186 results found
Davis D, Worboys J, Vowell K, et al., 2023, TIGIT can inhibit T cell activation via ligation-induced nanoclusters, independent of CD226 co-stimulation, Nature Communications, Vol: 14, ISSN: 2041-1723
TIGIT is an inhibitory receptor expressed on lymphocytes and can inhibit T cells by preventing CD226 co-stimulation through interactions in cis or through competition of shared ligands. Whether TIGIT directly delivers cell-intrinsic inhibitory signals in T cells remains unclear. Here we show, by analysing lymphocytes from matched human tumour and peripheral blood samples, that TIGIT and CD226 co-expression is rare on tumour-infiltrating lymphocytes. Using super-resolution microscopy and other techniques, we demonstrate that ligation with CD155 causes TIGIT to reorganise into dense nanoclusters, which coalesce with T cell receptor (TCR)-rich clusters at immune synapses. Functionally, this reduces cytokine secretion in a manner dependent on TIGIT’s intracellular ITT-like signalling motif. Thus, we provide evidence that TIGIT directly inhibits lymphocyte activation, acting independently of CD226, requiring intracellular signalling that is proximal to the TCR. Within the subset of tumours where TIGIT-expressing cells do not commonly co-express CD226, this will likely be the dominant mechanism of action.
Sasidharan S, Davis DM, Dunlop IE, 2023, Bioinspired Materials for Immunoengineering of T Cells and Natural Killer Cells, Advanced Functional Materials, ISSN: 1616-301X
Immune responses are directed by the complex interactions of different cell types, including T cells and Natural Killer (NK) cells, with a key type of interaction being the formation of close cell-cell adhesions: immune synapses. Drawing on biophysical characteristics of the immune synapse and the immune cell surface, researchers are developing bioinspired materials for immunoengineering. Here are reviewed key biophysical variables that impact immune cell signaling, and how these have been exploited to develop immunomodulatory biomaterials. Mechanical forces and material properties such as stiffness are sensed by immune cells. This has enabled the modulation of cell activation using mechanically-controlled biomaterials: hydrogels, micropillars, and nanowire arrays. In parallel, microscopy has revealed micro-scale and nanoscale molecular patterning at cell surfaces, inspiring the creation of micro- and nanopatterned materials using lithography and nanoparticle approaches. The complex 3D structures of immune cells have inspired the creation of topographically patterned substrates and controlled 3D microenvironments. Finally, technologies have been developed to externally modulate biophysical variables, using magnetic and optical fields to stimulate biomaterials and drive immune cell activation. Together, these bioinspired materials are enhancing the understanding of immunology. A challenge is translation to the clinic, e.g., via improved ex vivo cell engineering for adoptive immunotherapies.
Ambrose AR, Hazime KS, Davis DM, 2023, Analyzing Single Cell Secretions by "Shadow Imaging"., Methods Mol Biol, Vol: 2654, Pages: 409-420
Here, we describe a method, which we term "shadow imaging," to analyze the secretions of individual cells at immune synapses or other cell contacts. Following immune synapse formation and cellular activation on ligand-rich slides, the position of each cell is recorded using a pulsed immunofluorescence stain against the proteins on the ligand-rich slide surface. The pulsed stain does not penetrate the synaptic cleft, resulting in an unlabeled region or "shadow" beneath cells that is retained following cellular detachment. The secreted components, such as perforin, exosomes, or other types of extracellular vesicles, are retained on the slide and can be analyzed on a single-cell basis using immunofluorescence. The ability to identify single cells secreting different combinations of particles, proteins, and vesicles enables us to better understand the heterogeneity in immune cell secretions and can be used as a novel approach for phenotyping cell populations.
Davis DM, 2022, The Secret Body How the New Science of the Human Body Is Changing the Way We Live, Publisher: National Geographic Books, ISBN: 9781529110975
Welcome to a revolution in the science of human health… This book takes us to the frontier of medical research and reveals stunning recent advances that are changing our understanding of how human body works, how we combat and prevent ...
Dechantsreiter S, Ambrose AR, Worboys JD, et al., 2022, Heterogeneity in extracellular vesicle secretion by single human macrophages revealed by super-resolution microscopy, JOURNAL OF EXTRACELLULAR VESICLES, Vol: 11
Tuomela K, Ambrose AR, Davis DM, 2022, Escaping death: how cancer cells and infected cells resist cell-mediated cytotoxicity, Frontiers in Immunology, Vol: 13, ISSN: 1664-3224
Cytotoxic lymphocytes are critical in our immune defence against cancer and infection. Cytotoxic T lymphocytes and Natural Killer cells can directly lyse malignant or infected cells in at least two ways: granule-mediated cytotoxicity, involving perforin and granzyme B, or death receptor-mediated cytotoxicity, involving the death receptor ligands, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL). In either case, a multi-step pathway is triggered to facilitate lysis, relying on active pro-death processes and signalling within the target cell. Because of this reliance on an active response from the target cell, each mechanism of cell-mediated killing can be manipulated by malignant and infected cells to evade cytolytic death. Here, we review the mechanisms of cell-mediated cytotoxicity and examine how cells may evade these cytolytic processes. This includes resistance to perforin through degradation or reduced pore formation, resistance to granzyme B through inhibition or autophagy, and resistance to death receptors through inhibition of downstream signalling or changes in protein expression. We also consider the importance of tumour necrosis factor (TNF)-induced cytotoxicity and resistance mechanisms against this pathway. Altogether, it is clear that target cells are not passive bystanders to cell-mediated cytotoxicity and resistance mechanisms can significantly constrain immune cell-mediated killing. Understanding these processes of immune evasion may lead to novel ideas for medical intervention.
Davis D, 2022, Questioning cultures, Biologist, Vol: 69, Pages: 2-3, ISSN: 0006-3347
Culture was once thought to be specifically human, but recently there have been many discoveries relating to social learning in animals. This issue includes an article by Andrew Whitten FRSB on this topic, detailing how local ‘cultures’ influence the lives of mammals, birds, fish and even insects.
Tuomela K, Mukherjee D, Ambrose AR, et al., 2022, Radiotherapy transiently reduces the sensitivity of cancer cells to lymphocyte cytotoxicity, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 119, ISSN: 0027-8424
Davis D, 2022, Unintended consequences, Biologist, Vol: 69, ISSN: 0006-3347
Davis DM, 2021, Immune: A Journey into the Mysterious System That Keeps You Alive, SCIENCE, Vol: 374, Pages: 697-697, ISSN: 0036-8075
Diaz-del-Olmo I, Worboys J, Martin-Sanchez F, et al., 2021, Internalization of the Membrane Attack Complex Triggers NLRP3 Inflammasome Activation and IL-1 beta Secretion in Human Macrophages, FRONTIERS IN IMMUNOLOGY, Vol: 12, ISSN: 1664-3224
Davis DM, 2021, Engineering immunity, New Scientist, Vol: 250, Pages: 40-43, ISSN: 0262-4079
Antibodies are a vital weapon in our immune system's arsenal. Now we can redesign them from scratch to better fight disease, says immunologist Daniel M. Davis
Friedman D, Simmonds P, Hale A, et al., 2021, Natural killer cell immune synapse formation and cytotoxicity are controlled by tension of the target interface, JOURNAL OF CELL SCIENCE, Vol: 134, ISSN: 0021-9533
Karampatzakis A, Broz P, Rey C, et al., 2021, Antibody afucosylation augments CD16-mediated serial killing and IFN gamma secretion by human natural killer cells, Frontiers in Immunology, Vol: 12, Pages: 1-14, ISSN: 1664-3224
One mechanism by which monoclonal antibodies (mAb) help treat cancer or autoimmune disease is through triggering antibody-dependent cellular cytotoxicity (ADCC) via CD16 on Natural Killer (NK) cells. Afucosylation is known to increase the affinity of mAbs for CD16 on NK cells and here, we set out to assess how mAb afucosylation affects the dynamics of NK cell interactions, receptor expression and effector functions. An IgG1 version of a clinically important anti-CD20 mAb was compared to its afucosylated counterpart (anti-CD20-AF). Opsonization of CD20-expressing target cells, 721.221 or Daudi, with anti-CD20-AF increased NK cell cytotoxicity and IFNγ secretion, compared to anti-CD20. The afucosylated mAb also caused a more rapid and greater loss of CD16 from NK cell surfaces. Loss of CD16 has recently been shown to be important for NK cell detachment and sequential engagement of multiple target cells. Here, live-cell time-lapse microscopy of individual cell-cell interactions in an aqueous environment and a three-dimensional matrix, revealed that anti-CD20-AF induced more rapid killing of opsonized target cells. In addition, NK cells detached more quickly from target cells opsonized with anti-CD20-AF compared to anti-CD20, which increased engagement of multiple targets and enabled a greater proportion of NK cells to perform serial killing. Inhibition of CD16 shedding with TAPI-0 led to reduced detachment and serial killing. Thus, disassembly of the immune synapse caused by loss of cell surface CD16 is a factor determining the efficiency of ADCC and antibody afucosylation alters the dynamics of intercellular interactions to boost serial killing.
Davis D, 2021, Spoilt for choice, Biologist, Vol: 68, ISSN: 0006-3347
Davis D, 2021, A whole new world, Biologist, Vol: 68, Pages: 14-17, ISSN: 0006-3347
An exclusive extract from Professor Dan Davis’s new book, The Secret Body, explains how super-resolution microscopy is revealing the workings of cells in “magical and humbling” new detail.
Davis D, 2021, How we’ve missed the power of museums, Biologist, Vol: 68, Pages: 2-3, ISSN: 0006-3347
Gritsenko A, Yu S, Martin-Sanchez F, et al., 2021, Corrigendum: Priming Is Dispensable for NLRP3 Inflammasome Activation in Human Monocytes In Vitro., Front Immunol, Vol: 12
[This corrects the article DOI: 10.3389/fimmu.2020.565924.].
Bonavita E, Bromley CP, Jonsson G, et al., 2020, Antagonistic Inflammatory Phenotypes Dictate Tumor Fate and Response to Immune Checkpoint Blockade, IMMUNITY, Vol: 53, Pages: 1215-+, ISSN: 1074-7613
Ambrose AR, Dechantsreiter S, Shah R, et al., 2020, Corrected Super-Resolution Microscopy Enables Nanoscale Imaging of Autofluorescent Lung Macrophages, BIOPHYSICAL JOURNAL, Vol: 119, Pages: 2403-2417, ISSN: 0006-3495
Oldham MA, Slooter AJC, Cunningham C, et al., 2020, Characterising neuropsychiatric disorders in patients with COVID-19, LANCET PSYCHIATRY, Vol: 7, Pages: 932-933, ISSN: 2215-0374
Gritsenko A, Yu S, Martin-Sanchez F, et al., 2020, Priming Is Dispensable for NLRP3 Inflammasome Activation in Human MonocytesIn Vitro, FRONTIERS IN IMMUNOLOGY, Vol: 11, ISSN: 1664-3224
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
Simmonds P, Friedman D, Hale A, et al., 2020, Natural Killer cell immune synapse formation and cytotoxicity is controlled by mechanical tension of the target, Annual Meeting of the American-Association-of-Immunologists - Immunology 2020, Publisher: AMER ASSOC IMMUNOLOGISTS, ISSN: 0022-1767
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
Leung EYL, Ennis D, Kennedy PR, et al., 2020, NK cells augment oncolytic adenovirus cytotoxicity in ovarian cancer, Molecular Therapy - Oncolytics, Vol: 16, Pages: 289-301, ISSN: 2372-7705
Oncolytic viruses (OVs) can trigger profound innate and adaptive immune responses, which have the potential both to potentiate and reduce the activity of OVs. Natural killer (NK) cells can mediate potent anti-viral and anti-tumoral responses, but there are no data on the role of NK cells in oncolytic adenovirus activity. Here, we have used two different oncolytic adenoviruses—the Ad5 E1A CR2-deletion mutant dl922-947 (group C) and the chimeric Ad3/Ad11p mutant enadenotucirev (group B)—to investigate the effect of NK cells on overall anti-cancer efficacy in ovarian cancer. Because human adenoviruses do not replicate in murine cells, we utilized primary human NK cells from peripheral blood and ovarian cancer ascites. Our results show that dl922-947 and enadenotucirev do not infect NK cells, but induce contact-dependent activation and anti-cancer cytotoxicity against adenovirus-infected ovarian cancer cells. Moreover, manipulation of NK receptors DNAM-1 (DNAX accessory molecule-1) and TIGIT (T cell immunoreceptor with Ig and ITIM domains) significantly influences NK cytotoxicity against adenovirus-infected cells. Together, these results indicate that NK cells act to increase the activity of oncolytic adenovirus in ovarian cancer and suggest that strategies to augment NK activity further via the blockade of inhibitory NK receptor TIGIT could enhance therapeutic potential of OVs.
Williamson DJ, Burn GL, Simoncelli S, et al., 2020, Machine learning for cluster analysis of localization microscopy data, NATURE COMMUNICATIONS, Vol: 11
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
Tsui A, Richards M, Singh-Manoux A, et al., 2020, Longitudinal associations between diurnal cortisol variation and later-life cognitive impairment, NEUROLOGY, Vol: 94, Pages: E133-E141, ISSN: 0028-3878
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
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