ORCID Profile
0000-0003-1441-1727
Current Organisation
University of Oxford
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Publisher: The American Association of Immunologists
Date: 15-12-2011
Abstract: Semi-invariant NKT cells are thymus-derived innate-like lymphocytes that modulate microbial and tumor immunity as well as autoimmune diseases. These immunoregulatory properties of NKT cells are acquired during their development. Much has been learned regarding the molecular and cellular cues that promote NKT cell development, yet how these cells are maintained in the thymus and the periphery and how they acquire functional competence are incompletely understood. We found that IL-15 induced several Bcl-2 family survival factors in thymic and splenic NKT cells in vitro. Yet, IL-15–mediated thymic and peripheral NKT cell survival critically depended on Bcl-xL expression. Additionally, IL-15 regulated thymic developmental stage 2 to stage 3 lineage progression and terminal NKT cell differentiation. Global gene expression analyses and validation revealed that IL-15 regulated Tbx21 (T-bet) expression in thymic NKT cells. The loss of IL-15 also resulted in poor expression of key effector molecules such as IFN-γ, granzyme A and C, as well as several NK cell receptors, which are also regulated by T-bet in NKT cells. Taken together, our findings reveal a critical role for IL-15 in NKT cell survival, which is mediated by Bcl-xL, and effector differentiation, which is consistent with a role of T-bet in regulating terminal maturation.
Publisher: Proceedings of the National Academy of Sciences
Date: 25-03-2005
Abstract: T lineage commitment occurs in a discrete, stage-specific manner during thymic ontogeny. Intrathymic precursor transfer experiments and the identification of CD4 + 8 + double-positive (DP), Vα14Jα18 natural T (iNKT) cells suggest that commitment to this lineage might occur at the DP stage. Nevertheless, this matter remains contentious because others failed to detect Vα14Jα18-positive iNKT cells that are CD4 + 8 + . In resolution to this issue, we demonstrate that retinoic acid receptor-related orphan receptor γ (RORγ) 0/0 thymi, which accumulate immature single-positive (ISP) thymocytes that precede the DP stage, do not rearrange V α 14 -to- J α 18 gene segments, suggesting that this event occurs at a post-ISP stage. Mixed radiation bone marrow chimeras revealed that RORγ functions in an iNKT cell lineage-specific manner. Further, introgression of a Bcl-x L transgene into RORγ 0/0 mice, which promotes survival and permits secondary rearrangements of distal V α and J α gene segments at the DP stage, rescues V α 14 -to- J α 18 recombination. Similarly, introgression of a rearranged V α 14J α 18 transgene into RORγ 0/0 mice results in functional iNKT cells. Thus, our data support the “T cell receptor-instructive (mainstream precursor) model” of iNKT cell lineage specification where V α 14 -to- J α 18 rearrangement, positive selection, and iNKT cell lineage commitment occur at or after the DP stage of ontogeny.
Publisher: Elsevier BV
Date: 04-2020
Publisher: Frontiers Media SA
Date: 02-04-2021
DOI: 10.3389/FIMMU.2021.661162
Abstract: Pyroptosis is a proinflammatory form of cell death, mediated by membrane pore-forming proteins called gasdermins. Gasdermin pores allow the release of the pro-inflammatory cytokines IL-1β and IL-18 and cause cell swelling and cell lysis leading to release of other intracellular proteins that act as alarmins to perpetuate inflammation. The best characterized, gasdermin D, forms pores via its N-terminal domain, generated after the cleavage of full length gasdermin D by caspase-1 or -11 (caspase-4/5 in humans) typically upon sensing of intracellular pathogens. Thus, gasdermins were originally thought to largely contribute to pathogen-induced inflammation. We now know that gasdermin family members can also be cleaved by other proteases, such as caspase-3, caspase-8 and granzymes, and that they contribute to sterile inflammation as well as inflammation in autoinflammatory diseases or during cancer immunotherapy. Here we briefly review how and when gasdermin pores are formed, and then focus on emerging endogenous mechanisms and therapeutic approaches that could be used to control pore formation, pyroptosis and downstream inflammation.
Publisher: MDPI AG
Date: 22-09-2020
Abstract: In modern vaccines, adjuvants can be sophisticated immunological tools to promote robust and long-lasting protection against prevalent diseases. However, there is an urgent need to improve immunogenicity of vaccines in order to protect mankind from life-threatening diseases such as AIDS, malaria or, most recently, COVID-19. Therefore, it is important to understand the cellular and molecular mechanisms of action of vaccine adjuvants, which generally trigger the innate immune system to enhance signal transition to adaptive immunity, resulting in pathogen-specific protection. Thus, improved understanding of vaccine adjuvant mechanisms may aid in the design of “intelligent” vaccines to provide robust protection from pathogens. Various commonly used clinical adjuvants, such as aluminium salts, saponins or emulsions, have been identified as activators of inflammasomes - multiprotein signalling platforms that drive activation of inflammatory caspases, resulting in secretion of pro-inflammatory cytokines of the IL-1 family. Importantly, these cytokines affect the cellular and humoral arms of adaptive immunity, which indicates that inflammasomes represent a valuable target of vaccine adjuvants. In this review, we highlight the impact of different inflammasomes on vaccine adjuvant-induced immune responses regarding their mechanisms and immunogenicity. In this context, we focus on clinically relevant adjuvants that have been shown to activate the NLRP3 inflammasome and also present various experimental adjuvants that activate the NLRP3-, NLRC4-, AIM2-, pyrin-, or non-canonical inflammasomes and could have the potential to improve future vaccines. Together, we provide a comprehensive overview on vaccine adjuvants that are known, or suggested, to promote immunogenicity through inflammasome-mediated signalling.
Publisher: Proceedings of the National Academy of Sciences
Date: 13-09-2021
Abstract: The NLRP3 inflammasome is an innate sensor activated by signals released from pathogens or injured tissues. Activation of the NLRP3 inflammasome can be beneficial during infection and vaccination. Nonetheless, when NLRP3 activity is uncontrolled and chronic it becomes detrimental and contributes to inflammation-driven pathology in several diseases. Licensing mechanisms must exist that prevent unwanted NLRP3 inflammasome responses. Here, we characterize one such mechanism. We describe that TBK1 and IKKε, two closely related kinases activated upon TLR signaling, act as a novel OFF switch for the NLRP3 pathway. Using pharmacological and genetic approaches, we show that TBK1 and IKKε together limit the responses downstream of the NLRP3 inflammasome activation and work against the PP2A phosphatase ON switch to balance NLRP3 activity.
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.CELREP.2018.07.027
Abstract: IL-1β requires processing by caspase-1 to generate the active, pro-inflammatory cytokine. Acute IL-1β secretion from inflammasome-activated macrophages requires caspase-1-dependent GSDMD cleavage, which also induces pyroptosis. Mechanisms of IL-1β secretion by pyroptotic and non-pyroptotic cells, and the precise functions of caspase-1 and GSDMD therein, are unresolved. Here, we show that, while efficient early secretion of endogenous IL-1β from primary non-pyroptotic myeloid cells in vitro requires GSDMD, later IL-1β release in vitro and in vivo proceeds independently of GSDMD. IL-1β maturation is sufficient for slow, caspase-1/GSDMD-independent secretion of ectopic IL-1β from resting, non-pyroptotic macrophages, but the speed of IL-1β release is boosted by inflammasome activation, via caspase-1 and GSDMD. IL-1β cleavage induces IL-1β enrichment at PIP2-enriched plasma membrane ruffles, and this is a prerequisite for IL-1β secretion and is mediated by a polybasic motif within the cytokine. We thus reveal a mechanism in which maturation-induced IL-1β trafficking facilitates its unconventional secretion.
Publisher: Proceedings of the National Academy of Sciences
Date: 04-11-2014
Abstract: Helminths and allergens stimulate type 2 immune responses by largely unknown mechanisms. Proteolytic activity is a common feature of many helminths and allergens and can promote activation of the immune system. Signaling pathways activated by these proteases remain poorly characterized and are the focus of this study. Using basophils as model type 2 immune cells, we identified roles for the immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptor Fc receptor γ-chain and calcium signaling in protease-stimulated basophil activation. We suggest models to explain how protease sensing, ITAM signaling, and nuclear factor of activated T cells pathways contribute to produce allergic type 2 responses. Elucidation of these signaling pathways and ultimately the identity of protease allergen sensors will be important for the development of pharmacologic strategies to target the initiation of allergic responses.
Publisher: Springer Science and Business Media LLC
Date: 06-2009
DOI: 10.1038/NI0609-665A
Publisher: Frontiers Media SA
Date: 22-12-2017
Publisher: MDPI AG
Date: 12-04-2022
Abstract: About thirty years ago, a new form of pro-inflammatory lytic cell death was observed and termed pyroptosis. Only in 2015, gasdermins were defined as molecules that create pores at the plasma membrane and drive pyroptosis. Today, we know that gasdermin-mediated death is an important antimicrobial defence mechanism in bacteria, yeast and mammals as it destroys the intracellular niche for pathogen replication. However, excessive and uncontrolled cell death also contributes to immunopathology in several chronic inflammatory diseases, including arthritis. In this review, we discuss recent findings where pyroptosis contributes to tissue damage and inflammation with a main focus on injury-induced and autoimmune arthritis. We also review novel functions and regulatory mechanisms of the pyroptotic executors gasdermins. Finally, we discuss possible models of how pyroptosis may contribute to the cross-talk between fibroblast and macrophages, and also how this cross-talk may regulate inflammation by modulating inflammasome activation and pyroptosis induction.
Publisher: Wiley
Date: 12-08-2014
DOI: 10.1038/ICB.2014.71
Publisher: Wiley
Date: 04-2017
DOI: 10.1002/CPIM.22
Abstract: Semi‐invariant natural killer T (iNKT) cells are CD1d‐restricted innate‐like lymphocytes that recognize lipid agonists. Activated iNKT cells have immunoregulatory properties. Human and mouse iNKT cell functions elicited by different glycolipid agonists are highly conserved, making the mouse an excellent animal model for understanding iNKT cell biology in vivo. This unit describes basic methods for the characterization and quantification (see Basic Protocol 1) and functional analysis of mouse iNKT cells in vivo or in vitro. This unit also contains protocols that describe enrichment and purification of iNKT cells, generation of CD1d tetramer, and lipid antigen loading onto cell‐bound and soluble CD1d for activation of NKT cell hybridomas. © 2017 by John Wiley & Sons, Inc.
Publisher: Proceedings of the National Academy of Sciences
Date: 14-03-2013
Abstract: Invariant natural killer T (iNKT) cells recognize self lipid antigens presented by CD1d molecules. The nature of the self-antigens involved in the development and maturation of iNKT cells is poorly defined. Lysophospholipids are self-antigens presented by CD1d that are generated through the action of phospholipases A1 and A2. Lysosomal phospholipase A2 (LPLA2, group XV phospholipase A2) resides in the endocytic system, the main site where CD1d antigen acquisition occurs, suggesting that it could be particularly important in CD1d function. We find that Lp la2 −/− mice show a decrease in iNKT cell numbers that is neither the result of a general effect on the development of lymphocyte populations nor of effects on CD1d expression. However, endogenous lipid antigen presentation by CD1d is reduced in the absence of LPLA2. Our data suggest that LPLA2 plays a role in the generation of CD1d complexes with thymic lipids required for the normal selection and maturation of iNKT cells.
Publisher: EMBO
Date: 02-03-2023
Abstract: Membrane ion channels of the calcium homeostasis modulator (CALHM) family promote cell–cell crosstalk at neuronal synapses via ATP release, where ATP acts as a neurotransmitter. CALHM6, the only CALHM highly expressed in immune cells, has been linked to the induction of natural killer (NK) cell anti‐tumour activity. However, its mechanism of action and broader functions in the immune system remain unclear. Here, we generated Calhm6 −/− mice and report that CALHM6 is important for the regulation of the early innate control of Listeria monocytogenes infection in vivo . We find that CALHM6 is upregulated in macrophages by pathogen‐derived signals and that it relocates from the intracellular compartment to the macrophage‐NK cell synapse, facilitating ATP release and controlling the kinetics of NK cell activation. Anti‐inflammatory cytokines terminate CALHM6 expression. CALHM6 forms an ion channel when expressed in the plasma membrane of Xenopus oocytes, where channel opening is controlled by a conserved acidic residue, E119. In mammalian cells, CALHM6 is localised to intracellular compartments. Our results contribute to the understanding of neurotransmitter‐like signal exchange between immune cells that fine‐tunes the timing of innate immune responses.
Publisher: The Company of Biologists
Date: 2020
DOI: 10.1242/JCS.239871
Abstract: Complex inflammatory signalling cascades define the response to tissue injury but also control development and homeostasis, limiting these pathways as therapeutic targets. Primary cilia are sub-cellular regulators of cellular signalling, controlling how signalling is organized, encoded and, in some instances, driving or influencing pathogenesis. Our previous research revealed that disruption of ciliary intraflagellar transport (IFT), altered the cell response to IL-1β, supporting a putative link emerging between cilia and inflammation. Here, we show that IFT88 depletion affects specific cytokine-regulated behaviors, changing cytosolic NFκB translocation dynamics, but leaving MAPK unaffected. RNAseq analysis indicates IFT88 regulates one third of the genome-wide targets, including the pro-inflammatory genes Nos2, Il6 and Tnf. By microscopy, we find altered NFκB dynamics are independent to assembly of a ciliary axoneme. Indeed, depletion of IFT88 inhibits the inflammatory responses in the non-ciliated macrophage. We propose ciliary proteins, including IFT88, KIF3A, TTBK2 and NPHP4, act outside of the ciliary axoneme, to tune cytoplasmic NFκB signalling, and specify the downstream cell response. This is thus a non-canonical function for ciliary proteins in shaping cellular inflammation.
Publisher: Rockefeller University Press
Date: 06-02-2018
DOI: 10.1084/JEM.20172222
Abstract: Host-protective caspase-1 activity must be tightly regulated to prevent pathology, but mechanisms controlling the duration of cellular caspase-1 activity are unknown. Caspase-1 is activated on inflammasomes, signaling platforms that facilitate caspase-1 dimerization and autoprocessing. Previous studies with recombinant protein identified a caspase-1 tetramer composed of two p20 and two p10 subunits (p20 10) as an active species. In this study, we report that in the cell, the dominant species of active caspase-1 dimers elicited by inflammasomes are in fact full-length p46 and a transient species, p33 10. Further p33 10 autoprocessing occurs with kinetics specified by inflammasome size and cell type, and this releases p20 10 from the inflammasome, whereupon the tetramer becomes unstable in cells and protease activity is terminated. The inflammasome–caspase-1 complex thus functions as a holoenzyme that directs the location of caspase-1 activity but also incorporates an intrinsic self-limiting mechanism that ensures timely caspase-1 deactivation. This intrinsic mechanism of inflammasome signal shutdown offers a molecular basis for the transient nature, and coordinated timing, of inflammasome-dependent inflammatory responses.
Publisher: Elsevier BV
Date: 02-2012
DOI: 10.1016/J.COI.2011.12.010
Abstract: Diverse cell types use a small number of evolutionarily conserved signaling modules to integrate external cues and elicit distinct functions. A question thus arises as to how does a receptor, which contains a single signaling module, produce distinct outcomes to erse signals, particularly if such module is shared amongst a family of receptors? Emerging data suggest that many immunoreceptors, all of which use a conserved ITAM-module for their signaling, can couple with members of additional classes of membrane receptors to deliver unique signal(s) to the cell. We discuss the possible biological purposes and mechanisms behind these interactions at the plasma membrane. We offer a conceptual framework to understand information processing within the immune system and discuss the new biology of old receptors involving their structural and functional collaborations that evolved to deliver unique signal(s) to the cell using a limited set of conserved signaling modules.
Publisher: Oxford University Press (OUP)
Date: 2021
Abstract: Coronavirus disease 2019 has generated a rapidly evolving field of research, with the global scientific community striving for solutions to the current pandemic. Characterizing humoral responses towards SARS-CoV-2, as well as closely related strains, will help determine whether antibodies are central to infection control, and aid the design of therapeutics and vaccine candidates. This review outlines the major aspects of SARS-CoV-2-specific antibody research to date, with a focus on the various prophylactic and therapeutic uses of antibodies to alleviate disease in addition to the potential of cross-reactive therapies and the implications of long-term immunity.
Publisher: Springer US
Date: 2022
DOI: 10.1007/978-1-0716-2144-8_5
Abstract: The non-canonical inflammasome is a signaling platform that allows for the detection of cytoplasmic lipopolysaccharides (LPS) in immune and non-immune cells. Upon detection of LPS, this inflammasome activates the signaling proteases caspase-4 and -5 (in humans) and caspase-11 (in mice). Inflammatory caspases activation leads to caspase self-processing and the cleavage of the pore-forming protein Gasdermin D (GSDMD). GSDMD N-terminal fragments oligomerize and form pores at the plasma membranes, leading to an inflammatory form of cell death called pyroptosis. Here, we describe a simple method to activate the non-canonical inflammasome in myeloid and epithelial cells and to measure its activity using cell death assay and immunoblotting.
Publisher: Rockefeller University Press
Date: 15-08-2017
Abstract: Assembly of the ASC speck is critical for signaling by the inflammasome. In this issue, Kuri et al. (2017. J. Cell Biol. 0.1083/jcb.201703103) use live microscopy to track fluorescently tagged endogenous ASC in the zebrafish, describing the molecular domains driving ASC speck assembly and identifying a key role for macrophages in ASC speck removal in vivo.
Publisher: Wiley
Date: 02-2016
Abstract: Neutrophils express pattern recognition receptors (PRRs) and regulate immune responses via PRR-dependent cytokine production. An emerging theme is that neutrophil PRRs often exhibit cell type-specific adaptations in their signalling pathways. This prompted us to examine inflammasome signalling by the PRR NLRP3 in murine neutrophils, in comparison to well-established NLRP3 signalling pathways in macrophages. Here, we demonstrate that while murine neutrophils can indeed signal via the NLRP3 inflammasome, neutrophil NLRP3 selectively responds to soluble agonists but not to the particulate/crystalline agonists that trigger NLRP3 activation in macrophages via phagolysosomal rupture. In keeping with this, alum did not trigger IL-1β production from human PMN, and the lysosomotropic peptide Leu-Leu-OMe stimulated only weak NLRP3-dependent IL-1β production from murine neutrophils, suggesting that lysosomal rupture is not a strong stimulus for NLRP3 activation in neutrophils. We validated our in vitro findings for poor neutrophil NLRP3 responses to particles in vivo, where we demonstrated that neutrophils do not significantly contribute to alum-induced IL-1β production in mice. In all, our studies highlight that myeloid cell identity and the nature of the danger signal can strongly influence signalling by a single PRR, thus shaping the nature of the resultant immune response.
Publisher: Oxford University Press (OUP)
Date: 28-03-2008
Abstract: Members of the IL-6/IL-12 cytokine family play central roles in Crohn's disease. The present findings demonstrate that IL-27, a close relative of IL-12 and IL-23, can promote the onset of colitis in mice. We report that, compared with IL-10-deficient animals, which succumb to chronic intestinal disease at 3-6 months of age, mice lacking both IL-10 and the IL-27R (IL-27R/WSX-1) exhibit delayed pathology and prolonged survival (>1 year). Moreover, unlike highly susceptible IL-10-deficient counterparts, they were able to clear infection with Trichuris muris, a colon-dwelling nematode. In both models of intestinal inflammation, improved clinical outcome was associated with reduced inflammation and profound attenuation of T(h)1 responses and, consistent with these in vivo findings, we confirmed that during in vitro differentiation, IL-27 directly promotes CD4(+) T cell IFN-gamma production through effects on Tbet, a key T(h)1 transcription factor. We also found that its ability to suppress T(h)2 responses, which was clearly evident in helminth-infected IL-10-/-IL-27R-/- mice, was largely Tbet independent. Taken together, these studies demonstrate that, in the absence of IL-10, IL-27 can promote T(h)1-type and suppress T(h)2-type intestinal inflammation but, ultimately, is not required for the development of inflammatory bowel disease.
Publisher: Rockefeller University Press
Date: 15-12-2021
DOI: 10.1084/JEM.20211336
Abstract: The germinal center (GC) is a site where somatic hypermutation and clonal selection are coupled for antibody affinity maturation against infections. However, how GCs are formed and regulated is incompletely understood. Here, we identified an unexpected role of Tank-binding kinase-1 (TBK1) as a crucial B cell–intrinsic factor for GC formation. Using immunization and malaria infection models, we show that TBK1-deficient B cells failed to form GC despite normal Tfh cell differentiation, although some malaria-infected B cell–specific TBK1-deficient mice could survive by GC-independent mechanisms. Mechanistically, TBK1 phosphorylation elevates in B cells during GC differentiation and regulates the balance of IRF4/BCL6 expression by limiting CD40 and BCR activation through noncanonical NF-κB and AKTT308 signaling. In the absence of TBK1, CD40 and BCR signaling synergistically enhanced IRF4 expression in Pre-GC, leading to BCL6 suppression, and therefore failed to form GCs. As a result, memory B cells generated from TBK1-deficient B cells fail to confer sterile immunity upon reinfection, suggesting that TBK1 determines B cell fate to promote long-lasting humoral immunity.
Publisher: Portland Press Ltd.
Date: 02-12-2021
DOI: 10.1042/BST20200987
Abstract: Inflammasomes are protein complexes in the innate immune system that regulate the production of pro-inflammatory cytokines and inflammatory cell death. Inflammasome activation and subsequent cell death often occur within minutes to an hour, so the pathway must be dynamically controlled to prevent excessive inflammation and the development of inflammatory diseases. Phosphorylation is a fundamental post-translational modification that allows rapid control over protein function and the phosphorylation of inflammasome proteins has emerged as a key regulatory step in inflammasome activation. Phosphorylation of inflammasome sensor and adapter proteins regulates their inter- and intra-molecular interactions, subcellular localisation, and function. The control of inflammasome phosphorylation may thus provide a new strategy for the development of anti-inflammatory therapeutics. Herein we describe the current knowledge of how phosphorylation operates as a critical switch for inflammasome signalling.
Publisher: Proceedings of the National Academy of Sciences
Date: 07-2020
Abstract: Semi-invariant natural killer T (iNKT) cells are innate-like lymphocytes that control a variety of immune functions. iNKT cell functions are mediated by high-affinity interactions with self-agonists displayed by the lipid-presenting CD1d molecule. How iNKT cells attain tolerance to high-affinity interactions with self remains unknown. This understanding is of immunologic import, as an unbridled iNKT cell-mediated response can cause inflammatory diseases. We discovered that Nur77—a transcription factor expressed at high levels in iNKT cells—induced caspase-3–mediated apoptosis and markers of T cell exhaustion such as PD-1 in iNKT cell precursors, which led to hyporesponsiveness to a high-affinity lipid agonist. Thus, Nur77 plays a central role in self-tolerance induction of iNKT cells.
Publisher: Springer Science and Business Media LLC
Date: 21-10-2007
DOI: 10.1038/NI1524
Abstract: The effector functions of natural killer cells are regulated by activating receptors, which recognize stress-inducible ligands expressed on target cells and signal through association with signaling adaptors. Here we developed a mouse model in which a fusion of the signaling adaptor DAP10 and ubiquitin efficiently downregulated expression of the activating receptor NKG2D on the surfaces of natural killer cells. With this system, we identified coupling of the signaling pathways triggered by NKG2D and DAP10 to those initiated by the interleukin 15 receptor. We suggest that this coupling of activating receptors to other receptor systems could function more generally to regulate cell type-specific signaling events in distinct physiological contexts.
Publisher: Wiley
Date: 12-2015
Publisher: American Society of Hematology
Date: 10-2004
Publisher: Elsevier BV
Date: 09-2006
DOI: 10.1016/J.IMMUNI.2006.06.017
Abstract: Invariant natural killer T (iNKT) cell-derived cytokines have important functions in inflammation, host defense, and immunoregulation. Yet, when and how iNKT cells undergo effector differentiation, which endows them with the capacity to rapidly secrete cytokines upon activation, remains unknown. We discovered that granulocyte-macrophage colony-stimulating factor (Csf-2)-deficient mice developed iNKT cells that failed to respond to the model antigen alpha-galactosylceramide because of an intrinsic defect in the fusion of secretory vesicles with the plasma membrane. Exogenous Csf-2 corrected the functional defect only when supplied during the development of thymic, but not mature, splenic Csf-2-deficient iNKT cells. Thus, we ascribe a unique function to Csf-2, which regulates iNKT cell effector differentiation during development by a mechanism that renders them competent for cytokine secretion.
Publisher: Springer Science and Business Media LLC
Date: 09-03-2014
DOI: 10.1038/NI.2845
Publisher: Springer Science and Business Media LLC
Date: 19-03-2009
DOI: 10.1038/NI.1713
Abstract: Cytokines are soluble mediators of cell communication that are critical in immune regulation. They induce specific gene-expression programs in responsive cells. Recent findings, however, indicate that cytokine receptors can regulate immune cell functions by transcription-independent mechanisms. Here we review the current understanding of how cytokine signaling regulates the functions of other signaling pathways by first discussing the 'traditional' transcription-mediated consequences of cytokine signaling and then providing a detailed description of transcription-independent lateral communications between cytokine receptors and other cellular receptors.
Publisher: Springer Science and Business Media LLC
Date: 15-11-2017
DOI: 10.1038/S41598-017-15461-Y
Abstract: Semi-invariant natural killer T (NKT) cells are innate-like lymphocytes with immunoregulatory properties. NKT cell survival during development requires signal processing by activated RelA/NF-κB. Nonetheless, the upstream signal(s) integrated by NF-κB in developing NKT cells remains incompletely defined. We show that the introgression of Bcl-x L -coding Bcl2l1 transgene into NF-κB signalling-deficient I κ BΔN transgenic mouse rescues NKT cell development and differentiation in this mouse model. We reasoned that NF-κB activation was protecting developing NKT cells from death signals emanating either from high affinity agonist recognition by the T cell receptor (TCR) or from a death receptor, such as tumor necrosis factor receptor 1 (TNFR1) or Fas. Surprisingly, the single and combined deficiency in PKC-θ or CARMA-1—the two signal transducers at the NKT TCR proximal signalling node—only partially recapitulated the NKT cell deficiency observed in IκBΔN tg mouse. Accordingly, introgression of the Bcl2l1 transgene into PKC-θ null mouse failed to rescue NKT cell development. Instead, TNFR1-deficiency, but not the Fas-deficiency, rescued NKT cell development in IκBΔN tg mice. Consistent with this finding, treatment of thymocytes with an antagonist of the inhibitor of κB kinase —which blocks downstream NF-κB activation— sensitized NKT cells to TNF-α-induced cell death in vitro . Hence, we conclude that signal integration by NF-κB protects developing NKT cells from death signals emanating from TNFR1, but not from the NKT TCR or Fas.
Publisher: Springer Science and Business Media LLC
Date: 21-03-2016
DOI: 10.1038/CMI.2016.11
Publisher: Elsevier BV
Date: 04-2007
Publisher: The American Association of Immunologists
Date: 15-05-2018
Abstract: The mammalian inhibitor of apoptosis proteins (IAPs) are key regulators of cell death and inflammation. A major function of IAPs is to block the formation of a cell death–inducing complex, termed the ripoptosome, which can trigger caspase-8–dependent apoptosis or caspase-independent necroptosis. Recent studies report that upon TLR4 or TNF receptor 1 (TNFR1) signaling in macrophages, the ripoptosome can also induce NLRP3 inflammasome formation and IL-1β maturation. Whether neutrophils have the capacity to assemble a ripoptosome to induce cell death and inflammasome activation during TLR4 and TNFR1 signaling is unclear. In this study, we demonstrate that murine neutrophils can signal via TNFR1-driven ripoptosome assembly to induce both cell death and IL-1β maturation. However, unlike macrophages, neutrophils suppress TLR4-dependent cell death and NLRP3 inflammasome activation during IAP inhibition via deficiencies in the CD14/TRIF arm of TLR4 signaling.
Location: United States of America
Location: United Kingdom of Great Britain and Northern Ireland
Location: United States of America
No related grants have been discovered for Jelena Bezbradica.