A5041048448- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Monoclonal and Polyclonal Antibodies Research
- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- Cell Adhesion Molecules Research
- Nanofabrication and Lithography Techniques
- Virus-based gene therapy research
- Diabetes and associated disorders
- interferon and immune responses
- Cancer Immunotherapy and Biomarkers
- Respiratory viral infections research
- Cellular Mechanics and Interactions
- Microfluidic and Capillary Electrophoresis Applications
- Immune Response and Inflammation
- HIV Research and Treatment
- Ocular Oncology and Treatments
- Microfluidic and Bio-sensing Technologies
- Cell Image Analysis Techniques
- Cytokine Signaling Pathways and Interactions
- Chemokine receptors and signaling
- Force Microscopy Techniques and Applications
- Cytomegalovirus and herpesvirus research
- Advanced biosensing and bioanalysis techniques
- Immune cells in cancer
Immunocore (United Kingdom)
2020-2024
University of Oxford
2014-2023
Evotec (United Kingdom)
2021
New York University
2011-2020
Kennedy Center
2018
Institute of Rheumatology
2018
Nuffield Orthopaedic Centre
2015-2018
Cancer Research UK
2007-2013
The Honourable Society of Lincoln's Inn
2007-2013
NYU Langone Health
2012
Early events of B cell activation after receptor (BCR) triggering have been well characterized. However, little is known about the steady state BCR on surface. Here, we simultaneously visualize single particles and components membrane skeleton. We show that an ezrin- actin-defined network influenced steady-state diffusion by creating boundaries restrict diffusion. identified intracellular domain Igbeta as important in mediating this restriction Importantly, alteration was sufficient to...
Rho-associated kinase 2 (ROCK2) regulates the secretion of proinflammatory cytokines and development autoimmunity in mice. Data from a phase 1 clinical trial demonstrate that oral administration KD025, selective ROCK2 inhibitor, to healthy human subjects down-regulates ability T cells secrete IL-21 IL-17 by 90% 60%, respectively, but not IFN-γ response T-cell receptor stimulation vitro. Pharmacological inhibition with KD025 or siRNA-mediated ROCK2, ROCK1, significantly diminished STAT3...
Wiscott Aldrich Syndrome protein (WASP) deficiency results in defects calcium ion signaling, cytoskeletal regulation, gene transcription and overall T cell activation. The activation of WASP constitutes a key pathway for actin filament nucleation. Yet, when function is eliminated there negligible effect on polymerization at the immunological synapse, leading to gaps our understanding events connecting signaling. Here, we identify fraction total synaptic F-actin selectively generated by form...
B cell receptor (BCR) recognition of membrane-bound antigen initiates a spreading and contraction response, the extent which is controlled through formation signaling-active BCR-antigen microclusters ultimately affects outcome activation. We followed genetic approach to define molecular requirements BCR-induced microcluster formation. identify key role for phospholipase C-γ2 (PLCγ2), Vav, linker, Bruton's tyrosine kinase in highly coordinated “microsignalosomes,” efficient assembly...
Signaling microclusters are a common feature of lymphocyte activation. However, the mechanisms controlling size and organization these discrete structures poorly understood. The Ezrin-Radixin-Moesin (ERM) proteins, which link plasma membrane proteins with actin cytoskeleton regulate steady-state diffusion dynamics B cell receptor (BCR), transiently dephosphorylated upon antigen stimulation. In this study, we show that ERM ezrin moesin influence integrity BCR microclusters. BCR-driven...
A longstanding paradox in the activation of cytotoxic T lymphocytes (CTL) arises from observation that CTL recognize and rapidly destroy target cells with exquisite sensitivity despite fact cytokine production requires sustained signaling at immunological synapse. Here we solve this by showing establish synapses targets offering strong antigenic stimuli these persist after cell death. Simultaneously, polarize lytic granules toward different without discrimination regarding potential. Our...
Antigen recognition is a key event during T cell activation. Here, we introduce nanopatterned antigen arrays that mimic the presenting surface The assessment of activation related events revealed requirement minimal density 90-140 stimulating major histocompatibility complex class II proteins (pMHC) molecules per μm(2). We demonstrate these substrates induce responses in pMHC dose-dependent manner and number presented pMHCs dominates over local density.
Bioactive nanoscale arrays were constructed to ligate activating cell surface receptors on T cells (the CD3 component of the TCR complex) and natural killer (NK) (CD16). These are formed from biofunctionalized gold nanospheres with controlled interparticle spacing in range 25-104 nm. Responses these nanoarrays assessed using extent membrane-localized phosphotyrosine stimulated CD3-binding size contact area for NK CD16-binding nanoarrays. In both cases, strength response decreased increasing...
Significance Human respiratory syncytial virus (hRSV) is the leading cause of bronchiolitis and pneumonia in children worldwide. The induction poor T-cell immunological memory causes a high susceptibility to reinfections, which contributes hRSV spread. Previously, we showed that inhibits activation by impairing assembly dendritic cell (DC)−T-cell synapse (IS). Here, show nucleoprotein (N) hRSV—a canonical cytosolic protein—is expressed on surface infected DCs. Further, using...
T cells engage in two modes of interaction with antigen-presenting surfaces: stable synapses and motile kinapses. Although it is surmised that durable interactions involve synapses, situ 3D imaging cannot resolve the mode interaction. We have established vitro 2D platforms quantitative metrics to determine cell-intrinsic when are faced spatially continuous or restricted stimulation. All major resting human cell subsets, except memory CD8 cells, spend more time kinapse on stimulatory...
B cells undergo membrane spreading and contraction during activation in response to antigen-presenting cells.
Significance Src homology 2 (SH2) domains are phosphotyrosine binding motifs that play key roles in cellular signaling. There 110 proteins the human genome containing SH2 domains, of which 10 contain tandem domains. Tandem have been shown to improve avidity and specificity contribute allostery. Here, we show can also exhibit lifetimes accelerated by activity phosphatases. This unbinding requires engage their substrates dynamic modes cycle between single SH2-bound states. We experimentally...
The activation of T lymphocytes by specific antigen is accompanied the formation a specialized signaling region termed immunological synapse, characterized clustering and segregation surface molecules and, in particular, cell receptor (TCR) clustering.To better understand TCR motion during cellular activation, we used confocal microscopy photo-bleaching recovery techniques to investigate lateral mobility on human under various pharmacological treatments. Using drugs that cause an increase...
Single-molecule nanodot arrays, in which a biomolecule of choice (protein, nucleic acid, etc.) is bound to metallic nanoparticle on solid substrate, are becoming an increasingly important tool the study biomolecular and cellular interactions. We have developed on-chip measurement protocol monitor control molecular occupancy nanodots. Arrays widely spaced nanodots clusters were fabricated glass surfaces by nanolithography functionalized with fluorescently labeled proteins. The was determined...
Upon conjugation with cognate antigen-presenting cells (APCs), T lymphocytes undergo a sustained [Ca(2+)](i) increase resulting from the engagement of TCR and accessory molecules ligands expressed on surface APCs. We investigated contribution molecule CD2 to activation phospholipase Cgamma1 (PLCgamma1)/calcium pathway in antigen-stimulated cells. show that binding its ligand CD58 APCs augments sustains antigen-induced individual interacting also conditions which CD2-CD58 interaction is...