Imperial College London

ProfessorMaggieDallman

Central FacultyOffice of the Provost

Vice-President (International), Associate Provost (Acad P)
 
 
 
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Contact

 

+44 (0)20 7594 5406m.dallman Website

 
 
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Assistant

 

Ms Emelia Gobbe +44 (0)20 7594 7460

 
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Location

 

2.11Faculty BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

165 results found

Progatzky F, Jha A, Wane M, Thwaites RS, Makris S, Shattock RJ, Johansson C, Openshaw PJ, Bugeon L, Hansel TT, Dallman MJet al., 2019, Induction of innate cytokine responses by respiratory mucosal challenge with R848 in zebrafish, mice and humans, Journal of Allergy and Clinical Immunology, ISSN: 0091-6749

We compared live zebrafish, mouse and human nasal challenge responses to the TLR7/8 agonist resiquimod (R848). We found remarkably similar induction of mediators in the three species, offering novel mucosal models of innate anti-viral immunity.

Journal article

Vervoort SJ, de Jong OG, Roukens MG, Frederiks CL, Vermeulen JF, Louren├žo AR, Bella L, Vidakovic AT, Sandoval JL, Moelans C, van Amersfoort M, Dallman MJ, Bruna A, Caldas C, Nieuwenhuis E, van der Wall E, Derksen P, van Diest P, Verhaar MC, Lam EW-F, Mokry M, Coffer PJet al., 2018, Global transcriptional analysis identifies a novel role for SOX4 in 2 tumor-induced angiogenesis, eLife, Vol: 7, ISSN: 2050-084X

The expression of the transcription factor SOX4 is increased in many human cancers, however, the pro-oncogenic capacity of SOX4 can vary greatly depending on the type of tumor. Both the contextual nature and the mechanisms underlying the pro-oncogenic SOX4 response remain unexplored. Here, we demonstrate that in mammary tumorigenesis, the SOX4 transcriptional network is dictated by the epigenome and is enriched for pro-angiogenic processes. We show that SOX4 directly regulates endothelin-1 (ET-1) expression and can thereby promote tumor-induced angiogenesis both in vitro and in vivo. Furthermore, in breast tumors, SOX4 expression correlates with blood vessel density and size, and predicts poor-prognosis in patients with breast cancer. Our data provide novel mechanistic insights into context-dependent SOX4 target gene selection, and uncover a novel pro-oncogenic role for this transcription factor in promoting tumor-induced angiogenesis. These findings establish a key role for SOX4 in promoting metastasis through exploiting diverse pro-tumorigenic pathways.

Journal article

Lam EW, Yao S, Dallman M, Bugeon, Bella Let al., 2017, p62/SQSTM1 interacts with vimentin to enhance breast cancer metastasis, Carcinogenesis, Vol: 38, Pages: 1092-1103, ISSN: 1460-2180

The signalling adaptor p62 is frequently overexpressed in numerous cancer types. Here, we found that p62 expression was elevated in metastatic breast cancer and its overexpression correlated with reduced metastasis-free and relapse-free survival times. Analysis of p62 expression in breast cancer cell lines demonstrated that high p62 expression was associated with the invasive phenotypes of breast cancer. Indeed, silencing p62 expression attenuated the invasive phenotypes of highly metastatic cells, whereas overexpressing p62 promoted the invasion of non-metastatic cells in in vitro microfluidic model. Moreover, MDA-MB-231 cells with p62 depletion which were grown in a three-dimensional culture system exhibited a loss of invasive protrusions. Consistently, genetic ablation of p62 suppressed breast cancer metastasis in both zebrafish embryo and immunodeficient mouse models, as well as decreased tumorigenicity in vivo. To explore the molecular mechanism by which p62 promotes breast cancer invasion, we performed a co-immunoprecipitation (co-IP)-MS analysis and revealed that p62 interacted with vimentin, which mediated the function of p62 in promoting breast cancer invasion. Vimentin protein expression was downregulated upon p62 suppression and upregulated with p62 overexpression in breast cancer cells. Linear regression analysis of clinical breast cancer specimens showed a positive correlation between p62 and vimentin protein expression. Together, our findings provide strong evidence that p62 functions as a tumour metastasis promoter by binding vimentin and promoting its expression. This finding might help to develop novel molecular therapeutic strategies for breast cancer metastasis treatment.

Journal article

Watson, Andrews N, Davis S, Bugeon L, Dallman M, McGinty Jet al., 2017, OPTiM: optical projection tomography integrated microscope using open-source hardware and software, PLOS One, Vol: 12, ISSN: 1932-6203

We describe the implementation of an OPT plate to perform optical projection tomography (OPT) on a commercial wide-field inverted microscope, using our open-source hardware and software. The OPT plate includes a tilt adjustment for alignment and a stepper motor for sample rotation as required by standard projection tomography. Depending on magnification requirements, three methods of performing OPT are detailed using this adaptor plate: a conventional direct OPT method requiring only the addition of a limiting aperture behind the objective lens; an external optical-relay method allowing conventional OPT to be performed at magnifications >4x; a remote focal scanning and region-of-interest method for improved spatial resolution OPT (up to ~1.6 μm). All three methods use the microscope’s existing incoherent light source (i.e. arc-lamp) and all of its inherent functionality is maintained for day-to-day use. OPT acquisitions are performed on in vivo zebrafish embryos to demonstrate the implementations’ viability.

Journal article

Andrews N, Davis S, Hay C, Kumar S, Ramel M-C, Bugeon L, McGinty J, Dallman MJ, French PMWet al., 2017, Functional imaging of live Zebrafish using fluorescence lifetime optical projection tomography, Conference on Imaging, Manipulation, and Analysis of Biomolecules, Cells, and Tissues XV, Publisher: SPIE-INT SOC OPTICAL ENGINEERING, ISSN: 0277-786X

Conference paper

Jha A, Progatzky F, Wane M, Thwaites RS, McBrien M, Brimley J, Tunstall T, Shattock RJ, Bugeon L, Openshaw PJM, Dallman MJ, Hansel TTet al., 2016, Human nasal mucosal responses to TLR agonists are mirrored by the zebrafish gill, British Association of Lung Research Summer Congress

Introduction: There are few reliable ways to study respiratory mucosal immune responses to viruses, viral-type toll-like receptor (TLR) agonists and vaccines. To investigate innate immune responses to TLR agonists (TLR3: poly IC/ poly ICLC; TLR7/8: resiquimod), we compared the effects on human nasal mucosa and zebrafish gills in vivo. Methods: Nasal challenge of adult volunteers was performed with saline, poly IC (n=4), poly ICLC (n=4) or resiquimod (n=8; 5 non-atopic, 3 atopic). Nasal mucosal lining fluid (MLF) was obtained by nasosorption at regular intervals up to 24 hours after challenge; nasal obstruction was monitored by peak nasal inspiratory flow (PNIF) and total nasal symptom scores (TNSS). Cytokines and interferons were measured in MLF using electrochemiluminescence on the Meso Scale Discovery (MSD) platform. Adult zebrafish gills were exposed to the same TLR agonists and gene expression was quantified in gill tissue at similar time-points. Results: Nasal challenge with TLR3 agonists failed to elicit any significant responses when compared to saline. In contrast resiquimod (10μg/100μl per nostril) caused a potent induction of cytokines with an early release (1-3 hours) of IFN-α2a, TNF-α and IL-1β and a later release (after 4 hours) of IFN-γ. The 3 volunteers with the highest levels of IFN-α2a were atopic. Six volunteers were asymptomatic and two volunteers had flu-like symptoms. There were no significant changes in clinical correlates of nasal obstruction. After resiquimod administration, but not TLR3 agonists, zebrafish gills showed an immune profile remarkably analogous to human nasal responses. Conclusion: The TLR7/8 agonist resiquimod is a potent mucosal inducer of IFN-α2a, IFN-γ and proinflammatory cytokines, whilst TLR3 agonists failed to stimulate mucosal innate immune responses. Zebrafish gills accurately mimic human nasal mucosal responses following exposure to TLR agonists, offering translational app

Conference paper

Kumar S, Lockward N, Ramel M-C, Correia T, Ellis M, Alexandrov Y, Andrews N, Patel R, Bugeon L, Dallman M, Brandner S, Arridge S, Katan M, McGinty J, Frankel P, French PMWet al., 2016, Quantitative in vivo optical tomography of cancer progression & vasculature development in adult zebrafish, Oncotarget, Vol: 7, Pages: 43939-43948, ISSN: 1949-2553

We describe a novel approach to study tumour progression and vasculature development in vivo via global 3-D fluorescence imaging of live non-pigmented adult zebrafish utilising angularly multiplexed optical projection tomography with compressive sensing (CS-OPT). This “mesoscopic” imaging method bridges a gap between established ~μm resolution 3-D fluorescence microscopy techniques and ~mm-resolved whole body planar imaging and diffuse tomography. Implementing angular multiplexing with CS-OPT, we demonstrate the in vivo global imaging of an inducible fluorescently labelled genetic model of liver cancer in adult non-pigmented zebrafish that also present fluorescently labelled vasculature. In this disease model, addition of a chemical inducer (doxycycline) drives expression of eGFP tagged oncogenic K-RASV12 in the liver of immune competent animals. We show that our novel in vivo global imaging methodology enables non-invasive quantitative imaging of the development of tumour and vasculature throughout the progression of the disease, which we have validated against established methods of pathology including immunohistochemistry. We have also demonstrated its potential for longitudinal imaging through a study of vascular development in the same zebrafish from early embryo to adulthood. We believe that this instrument, together with its associated analysis and data management tools, constitute a new platform for in vivo cancer studies and drug discovery in zebrafish disease models.

Journal article

French PMW, andrews N, dallman M, ramel MC, kumar S, alexandrov Y, kelly D, warren S, kerry L, bugeon L, Lockwood N, Frolov Aet al., 2016, Visualising apoptosis in live zebrafish using fluorescence lifetime imaging with optical projection tomography to map FRET biosensor activity in space and time, Journal of Biophotonics, Vol: 9, Pages: 414-424, ISSN: 1864-0648

Fluorescence lifetime imaging (FLIM) combined with optical projection tomography (OPT) has the potential to map Förster resonant energy transfer (FRET) readouts in space and time in intact transparent or near transparent live organisms such as zebrafish larvae, thereby providing a means to visualise cell signalling processes in their physiological context. Here the first application of FLIM OPT to read out biological function in live transgenic zebrafish larvae using a genetically expressed FRET biosensor is reported. Apoptosis, or programmed cell death, is mapped in 3-D by imaging the activity of a FRET biosensor that is cleaved by Caspase 3, which is a key effector of apoptosis. Although apoptosis is a naturally occurring process during development, it can also be triggered in a variety of ways, including through gamma irradiation. FLIM OPT is shown here to enable apoptosis to be monitored over time, in live zebrafish larvae via changes in Caspase 3 activation following gamma irradiation at 24 hours post fertilisation. Significant apoptosis was observed at 3.5 hours post irradiation, predominantly in the head region.

Journal article

Watson TJ, Andrews N, Harry E, Bugeon L, Dallman MJ, French PMW, McGinty Jet al., 2016, Remote focal scanning and sub-volume optical projection tomography

© OSA 2016. We present a platform for sub-volume optical projection tomography utilising an electrically tunable lens and tracking technology. Applied to 3D fluorescent bead phantoms and zebrafish embryos, we demonstrate an improvement in resolution and light collection efficiency with respect to conventional optical projection tomography.

Conference paper

Andrews N, Ramel MC, Kumar S, Alexandrov Y, Kelly DJ, Warren SC, Kerry L, Lockwood N, Frolov A, Frankel P, Bugeon L, McGinty J, Dallman MJ, French PMWet al., 2016, Fluorescence lifetime optical projection tomography and FRET applied to visualizing apoptosis in live zebrafish larvae

© OSA 2016. We present the application of FLIM-OPT to read out biological function in live transgenic zebrafish larvae using a genetically expressed cleavable FRET biosensor for Caspase-3 as an indicator of gamma radiation induced apoptosis.

Conference paper

Watson TJ, Andrews N, Harry E, Bugeon L, Dallman MJ, French PMW, McGinty Jet al., 2016, Remote focal scanning and sub-volume optical projection tomography

© OSA 2016. We present a platform for sub-volume optical projection tomography utilising an electrically tunable lens and tracking technology. Applied to 3D fluorescent bead phantoms and zebrafish embryos, we demonstrate an improvement in resolution and light collection efficiency with respect to conventional optical projection tomography.

Conference paper

Progatzky F, Cook HT, Lamb JR, Bugeon L, Dallman MJet al., 2016, Mucosal inflammation at the respiratory interface: a zebrafish model, AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, Vol: 310, Pages: L551-L561, ISSN: 1040-0605

Journal article

Jones PJM, Sim A, Taylor HB, Bugeon L, Dallman MJ, Pereira B, Stumpf MPH, Liepe Jet al., 2015, Inference of random walk models to describe leukocyte migration, Physical Biology, Vol: 12, ISSN: 1478-3975

While the majority of cells in an organism are static and remain relatively immobile in their tissue, migrating cells occur commonly during developmental processes and are crucial for a functioning immune response. The mode of migration has been described in terms of various types of random walks. To understand the details of the migratory behaviour we rely on mathematical models and their calibration to experimental data. Here we propose an approximate Bayesian inference scheme to calibrate a class of random walk models characterized by a specific, parametric particle re-orientation mechanism to observed trajectory data. We elaborate the concept of transition matrices (TMs) to detect random walk patterns and determine a statistic to quantify these TM to make them applicable for inference schemes. We apply the developed pipeline to in vivo trajectory data of macrophages and neutrophils, extracted from zebrafish that had undergone tail transection. We find that macrophage and neutrophils exhibit very distinct biased persistent random walk patterns, where the strengths of the persistence and bias are spatio-temporally regulated. Furthermore, the movement of macrophages is far less persistent than that of neutrophils in response to wounding.

Journal article

Correia T, Lockwood N, Kumar S, Yin J, Ramel M-C, Andrews N, Katan M, Bugeon L, Dallman MJ, McGinty J, Frankel P, French PMW, Arridge Set al., 2015, Accelerated optical projection tomography applied to in vivo imaging of zebrafish, PLOS One, Vol: 10, ISSN: 1932-6203

Optical projection tomography (OPT) provides a non-invasive 3-D imaging modality that can be applied to longitudinal studies of live disease models, including in zebrafish. Current limitations include the requirement of a minimum number of angular projections for reconstruction of reasonable OPT images using filtered back projection (FBP), which is typically several hundred, leading to acquisition times of several minutes. It is highly desirable to decrease the number of required angular projections to decrease both the total acquisition time and the light dose to the sample. This is particularly important to enable longitudinal studies, which involve measurements of the same fish at different time points. In this work, we demonstrate that the use of an iterative algorithm to reconstruct sparsely sampled OPT data sets can provide useful 3-D images with 50 or fewer projections, thereby significantly decreasing the minimum acquisition time and light dose while maintaining image quality. A transgenic zebrafish embryo with fluorescent labelling of the vasculature was imaged to acquire densely sampled (800 projections) and under-sampled data sets of transmitted and fluorescence projection images. The under-sampled OPT data sets were reconstructed using an iterative total variation-based image reconstruction algorithm and compared against FBP reconstructions of the densely sampled data sets. To illustrate the potential for quantitative analysis following rapid OPT data acquisition, a Hessian-based method was applied to automatically segment the reconstructed images to select the vasculature network. Results showed that 3-D images of the zebrafish embryo and its vasculature of sufficient visual quality for quantitative analysis can be reconstructed using the iterative algorithm from only 32 projections—achieving up to 28 times improvement in imaging speed and leading to total acquisition times of a few seconds.

Journal article

Broncel M, Serwa RA, Ciepla P, Krause E, Dallman MJ, Magee AI, Tate EWet al., 2015, Myristoylation profiling in human cells and zebrafish., Data in Brief, Vol: 4, Pages: 379-383, ISSN: 2352-3409

Human cells (HEK 293, HeLa, MCF-7) and zebrafish embryos were metabolically tagged with an alkynyl myristic acid probe, lysed with an SDS buffer and tagged proteomes ligated to multifunctional capture reagents via copper-catalyzed alkyne azide cycloaddition (CuAAC). This allowed for affinity enrichment and high-confidence identification, by delivering direct MS/MS evidence for the modification site, of 87 and 61 co-translationally myristoylated proteins in human cells and zebrafish, respectively. The data have been deposited to ProteomeXchange Consortium (Vizcaíno et al., 2014 Nat. Biotechnol., 32, 223-6) (PXD001863 and PXD001876) and are described in detail in Multifunctional reagents for quantitative proteome-wide analysis of protein modification in human cells and dynamic protein lipidation during vertebrate developmentÎ│ by Broncel et al., Angew. Chem. Int. Ed.

Journal article

Broncel M, Serwa RA, Ciepla P, Krause E, Dallman MJ, Magee AI, Tate EWet al., 2015, Multifunctional Reagents for Quantitative Proteome-Wide Analysis of Protein Modification in Human Cells and Dynamic Profiling of Protein Lipidation During Vertebrate Development, Angewandte Chemie-International Edition, Vol: 54, Pages: 5948-5951, ISSN: 1521-3773

Novel multifunctional reagents were applied incombination with a lipid probe for affinity enrichment ofmyristoylated proteins and direct detection of lipid-modifiedtryptic peptides by mass spectrometry. This method enableshigh-confidence identification of the myristoylated proteomeon an unprecedented scale in cell culture, and allowed the firstquantitative analysis of dynamic changes in protein lipidationduring vertebrate embryonic development.

Journal article

Chen L, Alexandrov Y, Kumar S, Andrews N, Dallman MJ, French PMW, McGinty Jet al., 2015, Mesoscopic in vivo 3-D tracking of sparse cell populations using angular multiplexed optical projection tomography, BIOMEDICAL OPTICS EXPRESS, Vol: 6, Pages: 1253-1261, ISSN: 2156-7085

Journal article

McGinty J, Chen L, Kumar S, Alexandrov Y, Andrews N, Kelly D, Dallman MJ, French PMWet al., 2015, Techniques to improve the spatial and temporal resolution in optical projection tomography: Remote focal scanning and time-lapse cell tracking

© OSA 2015. Optical projection tomography is a 3-D imaging approach applicable to transparent samples and model organisms like zebrafish embryos. We present methods to improve the spatial resolution and realize 3-D cell tracking in OPT.

Conference paper

Progatzky F, Sangha NJ, Yoshida N, McBrien M, Cheung J, Shia A, Scott J, Marchesi JR, Lamb JR, Bugeon L, Dallman MJet al., 2014, Dietary cholesterol directly induces acute inflammasome-dependent intestinal inflammation, NATURE COMMUNICATIONS, Vol: 5, ISSN: 2041-1723

Journal article

Chen L, Kumar S, Kelly D, Andrews N, Dallman MJ, French PMW, McGinty Jet al., 2014, Remote focal scanning optical projection tomography with an electrically tunable lens, BIOMEDICAL OPTICS EXPRESS, Vol: 5, Pages: 3367-3375, ISSN: 2156-7085

Journal article

Progatzky F, Sangha NJ, Yoshida N, McBrien M, Cheung J, Shia A, Scott J, Marchesi JR, Lamb JR, Bugeon L, Dallman MJet al., 2014, Intestinal inflammation induced by dietary cholesterol in Zebrafish, 9th European-Mucosal-Immunology-Group Meeting, Publisher: WILEY-BLACKWELL, Pages: 27-28, ISSN: 0019-2805

Conference paper

Ciepla P, Konitsiotis AD, Serwa RA, Masumoto N, Leong WP, Dallman MJ, Magee AI, Tate EWet al., 2014, New chemical probes targeting cholesterylation of Sonic Hedgehog in human cells and zebrafish, Chemical Science, Vol: 5, Pages: 4249-4259, ISSN: 2041-6520

Sonic Hedgehog protein (Shh) is a morphogen molecule important in embryonic development and in theprogression of many cancer types in which it is aberrantly overexpressed. Fully mature Shh requiresattachment of cholesterol and palmitic acid to its C- and N-termini, respectively. The study of lipidatedShh has been challenging due to the limited array of tools available, and the roles of theseposttranslational modifications are poorly understood. Herein, we describe the development andvalidation of optimised alkynyl sterol probes that efficiently tag Shh cholesterylation and enable itsvisualisation and analysis through bioorthogonal ligation to reporters. An optimised probe was shown tobe an excellent cholesterol biomimetic in the context of Shh, enabling appropriate release of tagged Shhfrom signalling cells, formation of multimeric transport complexes and signalling. We have used thisprobe to determine the size of transport complexes of lipidated Shh in culture medium and expressionlevels of endogenous lipidated Shh in pancreatic ductal adenocarcinoma cell lines through quantitativechemical proteomics, as well as direct visualisation of the probe by fluorescence microscopy anddetection of cholesterylated Hedgehog protein in developing zebrafish embryos. These sterol probesprovide a set of novel and well-validated tools that can be used to investigate the role of lipidation onactivity of Shh, and potentially other members of the Hedgehog protein family

Journal article

Kumar S, Lockwood N, Ramel MC, Correia T, Ellis M, Alexandrov Y, Andrews N, Patel R, Bugeon L, Dallman MJ, Brandner S, Arridge S, Katan M, McGinty J, Frankel P, French PMWet al., 2014, In vivo multiplexed OPT and FLIM OPT of an adult zebrafish cancer disease model

© OSA 2016. We report angular multiplexed OPT and FLIM OPT applied to in vivo imaging of cancer and FRET biosensors in adult zebrafish. Multiple-spectral 3-D datasets of entire adult zebrafish can be acquired in 3 minutes.

Conference paper

Watson TJ, Andrews N, Harry E, Bugeon L, Dallman MJ, French PMW, McGinty Jet al., 2014, Remote focal scanning and sub-volume optical projection tomography

© OSA 2016. We present a platform for sub-volume optical projection tomography utilising an electrically tunable lens and tracking technology. Applied to 3D fluorescent bead phantoms and zebrafish embryos, we demonstrate an improvement in resolution and light collection efficiency with respect to conventional optical projection tomography.

Conference paper

Progatzky F, Dallman MJ, Lo Celso C, 2013, From seeing to believing: labelling strategies for in vivo cell-tracking experiments, INTERFACE FOCUS, Vol: 3, ISSN: 2042-8898

Journal article

Chen L, McGinty J, Taylor HB, Bugeon L, Lamb JR, Dallman MJ, French Pet al., 2012, Improved OPT reconstructions based on the MTF and extension to FLIM-OPT

We demonstrate the improved reconstruction of OPT datasets by incorporating the measured MTF in the reconstruction process. We also extend OPT to FLIM-OPT and demonstrate its use for imaging live zebrafish embryos displaying autofluorescence. © 2012 OSA.

Conference paper

Taylor HB, Liepe J, Barthen C, Bugeon L, Huvet M, Kirk PDW, Brown SB, Lamb JR, Stumpf MPH, Dallman MJet al., 2012, P38 and JNK have opposing effects on persistence of in vivo leukocyte migration in zebrafish, Immunology and Cell Biology, Vol: 91, Pages: 60-69, ISSN: 1440-1711

The recruitment and migration of macrophages and neutrophils is an important process during the early stages of the innate immune system in response to acute injury. Transgenic pu.1:EGFP zebrafish permit the acquisition of leukocyte migration trajectories during inflammation. Currently, these high-quality live-imaging data are mainly analysed using general statistics, for example, cell velocity. Here, we present a spatio-temporal analysis of the cell dynamics using transition matrices, which provide information of the type of cell migration. We find evidence that leukocytes exhibit types of migratory behaviour, which differ from previously described random walk processes. Dimethyl sulfoxide treatment decreased the level of persistence at early time points after wounding and ablated temporal dependencies observed in untreated embryos. We then use pharmacological inhibition of p38 and c-Jun N-terminal kinase mitogen-activated protein kinases to determine their effects on in vivo leukocyte migration patterns and discuss how they modify the characteristics of the cell migration process. In particular, we find that their respective inhibition leads to decreased and increased levels of persistent motion in leukocytes following wounding. This example shows the high level of information content, which can be gained from live-imaging data if appropriate statistical tools are used.

Journal article

Le Friec G, Sheppard D, Whiteman P, Karsten CM, Shamoun SA-T, Laing A, Bugeon L, Dallman MJ, Melchionna T, Chillakuri C, Smith RA, Drouet C, Couzi L, Fremeaux-Bacchi V, Koehl J, Waddington SN, McDonnell JM, Baker A, Handford PA, Lea SM, Kemper Cet al., 2012, The CD46-Jagged1 interaction is critical for human T(H)1 immunity, Nature Immunology, Vol: 13, Pages: 1213-1221, ISSN: 1529-2908

CD46 is a complement regulator with important roles related to the immune response. CD46 functions as a pathogen receptor and is a potent costimulator for the induction of interferon-γ (IFN-γ)-secreting effector T helper type 1 (TH1) cells and their subsequent switch into interleukin 10 (IL-10)-producing regulatory T cells. Here we identified the Notch family member Jagged1 as a physiological ligand for CD46. Furthermore, we found that CD46 regulated the expression of Notch receptors and ligands during T cell activation and that disturbance of the CD46-Notch crosstalk impeded induction of IFN-γ and switching to IL-10. Notably, CD4+ T cells from CD46-deficient patients and patients with hypomorphic mutations in the gene encoding Jagged1 (Alagille syndrome) failed to mount appropriate TH1 responses in vitro and in vivo, which suggested that CD46-Jagged1 crosstalk is responsible for the recurrent infections in subpopulations of these patients.

Journal article

Le Friec G, Shamoun S, Couzi L, Fremeaux-Bacchi V, Baker A, Bugeon L, Dallman M, Handford P, Lea S, Kemper Cet al., 2012, Jagged1 is a CD46 ligand and disturbance in CD46/Jagged 1 interaction leads to abnormal Th1 function and infections in humans, European Congress of Immunology, Publisher: WILEY-BLACKWELL, Pages: 8-8, ISSN: 0019-2805

Conference paper

Progatzky F, Taylor H, Bugeon L, Cassidy S, Radbruch A, Dallman MJ, Lamb JRet al., 2012, The role of Nfil3 in zebrafish hematopoiesis, DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY, Vol: 38, Pages: 187-192, ISSN: 0145-305X

Journal article

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