A5035880365- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Cellular transport and secretion
- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- Cytomegalovirus and herpesvirus research
- Lipid Membrane Structure and Behavior
- Genetic and Kidney Cyst Diseases
- Autoimmune and Inflammatory Disorders Research
- Protist diversity and phylogeny
- T-cell and Retrovirus Studies
- Epigenetics and DNA Methylation
- Pancreatic function and diabetes
- Vector-Borne Animal Diseases
- Micro and Nano Robotics
- melanin and skin pigmentation
- Receptor Mechanisms and Signaling
- Gene Regulatory Network Analysis
- Parvovirus B19 Infection Studies
- Animal Disease Management and Epidemiology
- Photoreceptor and optogenetics research
- 14-3-3 protein interactions
- Endoplasmic Reticulum Stress and Disease
- RNA regulation and disease
- Mast cells and histamine
National Institute for Health Research
2016-2023
University of Cambridge
2010-2022
Google (United States)
2014
Addenbrooke's Hospital
2007-2011
University of Oxford
1999-2006
Sir Robert McAlpine (United Kingdom)
2001-2006
University of Brescia
2006
MRC Laboratory for Molecular Cell Biology
1995-1996
University College London
1995-1996
Medical Research Council
1995-1996
Cell contact is required for efficient transmission of human T cell leukemia virus– type 1 (HTLV-I) between cells and individuals, because naturally infected lymphocytes produce virtually no cell-free infectious HTLV-I particles. However, the mechanism cell-to-cell spread not understood. We show here that rapidly induces polarization cytoskeleton to cell-cell junction. core (Gag protein) complexes genome accumulate at junction are then transferred uninfected cell. Other lymphotropic viruses,...
Rab27a activity is affected in several mouse models of human disease including Griscelli (ashen mice) and Hermansky-Pudlak (gunmetal syndromes. A loss function mutation occurs the gene ashen (ash), whereas gunmetal (gm) dysfunction secondary to a α subunit Rab geranylgeranyl transferase, an enzyme required for prenylation activation Rabs. We show here that normally expressed cytotoxic T lymphocytes (CTLs), but absent homozygotes (ash/ash). Cytotoxicity secretion assays ash/ash CTLs are...
Cytotoxic T lymphocytes (CTLs) use polarized secretion to rapidly destroy virally infected and tumor cells. To understand the temporal relationships between key events leading secretion, we used high-resolution 4D imaging. CTLs approached targets with actin-rich projections at edge, creating an initially actin-enriched contact rearward-flowing actin. Within 1 min, cortical actin reduced across synapse, cell receptors (TCRs) clustered centrally form central supramolecular activation cluster...
Abstract Tumor-specific T cells are frequently exhausted by chronic antigenic stimulation. We here report on a human antigen-specific ex vivo model to explore new therapeutic options for cell immunotherapies. generated with this resemble tumor-infiltrating phenotypic and transcriptional level. Using targeted pooled CRISPR-Cas9 screen individual gene knockout validation experiments, we uncover sorting nexin-9 (SNX9) as mediator of exhaustion. Upon TCR/CD28 stimulation, deletion SNX9 in CD8...
Killing by cytotoxic T lymphocytes (CTLs) is mediated the secretion of lytic granules. The centrosome plays a key role in granule delivery, polarizing to central supramolecular activation complex (cSMAC) within immunological synapse upon cell receptor (TCR) activation. Although stronger TCR signals lead increased target death than do weaker signals, it not known how strength signal controls polarization and By using transgenic OT-I CTLs, we showed that both high- low-avidity interactions led...
Abstract During early pregnancy, decidual innate lymphoid cells (dILCs) interact with surrounding maternal and invading fetal extravillous trophoblasts (EVT). Here, using mass cytometry, we characterise five main dILC subsets: NK (dNK)1–3, ILC3s proliferating cells. Following stimulation, dNK2 dNK3 produce more chemokines than dNK1 including XCL1 which can act on both dendritic EVT. In contrast, express receptors Killer-cell Immunoglobulin-like Receptors (KIR), indicating they respond to HLA...
Mitochondria drive CTLs’ killer instinct Cytotoxic T lymphocytes (CTLs) can terminate both virally infected cells and cancer by secreting cytolytic proteins such as perforin granzyme B. CTLs are particularly effective because they sequentially kill multiple targets in a process called serial killing. Lisci et al . have identified mitochondria important regulators of CTL Mice lacking the deubiquitinase USP30 acutely depleted mitochondria, these reduced killing ability but normal motility,...
CD8 cytotoxic T lymphocytes (CTLs) rely on rapid reorganization of the branched F-actin network to drive polarized secretion lytic granules, initiating target cell death during adaptive immune response. Branched is generated by nucleation factor actin-related protein 2/3 (Arp2/3) complex. Patients with mutations in complex 1B (ARPC1B) subunit Arp2/3 show combined immunodeficiency, symptoms dysregulation, including recurrent viral infections and reduced CD8+ count. Here, we that loss ARPC1B...
Cytotoxic T lymphocytes (CTLs) kill virus-infected and cancer cells through cell receptor (TCR) recognition. How CTLs terminate signaling disengage to allow serial killing has remained a mystery. TCR activation triggers membrane specialization within the immune synapse, including production of diacylglycerol (DAG), lipid that can induce negative curvature. We found activated TCRs were shed into DAG-enriched ectosomes at synapse rather than internalized endocytosis, suggesting DAG may...
Vesicular transport is a complex multistep process regulated by distinct Rab GTPases. Here, we show for the first time that an EGFP-Rab fusion protein fully functional in mammalian organism. We constructed PAC-based transgenic mouse, which expresses EGFP-Rab27a under control of endogenous Rab27a promoter. The transgene was and rescued two major defects ashen knockout mouse. achieved cell-specific expression EGFP-Rab27a, faithfully followed pattern Rab27a. found expressed exceptionally broad...
Docking of the centrosome at plasma membrane directs lytic granules to immunological synapse. To identify signals controlling docking synapse, we have studied cytotoxic T lymphocytes (CTLs) in which expression cell receptor–activated tyrosine kinase Lck is ablated. In absence Lck, able translocate around nucleus toward synapse but unable dock membrane. Lytic fail polarize and release their contents, target cells are not killed. CTLs deficient both related Fyn, translocation impaired, remains...
Cytotoxic T lymphocytes (CTLs) are highly effective serial killers capable of destroying virally infected and cancerous targets by polarized release from secretory lysosomes. Upon target contact, the CTL centrosome rapidly moves to immunological synapse, focusing microtubule-directed at this point [1-3]. Striking similarities have been noted between polarization synapse basal body docking during ciliogenesis [1, 4-8], suggesting that centrosomes might dock with plasma membrane killing, in a...
The transfer of newly synthesized membrane proteins moving from the rough endoplasmic reticulum (RER) to Golgi complex has been studied by electron microscopy in HEp-2 cells transfected with cDNAs for chimeric proteins. These consist a reporter enzyme, horseradish peroxidase (HRP), anchored transmembrane domains two integral proteins, transferrin receptor and sialyl-transferase. chimeras are distributed throughout nuclear envelope, RER, vesicular tubular clusters (VTCs) network tubules...
Cytolytic cells of the immune system destroy pathogen-infected by polarised exocytosis secretory lysosomes containing pore-forming protein perforin. Precise delivery this lethal hit is essential to ensuring that only target cell destroyed. In cytotoxic T lymphocytes (CTLs), accomplished an unusual movement centrosome contact plasma membrane at centre immunological synapse formed between killer and cells. Secretory are directed towards along microtubules delivered precisely point recognition...