A5107500381- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- Monoclonal and Polyclonal Antibodies Research
- Enzyme Catalysis and Immobilization
- Enzyme Structure and Function
- Microbial metabolism and enzyme function
- Porphyrin Metabolism and Disorders
- Biochemical and Molecular Research
- Cardiovascular Effects of Exercise
- vaccines and immunoinformatics approaches
- Skin and Cellular Biology Research
- Microbial Metabolic Engineering and Bioproduction
- Cytokine Signaling Pathways and Interactions
- RNA and protein synthesis mechanisms
- Glycosylation and Glycoproteins Research
- Cellular Mechanics and Interactions
- Bacterial Genetics and Biotechnology
- Cardiomyopathy and Myosin Studies
- Bipolar Disorder and Treatment
- Protein Structure and Dynamics
- Hemoglobin structure and function
- Folate and B Vitamins Research
- Angiogenesis and VEGF in Cancer
University of Birmingham
2013-2025
Cancer Research UK
2005-2021
Institute of Immunology
2018-2019
Egyptian Petroleum Research Institute
2012
University of Southampton
2001-2009
Cancer Research UK Clinical Trials Unit
2007-2008
Northwest Medical Specialties
2008
Duluth Clinic
2008
Abstract γδ T cells are considered to be innate-like lymphocytes that respond rapidly stress without clonal selection and differentiation. Here we use next-generation sequencing probe how this paradigm relates human Vδ2 neg cells, implicated in responses viral infection cancer. The prevalent Vδ1 cell receptor (TCR) repertoire is private initially unfocused cord blood, typically becoming strongly focused on a few high-frequency clonotypes by adulthood. Clonal expansions have differentiated...
Abstract Vδ2 + T cells form the predominant human γδ T-cell population in peripheral blood and mediate receptor (TCR)-dependent anti-microbial anti-tumour immunity. Here we show that compartment comprises both innate-like adaptive subsets. Vγ9 display semi-invariant TCR repertoires, featuring public sequences equivalent cord adult blood. By contrast, also identify a separate, − subset typically has CD27 hi CCR7 CD28 IL-7Rα naive-like phenotype diverse repertoire, however response to viral...
Butyrophilin (BTN) and butyrophilin-like (BTNL/Btnl) heteromers are major regulators of human mouse γδ T cell subsets, but considerable contention surrounds whether they represent direct receptor (TCR) ligands. We demonstrate that the BTNL3 IgV domain binds directly specifically to a Vγ4+ TCR, "LES" with an affinity (∼15–25 μM) comparable many αβ TCR-peptide histocompatibility complex interactions. Mutations in germline-encoded Vγ4 CDR2 HV4 loops, not somatically recombined CDR3 drastically...
Vγ9Vδ2 T cells play critical roles in microbial immunity by detecting target exposed to pathogen-derived phosphoantigens (P-Ags). Target cell expression of BTN3A1, the "P-Ag sensor," and BTN2A1, a direct ligand for receptor (TCR) Vγ9, is essential this process; however, molecular mechanisms involved are unclear. Here, we characterize BTN2A1 interactions with TCR BTN3A1. Nuclear magnetic resonance (NMR), modeling, mutagenesis establish BTN2A1-immunoglobulin V (IgV)/BTN3A1-IgV structural model...
Butyrophilin (BTN)-3A and BTN2A1 molecules control the activation of human Vγ9Vδ2 T cells during cell receptor (TCR)-mediated sensing phosphoantigens (PAg) derived from microbes tumors. However, molecular rules governing PAg remain largely unknown. Here, we establish three mechanistic principles PAg-mediated γδ activation. First, in humans, following binding to intracellular BTN3A1-B30.2 domain, TCR triggering involves extracellular V-domain BTN3A2/BTN3A3. Moreover, localization both protein...
The C-type lectin domain containing group 14 family members CLEC14A and CD93 are proteins expressed by endothelium implicated in tumour angiogenesis. CD248 (alternatively known as endosialin or endothelial marker-1) is also a member of this tumour-associated fibroblasts pericytes. Multimerin-2 (MMRN2) unique specific extracellular matrix protein that has been angiogenesis progression. We show the lectins CLEC14A, directly bind to MMRN2 only thrombomodulin does not. Binding dependent on...
Abstract TCR-gene-transfer is an efficient strategy to produce therapeutic T cells of defined antigen specificity. However, there are substantial variations in the cell surface expression levels human TCRs, which can impair function engineered cells. Here we demonstrate that substitutions 3 amino acid residues framework TCR variable domains consistently increase TCRs on cells.The modified mediate enhanced proliferation, cytokine production and cytotoxicity, while reducing peptide...
γδ T cells are generally considered innate-like lymphocytes, however, an "adaptive-like" compartment has now emerged. To understand transcriptional regulation of adaptive cell immunobiology, we combined single-cell transcriptomics, receptor (TCR)-clonotype assignment, ATAC-seq, and immunophenotyping. We show that adult Vδ1+ segregate into TCF7+LEF1+Granzyme Bneg (Tnaive) or T-bet+Eomes+BLIMP-1+Granzyme B+ (Teffector) subtypes, with clonotypically expanded TCRs detected exclusively in...
Human Vγ9/Vδ2 T-cells detect tumor cells and microbial infections by recognizing small phosphorylated prenyl metabolites termed phosphoantigens (P–Ag). The type-1 transmembrane protein Butyrophilin 3A1 (BTN3A1) is critical to the P–Ag-mediated activation of T-cells; however, molecular mechanisms involved in BTN3A1-mediated metabolite sensing are unclear, including how P–Ag’s discriminated from nonantigenic molecules. Here, we utilized NMR X-ray crystallography probe P–Ag BTN3A1. Whereas...
// Fiyaz Mohammed 1, * , Daniel H. Stones Angela L. Zarling 2 Carrie R. Willcox 1 Jeffrey Shabanowitz 3 Kara Cummings Donald F. Hunt Mark Cobbold 4, 5, 6 Victor Engelhard and Benjamin E. Cancer Immunology Immunotherapy Centre, Institute of Immunotherapy, University Birmingham, Edgbaston, Birmingham B15 2TT, UK Carter Center Department Microbiology, Virginia School Medicine, Charlottesville, 22908, USA Chemistry, Virginia, 4 Immunity Infection, 5 Current address: Massachusetts General...
Human γδ T cells contribute to tissue homeostasis and participate in epithelial stress surveillance through mechanisms that are not well understood. Here, we identified ephrin type-A receptor 2 (EphA2) as a antigen recognized by human Vγ9Vδ1 TCR. EphA2 is coordinately A enable TCR activation. We putative binding site on the ligand-binding domain of was distinct from site. Expression up-regulated upon AMP-activated protein kinase (AMPK)-dependent metabolic reprogramming cancer cells,...
The crystal structure of methanol dehydrogenase (MDH) from Methylobacterium extorquens has been refined without stereochemical restraints at a resolution 1.2 Å. high-resolution data have defined the conformation tricyclic pyrroloquinoline quinone (PQQ) cofactor ring as entirely planar. detailed definition active-site geometry shown many features that are similar to quinohaemoprotein alcohol dehydrogenases Comamonas testosteroni and Pseudomonas putida, both which possess MDH-like cytochrome...
Mutations in the human PBGD (porphobilinogen deaminase) gene cause inherited defect AIP (acute intermittent porphyria). In present study we report structure of uPBGD (ubiquitous PBGD) mutant, R167Q, that has been determined by X-ray crystallography and refined to 2.8 A (1 A=0.1 nm) resolution (Rfactor=0.26, Rfree=0.29). The protein crystallized space group P2(1)2(1)2 with two molecules asymmetric unit (a=81.0 A, b=104.4 c=109.7 A). Phases were obtained molecular replacement using Escherichia...
The immune microenvironment in breast cancer (BCa) is controlled by a complex network of communication between various cell types. Here, we find that recruitment B lymphocytes to BCa tissues via mechanisms associated with cell-derived extracellular vesicles (CCD-EVs). Gene expression profiling identifies the Liver X receptor (LXR)-dependent transcriptional as key pathway controls both CCD-EVs-induced migration cells and accumulation tissues. increased oxysterol ligands for LXR (i.e.,...
Two proteins specifically involved in methanol oxidation the methylotrophic bacterium Methylobacterium extorquens have been modified by site-directed mutagenesis. Mutation of proposed active site base (Asp303) to glutamate dehydrogenase (MDH) gave an enzyme (D303E-MDH) with a greatly reduced affinity for substrate and lower activation energy. Results kinetic deuterium isotope studies showed that essential mechanism mutant protein was unchanged, step requiring ammonia remained rate limiting....
The myeloid inhibitory receptor LILRB4 (also called ILT3, LIR-5, CD85k), a member of the leukocyte immunoglobulin-like receptors (LILRs/LIRs), is an important mediator immune tolerance. Up-regulated on tolerogenic dendritic cells, it has been shown to modulate responses via induction T cell anergy and differentiation CD8(+) suppressor cells may play role in establishing tolerance cancer. Consequently, characterizing molecular mechanisms involved function particular its structure ligands key...
NKG2D (natural killer group 2, member D) is an activating receptor found on the surface of immune cells, including natural (NK) which regulates innate and adaptive immunity through recognition stress-induced ligands ULBP1 (UL16 binding protein 1) to ULBP6 MICA/B. Similar class I human leukocyte antigen (HLA), these have a major histocompatibility complex-like fold exhibit pronounced polymorphism, influences disease susceptibility. However, whereas HLA polymorphisms occur predominantly in...
MuRF1 [muscle RING (Really Interesting New Gene)-finger protein-1] is an ubiquitin-protein ligase (E3), which encode by TRIM63 (tripartite motif containing 63) gene, playing a crucial role in regulating cardiac muscle size and function through ubiquitylation. Among hypertrophic cardiomyopathy (HCM) patients, 24 variants have been identified, with 1 additional variant linked to restrictive cardiomyopathy. However, only three previously investigated for their functional effects. The structural...