A5012406636- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Monoclonal and Polyclonal Antibodies Research
- CAR-T cell therapy research
- Immunotherapy and Immune Responses
- SARS-CoV-2 and COVID-19 Research
- Cell Adhesion Molecules Research
- COVID-19 Clinical Research Studies
- Lipid Membrane Structure and Behavior
- Protein Tyrosine Phosphatases
- Nanowire Synthesis and Applications
- Glycosylation and Glycoproteins Research
- Advanced Fluorescence Microscopy Techniques
- Receptor Mechanisms and Signaling
- Immune Response and Inflammation
- Advancements in Semiconductor Devices and Circuit Design
- Protein Structure and Dynamics
- Phagocytosis and Immune Regulation
- Cellular transport and secretion
- Cancer Immunotherapy and Biomarkers
- Galectins and Cancer Biology
- Viral Infections and Outbreaks Research
- Gene Regulatory Network Analysis
- vaccines and immunoinformatics approaches
- Biochemical and Structural Characterization
University of Oxford
2016-2025
Diamond Light Source
2024
Oxfam
2021-2023
University of British Columbia
2007-2009
Western University
2004
The interaction between the SARS-CoV-2 virus Spike protein receptor binding domain (RBD) and ACE2 cell surface is required for viral infection of cells. Mutations in RBD are present variants concern that have emerged independently worldwide. For example, B.1.1.7 lineage has a mutation (N501Y) its enhances to ACE2. There also alleles humans with mutations site. Here we perform detailed affinity kinetics analysis effect five common (K417N, K417T, N501Y, E484K, S477N) two (S19P K26R) on...
T cell antigen receptor (TCR) and coreceptor ligation is thought to initiate signal transduction by inducing activation of the kinase Lck.Here we showed that catalytically active Lck was present in unstimulated naive cells thymocytes readily detectable these lymphoid organs.In up ∼40% total constitutively activated, part which also phosphorylated on C-terminal inhibitory site.Formation activated independent TCR coreceptors but required catalytic activity its maintenance relied monitoring...
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...
T cell receptor (TCR) binding to diverse peptide-major histocompatibility complex (pMHC) ligands results in various degrees of activation. Here we analyze which properties the TCR-pMHC interaction are responsible for this variation pMHC activation potency. We have analyzed 1G4 cytotoxic lymphocyte clone by cognate variants and performed thorough correlation analysis with measured solution. found that both on rate (k(on)) off (k(off)) contribute Based our results, propose a model rapid TCR...
Research Article8 December 2016Open Access Source DataTransparent process PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy Abul Azad Department Oncology, CRUK/MRC Oxford Institute for Radiation University Oxford, UK Search more papers by this author Su Yin Lim Zenobia D'Costa Keaton Jones Angela Diana Owen J Sansom orcid.org/0000-0001-9540-3010 CRUK Beatson Cancer Institute, Glasgow, Philipp Kruger Sir William Dunn School Pathology, Stanley Liu Sunnybrook...
BA.2.86, a recently described sublineage of SARS-CoV-2 Omicron, contains many mutations in the spike gene. It appears to have originated from BA.2 and is distinct XBB variants responsible for infections 2023. The global spread plethora BA.2.86 has caused concern that it may possess greater immune-evasive potential, leading new wave infection. Here, we examine ability evade antibody response infection using panel vaccinated or naturally infected sera find shows marginally less immune evasion...
Abstract Adoptive T cell therapies have achieved significant clinical responses, especially in hematopoietic cancers. Two types of receptor systems been used to redirect the activity cells, normal heterodimeric TCRs or synthetic chimeric Ag receptors (CARs). recognize peptide-HLA complexes whereas CARs typically use an Ab-derived single-chain fragments variable that recognizes cancer-associated cell-surface Ags. Although both mediate diverse effector functions, a quantitative comparison...
The T-cell receptor (TCR) consists of a TCRαβ heterodimer, TCRζ homodimer, and CD3γε CD3δε heterodimers. precise mechanism triggering following TCR ligand engagement remains elusive. Previous studies reported that the cytoplasmic tail CD3ε binds to plasma membrane through basic residue-rich stretch (BRS) proposed dissociation from is required for phosphorylation thereof. In this report we show BRS motifs within mediate association with results in membrane. This requires immunoreceptor...
Significance T lymphocytes use their cell receptors (TCRs) to discriminate between similar peptide-MHC (pMHC) antigens. The mechanisms employed achieve this discrimination are debated. TCR–pMHC interaction is subjected forces, and recent work in live cells has suggested that force paradoxically increases bond lifetimes for activating peptides, forming so-called “catch bonds,” facilitating from nonactivating peptides. A question whether behavior intrinsic the or a cellular response. We...
T cells engineered to express chimeric antigen receptors (CAR-T cells) have shown impressive clinical efficacy in the treatment of B cell malignancies. However, development CAR-T therapies for solid tumors is hampered by lack truly tumor-specific antigens and poor control over activity. Here we present an avidity-controlled CAR (AvidCAR) platform with inducible logic functions. The key combination (i) improved design which enables controlled dimerization (ii) a significant reduction...
Abstract The immunological synapse is a molecular hub that facilitates the delivery of three activation signals, namely antigen, costimulation/corepression and cytokines, from antigen-presenting cells (APC) to T cells. release fourth class signaling entities, trans-synaptic vesicles (tSV), mediate bidirectional communication. Here we present bead-supported lipid bilayers (BSLB) as versatile synthetic APCs capture, characterize advance understanding tSV biogenesis. Specifically, integration...
Abstract T cells use their T‐cell receptors (TCRs) to discriminate between lower‐affinity self and higher‐affinity foreign peptide major‐histocompatibility‐complexes (pMHCs) based on the TCR/pMHC off‐rate. It is now appreciated that generate mechanical forces during this process but how force impacts off‐rate remains debated. Here, we measured effect of multiple interactions. Unexpectedly, found TCR/pMHCs with faster solution off‐rates were more resistant (weak slip or catch bonds) than...
Chimeric antigen receptors (CARs) can redirect T cells to target abnormal cells, but their activity is limited by a profound defect in sensitivity, the source of which remains unclear. Here, we show that CARs have > 100-fold lower sensitivity compared cell receptor (TCR) when presented on antigen-presenting (APCs) nearly identical as purified protein. We next systematically measured impact engaging important accessory (CD2, LFA-1, CD28, CD27, and 4-1BB) adding ligands. Unexpectedly, found...
THEMIS is critical for conventional T-cell development, but its precise molecular function remains elusive. Here, we show that constitutively associates with the phosphatases SHP1 and SHP2. This complex requires adapter GRB2, which bridges SHP to in a Tyr-phosphorylation-independent fashion. Rather, engage N-SH3 C-SH3 domains of respectively, configuration allows GRB2-SH2 recruit onto LAT. Consistent THEMIS-mediated recruitment TCR signalosome, knock-down increased TCR-induced CD3-ζ...
Significance T cells initiate and regulate adaptive immune responses when their T-cell antigen receptors recognize antigens. The response is known to depend on the affinity/dose, but precise relationship, mechanisms underlying it, are debated. To resolve debate, we stimulated with antigens spanning a 1 million-fold range in affinity/dose. We found that different (and hence affinity) produced largest at doses. Using model identification algorithms, report simple mechanistic can predict from...
The T cell receptor (TCR) initiates the elimination of pathogens and tumors by cells. To avoid damage to host, must be capable discriminating between wild-type mutated self nonself peptide ligands presented host Exactly how TCR does this is unknown. In resting cells, largely unphosphorylated due dominance phosphatases over kinases expressed at surface. However, when agonist peptides are major histocompatibility complex proteins antigen-presenting cells (APCs), very fast triggering, i.e.,...
The capture of biotin by streptavidin is an inspiration for supramolecular chemistry and a central tool biological nanotechnology, because the rapid exceptionally stable interaction. However, there no robust orthogonal interaction to this hub, limiting size complexity molecular assemblies that can be created. Here we combined traptavidin (a variant maximizing binding strength) with irreversible SpyTag peptide engineered form spontaneous isopeptide bond its protein partner SpyCatcher. or...
T cells use their cell receptors (TCRs) to discriminate between lower-affinity self and higher-affinity non-self peptides presented on major histocompatibility complex (pMHC) antigens. Although the discriminatory power of TCR is widely believed be near-perfect, technical difficulties have hampered efforts precisely quantify it. Here, we describe a method for measuring very low TCR/pMHC affinities it measure factors affecting We find that discrimination, although enhanced compared with...
Efficient T cell activation depends on the rate with which receptors and antigens bind unbind, rather than simply their equilibrium affinity.
Experimental work has shown that T cells of the immune system rapidly and specifically respond to antigenic molecules presented on surface antigen-presenting-cells are able discriminate between potential stimuli based kinetic parameters cell receptor-antigen bond. These among thousands chemically similar endogenous peptides, raising question how can reliably make a decision certain antigens but not others within minutes encountering an antigen presenting cell. In this theoretical study, we...