Signal transduction

  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • 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