154 results found
Ambrose AR, Hazime KS, Worboys JD, et al., 2020, Synaptic secretion from human natural killer cells is diverse and includes supramolecular attack particles, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 117, Pages: 23717-23720, ISSN: 0027-8424
Smith SL, Kennedy PR, Stacey KB, et al., 2020, Diversity of peripheral blood human NK cells identified by single-cell RNA sequencing, BLOOD ADVANCES, Vol: 4, Pages: 1388-1406, ISSN: 2473-9529
Williamson DJ, Burn GL, Simoncelli S, et al., 2020, Machine learning for cluster analysis of localization microscopy data, NATURE COMMUNICATIONS, Vol: 11, ISSN: 2041-1723
Gritsenko A, Yu S, Martin-Sanchez F, et al., 2020, Priming is dispensable for NLRP3 inflammasome activation in human monocytes
<jats:title>ABSTRACT</jats:title><jats:p>Interleukin (IL)-1 family of cytokines modulate immune responses during infection and inflammation. IL-18 and IL-1β are members of the IL-1 family, which contribute to inflammatory conditions such as rheumatoid arthritis and Alzheimer’s disease. IL-18 and IL-1β are produced as inactive precursors that are activated by large macromolecular complexes called inflammasomes upon sensing damage or pathogenic signals. Canonical NLRP3 inflammasome activation is regarded to require a priming step that causes NLRP3 and IL-1β gene upregulation, and also NLRP3 post-translational licencing. A subsequent activation step leads to the assembly of the inflammasome and the cleavage of pro-IL-18 and pro-IL-1β by caspase-1 into their mature forms, allowing their release. Here we show that in primary human monocytes, the initial priming step is dispensable to form an active NLRP3 inflammasome. We found that, in the absence of priming, the NLRP3 activator nigericin caused the processing and release of constitutively expressed IL-18. Another IL-1 family member, IL-37, is constitutively cleaved but the release of its mature form was mediated by inflammasome activation, also in the absence of a priming step. This NLRP3 activation was characterised by ASC oligomerisation as well as caspase-1 and GSDMD cleavage and was blocked by the NLRP3 inhibitor MCC950 and in NLRP3 deficient cells. IL-18 and IL-37 release were impaired in GSDMD deficient THP-1s, suggesting that pyroptosis is required for release of these cytokines. This work highlights the readiness of the NLRP3 inflammasome to assemble in the absence of priming and hence contribute to sterile inflammatory processes in health and disease.</jats:p><jats:sec><jats:title>Significance Statement</jats:title><jats:p>The NLRP3 inflammasome is a driver of inflammation through the processing of Interleukins (IL)-1β and IL-18. Hum
Kennedy PR, Barthen C, Williamson DJ, et al., 2019, Genetic diversity affects the nanoscale membrane organization and signaling of natural killer cell receptors, SCIENCE SIGNALING, Vol: 12, ISSN: 1945-0877
Kolba MD, Dudka W, Zareba-Koziol M, et al., 2019, Tunneling nanotube-mediated intercellular vesicle and protein transfer in the stroma-provided imatinib resistance in chronic myeloid leukemia cells, CELL DEATH & DISEASE, Vol: 10, ISSN: 2041-4889
Kennedy PR, Barthen C, Williamson DJ, et al., 2019, HLA-B and HLA-C differ in their nanoscale organization at cell surfaces, Frontiers in Immunology, Vol: 10, ISSN: 1664-3224
The particular HLA class I variants an individual carries influences their resistance and susceptibility to a multitude of diseases. Expression level and variation in the peptide binding region correlates with, for example, a person's progression to AIDS after HIV infection. One factor which has not yet been addressed is whether or not different HLA class I proteins organize differently in the cell membrane on a nanoscale. Here, we examined the organization of three HLA-B allotypes (B*2705, B*5301, and B*5701) and two HLA-C allotypes (C*0602 and C*0702) in the membrane of 721.221 cells which otherwise lack expression of HLA-B or HLA-C. All these allotypes are ligands for the T cell receptor and leukocyte immunoglobulin-like receptors, but additionally, the HLA-B allotypes are ligands for the killer-cell immunoglobulin-like receptor family member KIR3DL1, HLA-C*0602 is a ligand for KIR2DL1, and HLA-C*0702 is a ligand for KIR2DL2/3. Using super-resolution microscopy, we found that both HLA-B and HLA-C formed more clusters and a greater proportion of HLA contributed to clusters, when expressed at lower levels. Thus, HLA class I organization is a covariate in genetic association studies of HLA class I expression level with disease progression. Surprisingly, we also found that HLA-C was more clustered than HLA-B when expression level was controlled. HLA-C consistently formed larger and more numerous clusters than HLA-B and a greater proportion of HLA-C contributed to clusters than for HLA-B. We also found that the organization of HLA class I proteins varied with cell type. T cells exhibited a particularly clustered organization of HLA class I while B cells expressed a more uniform distribution. In summary, HLA class I variants are organized differently in the cell surface membrane which may impact their functions.
Walwyn-Brown K, Guldevall K, Saeed M, et al., 2018, Human NK Cells Lyse Th2-Polarizing Dendritic Cells via NKp30 and DNAM-1, JOURNAL OF IMMUNOLOGY, Vol: 201, Pages: 2028-2041, ISSN: 0022-1767
Gil-Krzewska A, Saeed MB, Oszmiana A, et al., 2018, An actin cytoskeletal barrier inhibits lytic granule release from natural killer cells in patients with Chediak-Higashi syndrome, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 142, Pages: 914-+, ISSN: 0091-6749
Srpan K, Ambrose A, Karampatzakis A, et al., 2018, Shedding of CD16 disassembles the NK cell immune synapse and boosts serial engagement of target cells, JOURNAL OF CELL BIOLOGY, Vol: 217, Pages: 3267-3283, ISSN: 0021-9525
Leung EYL, Ennis DP, Athineos D, et al., 2018, Oncolytic adenovirus infection leads to contact-dependent activation of natural killer cells and augments virotherapy effectiveness for ovarian cancer., AACR Special Conference on Addressing Critical Questions in Ovarian Cancer Research and Treatment, Publisher: AMER ASSOC CANCER RESEARCH, Pages: 97-98, ISSN: 1078-0432
Tordo J, O'Leary C, Antunes ASLM, et al., 2018, A novel adeno-associated virus capsid with enhanced neurotropism corrects a lysosomal transmembrane enzyme deficiency, BRAIN, Vol: 141, Pages: 2014-2031, ISSN: 0006-8950
Davis DM, 2018, The art of medicine How studying the immune system leads us to new medicines, LANCET, Vol: 391, Pages: 2205-2206, ISSN: 0140-6736
Davis DM, 2018, NEW INSIGHTS INTO ANTIBODY-BASED THERAPIES AND DISEASE SUSCEPTIBILITIES REVEALED BY MICROSCOPY OF HUMAN NK CELLS, Congress of the European-League-Against-Rheumatism (EULAR), Publisher: BMJ PUBLISHING GROUP, Pages: 25-26, ISSN: 0003-4967
Loftus C, Saeed M, Davis D, et al., 2018, Activation of human Natural Killer cells by graphene oxide-templated antibody nanoclusters, Nano Letters, Vol: 18, Pages: 3282-3289, ISSN: 1530-6984
An emerging new paradigm is that immune cell activation is controlled by transient interactions between supramolecular assemblies of receptors and ligands. Current immunotherapy biologic pharmaceuticals that activate or desensitize NK cells are, however, individual molecules that do not replicate this nanoscale organization of proteins. Here, we use nanoscale graphene oxide (NGO) as a template to generate soluble nanoscale clusters of Natural Killer cell-activating antibodies. We control nanocluster size and molecular number to mimic reported values for cell surface proteins. These NGO-templated molecular nanoclusters, used to stimulate NK cells via the CD16 receptor, successfully induced cellular activation, indicated by degranulation of cytolytic granules and IFN-γ secretion. Importantly, activation significantly exceeded that induced by the same antibodies applied as a solution of individual molecules. These results demonstrate that future immunotherapies could be enhanced by assembling immunomodulatory drugs into nanoclusters and establish NGO-templating as a candidate technology.
Balint S, Lopes FB, Davis DM, 2018, A nanoscale reorganization of the IL-15 receptor is triggered by NKG2D in a ligand-dependent manner, SCIENCE SIGNALING, Vol: 11, ISSN: 1945-0877
Carisey AF, Mace EM, Saeed MB, et al., 2018, Nanoscale Dynamism of Actin Enables Secretory Function in Cytolytic Cells, CURRENT BIOLOGY, Vol: 28, Pages: 489-+, ISSN: 0960-9822
Critchley WR, Reid A, Morris J, et al., 2018, The effect of 1.5T cardiac magnetic resonance on human circulating leucocytes, EUROPEAN HEART JOURNAL, Vol: 39, Pages: 305-312, ISSN: 0195-668X
Webb LM, Lundie RJ, Borger JG, et al., 2017, Type I interferon is required for T helper (Th) 2 induction by dendritic cells, EMBO JOURNAL, Vol: 36, Pages: 2404-2418, ISSN: 0261-4189
Type 2 inflammation is a defining feature of infection with parasitic worms (helminths), as well as being responsible for widespread suffering in allergies. However, the precise mechanisms involved in T helper (Th) 2 polarization by dendritic cells (DCs) are currently unclear. We have identified a previously unrecognized role for type I IFN (IFN‐I) in enabling this process. An IFN‐I signature was evident in DCs responding to the helminth Schistosoma mansoni or the allergen house dust mite (HDM). Further, IFN‐I signaling was required for optimal DC phenotypic activation in response to helminth antigen (Ag), and efficient migration to, and localization with, T cells in the draining lymph node (dLN). Importantly, DCs generated from Ifnar1−/− mice were incapable of initiating Th2 responses in vivo. These data demonstrate for the first time that the influence of IFN‐I is not limited to antiviral or bacterial settings but also has a central role to play in DC initiation of Th2 responses.
Morgan DJ, Davis DM, 2017, Distinct effects of Dexamethasone on human natural Killer cell responses Dependent on cytokines, FRONTIERS IN IMMUNOLOGY, Vol: 8, Pages: 1-15, ISSN: 1664-3224
Lopes FB, Balint S, Valvo S, et al., 2017, Membrane nanoclusters of Fc gamma RI segregate from inhibitory SIRP alpha upon activation of human macrophages, JOURNAL OF CELL BIOLOGY, Vol: 216, Pages: 1123-1141, ISSN: 0021-9525
Koller T, Blok S, Santos AM, et al., 2017, Rituximab capping triggers intracellular reorganization of B cells, Matters, ISSN: 2297-8240
Carisey AF, Mace EM, Saeed MB, et al., 2017, Nanoscale dynamism of F-actin enables secretory function in cytolytic cells., Annual Joint Meeting of the American-Society-for-Cell-Biology and the European-Molecular-Biology-Organization (ASCB/EMBO), Publisher: AMER SOC CELL BIOLOGY, ISSN: 1059-1524
Oszmiana A, Williamson DJ, Cordoba SP, et al., 2016, The Size of Activating and Inhibitory Killer Ig-like Receptor Nanoclusters Is Controlled by the Transmembrane Sequence and Affects Signaling, Cell Reports, Vol: 15, Pages: 1957-1972, ISSN: 2211-1247
Super-resolution microscopy has revealed that immune cell receptors are organized in nanoscale clusters at cell surfaces and immune synapses. However, mechanisms and functions for this nanoscale organization remain unclear. Here, we used super-resolution microscopy to compare the surface organization of paired killer Ig-like receptors (KIR), KIR2DL1 and KIR2DS1, on human primary natural killer cells and cell lines. Activating KIR2DS1 assembled in clusters two-fold larger than its inhibitory counterpart KIR2DL1. Site-directed mutagenesis established that the size of nanoclusters is controlled by transmembrane amino acid 233, a lysine in KIR2DS1. Super-resolution microscopy also revealed two ways in which the nanoscale clustering of KIR affects signaling. First, KIR2DS1 and DAP12 nanoclusters are juxtaposed in the resting cell state but coalesce upon receptor ligation. Second, quantitative super-resolution microscopy revealed that phosphorylation of the kinase ZAP-70 or phosphatase SHP-1 is favored in larger KIR nanoclusters. Thus, the size of KIR nanoclusters depends on the transmembrane sequence and affects downstream signaling.
Webb LM, Lundie RJ, Borger JG, et al., 2016, A central role for Type I IFN in the induction of Th2 responses by dendritic cells, Annual Meeting of the American-Association-of-Immunologists (AAI), Publisher: AMER ASSOC IMMUNOLOGISTS, ISSN: 0022-1767
Srpan K, Cartwright ANR, Davis DM, 2016, Regulation of Natural Killer cell cytotoxicity by shedding of the Fc receptor CD16, Annual Meeting of the American-Association-of-Immunologists (AAI), Publisher: AMER ASSOC IMMUNOLOGISTS, ISSN: 0022-1767
Saeed M, Gil-krzewska A, Oszmiana A, et al., 2016, Cortical Actin Remodelling for Effective Lytic Synapse Formation, Annual Meeting of the American-Society-for-Cell-Biology (ASCB), Publisher: AMER SOC CELL BIOLOGY, ISSN: 1059-1524
Lagrue K, Carisey A, Morgan DJ, et al., 2015, Lenalidomide augments actin remodeling and lowers NK-cell activation thresholds, BLOOD, Vol: 126, Pages: 50-60, ISSN: 0006-4971
Cartwright ANR, Griggs J, Davis DM, 2015, The immune synapse clears and excludes molecules above a size threshold (vol 5, 5479, 2014), NATURE COMMUNICATIONS, Vol: 6, ISSN: 2041-1723
Cartwright ANR, Griggs J, Davis DM, 2014, The immune synapse clears and excludes molecules above a size threshold, NATURE COMMUNICATIONS, Vol: 5, ISSN: 2041-1723
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