiaoming Feng

  • Article
    | Open Access

    Dendritic cells (DC) are important regulators of both innate and adaptive immunity, but how the DC pool is homeostatically maintained in vivo is unclear. Here the authors show that combined deficiency of FLT3 and CSF1R impedes the differentiation of spleen macrophages of embryonic origin that are required for DC homeostasis.

    • Gulce Itir Percin
    • , Jiri Eitler
    •  & Claudia Waskow

  • Article
    | Open Access

    Natural killer (NK) cells eliminate damaged cells, but spare healthy ones by recognizing their expressed ligands via NK inhibitory receptors. Here the authors solve the structure of an NK inhibitory receptor, NKR-P1B, bound to its ligand, Clr-b, with further data suggesting a weak interaction and informing on the basis of missing-self recognition.

    • Gautham R. Balaji
    • , Oscar A. Aguilar
    •  & Richard Berry

  • Article
    | Open Access

    Nuclear factor-kappa B (NF-κB) signaling is regulated by ubiquitin to maintain immune homeostasis. Here the authors show that a peptidylprolyl isomerase, CYPJ, blocks TAB2/3 or LUBAC ubiquitin chain sensing and suppress NF-κB activation, with CYPJ-deficiency leading to susceptibility to inflammatory stimuli.

    • Chunjie Sheng
    • , Chen Yao
    •  & Shuai Chen

  • Article
    | Open Access

    T helper 2 (Th2) cells and type 2 innate lymphoid cells (ILC2) respond differently to interleukin-33 (IL-33) stimulation. Here the authors show that a phosphatase, Dusp10, is expressed in Th2, but not ILC2, to dephosphorylate p38 kinase, reduce GATA3 transcription factor activity, and suppress the induction of IL-5 in response to IL-33.

    • Takeshi Yamamoto
    • , Yusuke Endo
    •  & Toshinori Nakayama

  • Article
    | Open Access

    The BCL10-MALT1 complex is a central signaling hub in lymphocytes and linked to various human immune pathologies. Here the authors present the cryo-EM structure of the BCL10-MALT1 filament core and verify the identified BCL10/MALT1 interface with mutagenesis studies.

    • Florian Schlauderer
    • , Thomas Seeholzer
    •  & Katja Lammens

  • Article
    | Open Access

    The molecular mechanisms leading to heart failure in patients with Duchenne muscular dystrophy are unclear. Here the authors show that NF-κB is activated in the heart of dystrophin-deficient mice and that its ablation rescues cardiac function through chromatin remodeling and activation of gene expression.

    • Jennifer M. Peterson
    • , David J. Wang
    •  & Denis C. Guttridge

  • Article
    | Open Access

    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

  • Article
    | Open Access

    Interleukin-15 (IL-15) regulates the homeostasis of many immune cell types, including natural killer T (NKT) cells, but the underlying mechanism is not completely clear. Here the authors analyse Tbkbp1-deficient mice and show that IL-15 induces Tbkbp1-dependent autophagy to modulate NKT survival.

    • Lele Zhu
    • , Xiaoping Xie
    •  & Shao-Cong Sun

  • Article
    | Open Access

    The innate immunity system detects viral pathogens by sensing viral DNA or RNA via distinct pathways, but whether these pathways cross-regulate is unclear. Here the authors show that TRAF3, a known regulator of the RNA-sensing pathway, modulates an NF-κB activator NIK to control DNA-sensing by the adaptor STING in immune cells.

    • Kislay Parvatiyar
    • , Jose Pindado
    •  & Genhong Cheng

  • Article
    | Open Access

    Invariant natural killer T (iNKT) cells can be subsetted by their cytokine profiles, but how they develop in the thymus is unclear. Here the authors show, by analysing mice carrying mutant Zap70 genes, that T cell receptor signaling strength induces epigenetic changes of genes to modulate iNKT lineages.

    • Kathryn D. Tuttle
    • , S. Harsha Krovi
    •  & Laurent Gapin

  • Article
    | Open Access

    Invariant natural killer T (iNKT) cells can be subsetted based on their cytokine productions. Here the authors show, using Zap70 mutant mice, that interferon-γ secreting (IFN-γ) iNKT cells may be induced by hampered T cell receptor signallings to help ameliorate interleukin-17-mediated joint inflammation.

    • Meng Zhao
    • , Mattias N. D. Svensson
    •  & Mitchell Kronenberg

  • Article
    | Open Access

    T cells can be activated by a small, two-digit, number of antigen peptide molecules even though the receptor for antigen (TCR) is of low affinity. Here the authors present evidence that all TCRs within a nanocluster can become activated when only a subset is bound to antigen.

    • N. Martin-Blanco
    • , R. Blanco
    •  & B. Alarcon

  • Article
    | Open Access

    Glutamine can feed into the TCA cycle as a fuel for oxidative phosphorylation and thereby can affect metabolic pathways in lymphocytes. Yet here the authors show that glutamine serves predominantly as a signalling molecule that sustains cMyc expression to control NK cell metabolism and effector function.

    • Róisín M. Loftus
    • , Nadine Assmann
    •  & David K. Finlay

  • Article
    | Open Access

    Systemic lupus erythematosus (SLE) is an autoimmune disorder mediated by excessive autoantibodies. Here the authors show that an E3 ubiquitin ligase, Peli1, negatively modulates noncanonical NF-κB signaling to restrain lupus-like symptoms in mice, and that Peli1 expression inversely correlates with SLE severity in humans.

    • Junli Liu
    • , Xinfang Huang
    •  & Yichuan Xiao

  • Article
    | Open Access

    CD28 transmits co-stimulatory signals for the activation of both mouse and human T cells, but in vivo hyperactivation of CD28 has opposite effects on system immunity. Here, the authors show that a single amino acid difference between mouse and human CD28 dictates this function distinction via differential recruitment of Nck.

    • Nicla Porciello
    • , Paola Grazioli
    •  & Loretta Tuosto

  • Article
    | Open Access

    T cell activation is critically controlled by T cell receptor (TCR) signalling. Here the authors show, using live cell imaging, atomic force microscopy and modelling simulation, a prompt separation of TCR and CD45 that negatively correlates with TCR activation, supporting a refined kinetic segregation model of TCR signalling.

    • Yair Razvag
    • , Yair Neve-Oz
    •  & Eilon Sherman

  • Article
    | Open Access

    Semaphorin-4A is a cell surface protein with known functions in neural development and immune regulation, but the mechanism for immune modulation is unclear. Here the authors show that ILT-4, previously found on myeloid cells, is the receptor of Semaphorin-4A on activate human CD4 T cells for mediating T cell co-stimulation.

    • Ning Lu
    • , Ying Li
    •  & Lieping Chen

  • Article
    | Open Access

    The N-terminal domain (NTD) of interleukin-3 receptor α-subunit (IL3Rα) is involved in IL-3 recognition but the underlying mechanism is unknown. Here, the authors present crystal structures of the IL3Rα complex and provide biochemical evidence that the NTD regulates IL-3 binding and signalling complex assembly.

    • Sophie E. Broughton
    • , Timothy R. Hercus
    •  & Michael W. Parker

  • Article
    | Open Access

    Inflammasomes are protein complexes induced by pathogens for the secretion of pro-inflammatory cytokines IL-1β and IL-18 in immune cells. Here the authors show, using a new mouse model, that aberrant NLRC4 and ASC-dependent inflammasome activation in neutrophils contributes to systemic inflammation.

    • Randilea D. Nichols
    • , Jakob von Moltke
    •  & Russell E. Vance

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