A5066013716- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Amino Acid Enzymes and Metabolism
- Metabolism and Genetic Disorders
- Immunotherapy and Immune Responses
- Diet and metabolism studies
- Lysosomal Storage Disorders Research
- CAR-T cell therapy research
- Ion channel regulation and function
- Autoimmune and Inflammatory Disorders Research
- Cancer Research and Treatments
- Epigenetics and DNA Methylation
- Neuroscience and Neuropharmacology Research
- Immune Response and Inflammation
- Infant Nutrition and Health
- Calcium signaling and nucleotide metabolism
- Computational Drug Discovery Methods
- Cholinesterase and Neurodegenerative Diseases
- Nicotinic Acetylcholine Receptors Study
- Surgical Sutures and Adhesives
- Tryptophan and brain disorders
- Child Nutrition and Feeding Issues
- Wound Healing and Treatments
- Force Microscopy Techniques and Applications
- Tuberculosis Research and Epidemiology
University of Oxford
2015-2025
MRC Human Immunology Unit
2009-2021
Oregon State University
2020
Medical Research Council
2004-2018
Parkland Memorial Hospital
2018
Institute of Molecular Medicine
2003-2017
John Radcliffe Hospital
2001-2016
Parkland Health & Hospital System
2016
MRC Weatherall Institute of Molecular Medicine
2003-2016
Cancer Research UK
2004-2010
Desensitization is a phenomenon that common to many ligand-gated ion channels but has been demonstrated only rarely with physiological stimulation. Numerous studies describe desensitization of the N -methyl-D-aspartate (NMDA) subtype glutamate receptor by exogenous agonists, whether synaptic stimulation causes unknown. Synaptic NMDA receptors on rat hippocampal neurons resulted in was prevented intracellular 1,2-bis( o -aminophenoxy)ethane- N,N,N′,N′ -tetraacetic acid (BAPTA), adenosine-5′-...
We have measured the total and differential cell counts, histamine, leukotriene (LT) B4 LTC4, immunoglobulins, complement (C3), eosinophil-derived basic proteins, monocyte rosettes in bronchoalveolar lavage (BAL) 6 h after challenge with either antigen or diluent control seven patients antigen-induced single early reactions, dual (early late phase) reactions. In both groups, counts BAL were similar, irrespective of whether they challenged diluent. However, late-phase responders (LPR), there...
CD1d-restricted lymphocytes recognize a broad lipid range. However, how translate T cell receptor (TCR) recognition of lipids with similar group heads into distinct biological responses remains unclear. Using soluble invariant NKT (iNKT) TCR and newly engineered antibody specific for α-galactosylceramide (α-GalCer)–human CD1d (hCD1d) complexes, we measured the affinity binding iNKT to hCD1d molecules loaded panel α-GalCer analogues assessed rate dissociation from molecules. We extended this...
Abstract Plasmacytoid dendritic cells (PDC) are a small population of leukocytes specialized in the production type I IFN. It has been shown that PDC have potent T cell stimulatory capacity allogeneic mixed lymphocyte reaction, However, their role initiating primary immune responses remains elusive. We report blood efficiently prime naive CD8 + lymphocytes specific forthe melan‐A 26–35 epitope to become IFN‐γ producing vitro . In addition, we found CD40L‐stimulated induce expression on...
Invariant natural killer T (iNKT) cells are a subset of nonconventional recognizing endogenous and/or exogenous glycolipid antigens in the context CD1d molecules. It remains unclear whether innate stimuli can modify profile lipids recognized by iNKT on surface antigen-presenting (APCs). We report that activation human APCs Toll-like receptor ligands (TLR-L) modulates lipid biosynthetic pathway, resulting enhanced recognition CD1d-associated cells, as defined IFN-gamma secretion. APC-derived...
Abstract Mucosal-associated invariant T (MAIT) cells are innate-like that can detect bacteria-derived metabolites presented on MR1. Here we show, using a controlled infection of humans with live Salmonella enterica serovar Paratyphi A, MAIT activated during infection, an effect maintained even after antibiotic treatment. At the peak cell T-cell receptor (TCR)β clonotypes over-represented prior to transiently contract. Select TCRβ expand have stronger TCR-dependent activation than do...
Significance Autophagy is an evolutionarily conserved catabolic process essential to maintaining cellular homeostasis through the breakdown and recycling of damaged organelles long-lived proteins. We report that autophagy plays cell-intrinsic role in survival a subset innate-like cells known as invariant natural killer T (iNKT) cells. deficiency prevents transition quiescent state after population expansion thymic iNKT Hence, autophagy-deficient accumulate mitochondria oxygen radicals...
Activation of invariant CD1d-dependent NK T cells (iNKT cells) in vivo through administration the glycolipid ligand α-galactosylceramide (α-GalCer) or sphingosine-truncated α-GalCer analog OCH leads to CD40 signaling as well release soluble molecules including type 1 and γ interferons that contribute DC maturation. This process enhances cell immunity antigens presented by DC. The adjuvant activity is further amplified if APCs are stimulated Toll-like receptor 4, suggesting iNKT signals can...
Abstract The human MHC class I-like molecule CD1b is distinctive among CD1 alleles in that it capable of presenting a set glycolipid species show very broad range variation the lengths their acyl chains. A structure complexed with relatively short chain glycolipids plus detergent suggested how an interlinked network channels within Ag-binding groove could accommodate up to 80 carbons. glucose monomycolate, reported this study, confirms hypothesis and illustrates substituents intracellular...
Abstract In a significant proportion of melanoma patients, CTL specific for the melan-A26/7–35 epitope can be detected in peripheral blood using HLA-A2/peptide tetramers. However, functional capacity these has been controversial, since although they prove to effective killers after vitro expansion, some patients have blunted activation responses ex vivo. We used phenotypic markers characterize melan-A tetramer+ cells both normal individuals and correlated with vivo assays function. Melanoma...
Neuronal growth factors regulate the expression of voltage-activated sodium current in differentiating sympathetic neurons and PC12 cells. We show that, cells, NGF- FGF-induced results from increased two distinct channel types. Sodium rapid induction a novel transcript, also found peripheral neurons, long term brain type II/IIA mRNA. Expression requires activation cyclic AMP-dependent protein kinase (A-kinase), whereas neuron occurs through an A-kinase-independent signal transduction...
Abstract The quality of signals received by dendritic cells (DC) in response to pathogens influences the nature adaptive response. We show that pathogen-derived DC mediated via TLRs can be modulated activated invariant NKT (iNKT) cells. maturation induced vivo with any one a variety TLR ligands was greatly improved through simultaneous administration iNKT cell ligand α-galactosylceramide. isolated from animals treated simultaneously and were potent stimulators naive T vitro compared...
Invariant human TCR Vα24-Jα18+/Vβ11+ NKT cells (iNKT) are restricted by CD1d–α-glycosylceramides. We analyzed crystal structures and binding characteristics for an iNKT plus two CD1d–α-GalCer–specific Vβ11+ TCRs that use different Vα chains. The results were similar to those previously reported MHC–peptide-specific TCRs, illustrating the versatility of platform. Docking CD1d–α-GalCer provided plausible insights into their interaction. model supports a diagonal orientation on CD1d suggests...
Abstract Invariant NKT cells (iNKT cells) recognize CD1d/glycolipid complexes. We demonstrate that the nonglycosidic compound threitolceramide efficiently activates iNKT cells, resulting in dendritic cell (DC) maturation and priming of Ag-specific T B cells. Threitolceramide-pulsed DCs are more resistant to cell-dependent lysis than α-galactosylceramide-pulsed due weaker affinity human TCR for CD1d/ CD1d/α-galactosylceramide stimulated with also recover quickly from activation-induced...
Mucosal-associated invariant T (MAIT) cells represent an innate T-cell population that can recognize ligands generated by the microbial riboflavin synthesis pathway, presented via major histocompatibility complex class I–related molecule (MR1). Streptococcus pneumoniae is a human pathogen also associated with commensal carriage; thus, host control at mucosal interface critical. The recognition of pneumococci MAIT has not been defined nor have genomics and transcriptomics operon. We observed...
Abstract Tryptophan degradation is an immune escape strategy shared by many tumors. However, cancer cells' compensatory mechanisms remain unclear. We demonstrate here that a shortage of tryptophan caused expression indoleamine 2,3-dioxygenase (IDO) and (TDO) resulted in ATF4-dependent upregulation several amino acid transporters, including SLC1A5 its truncated isoforms, which turn enhanced glutamine uptake. Importantly, failed to be upregulated resting human T cells kept under low conditions...
Abstract Recombinant plasmid DNA and attenuated poxviruses are under development as cancer infectious disease vaccines. We present the results of a phase I clinical trial recombinant modified vaccinia Ankara (MVA), both encoding 7 melanoma tumor antigen cytotoxic T lymphocyte (CTL) epitopes. HLA‐A*0201‐positive patients with surgically treated received either “prime‐boost” DNA/MVA or homologous MVA‐only regimen. Ex vivo tetramer analysis, performed at multiple time points, provided detailed...
NKT cells with an invariant Ag receptor (iNKT cells) represent a highly conserved and unique subset of T lymphocytes having properties innate adaptive immune cells. They have been reported to regulate variety responses, including the response cancers development autoimmunity. The activation iNKT is dependent on self-Ags presented by CD1d Ag-presenting molecule. It widely believed that these are glycosphingolipids (GSLs), molecules contain ceramide as lipid backbone. In this study, we used...
The mechanisms behind destruction of the adrenal glands in autoimmune Addison's disease remain unclear. Autoantibodies against steroid 21-hydroxylase, an intracellular key enzyme cortex, are found >90% patients, but these autoantibodies not thought to mediate disease. In this article, we demonstrate highly frequent 21-hydroxylase-specific T cells detectable 20 patients with Using overlapping 18-aa peptides spanning full length identified immunodominant CD8(+) and CD4(+) cell responses a...
Abstract Priming of melan-A26/27–35-specific CTL occurs only in a fraction late stage melanoma patients, whereas during the early stages disease and healthy volunteers, melan-A have functional phenotypic markers consistent with naive phenotype. To study requirements for expansion from donors, we set up an vitro priming protocol and, using tetramer assays, demonstrate that activity phenotype expanded are profoundly influenced by type APC used. nonprofessional leads to reduced cytolytic low...