A5039033149- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Immune cells in cancer
- PI3K/AKT/mTOR signaling in cancer
- Metabolism, Diabetes, and Cancer
- Cancer, Hypoxia, and Metabolism
- Pancreatic function and diabetes
- CAR-T cell therapy research
- Mast cells and histamine
- Polyamine Metabolism and Applications
- Genomics, phytochemicals, and oxidative stress
- Ubiquitin and proteasome pathways
- Tryptophan and brain disorders
- Cancer-related gene regulation
- Wnt/β-catenin signaling in development and cancer
- Epigenetics and DNA Methylation
- Diabetes and associated disorders
- Circadian rhythm and melatonin
- Amino Acid Enzymes and Metabolism
- Single-cell and spatial transcriptomics
- IL-33, ST2, and ILC Pathways
- Diet, Metabolism, and Disease
- Cytokine Signaling Pathways and Interactions
- Cancer Immunotherapy and Biomarkers
- Cholesterol and Lipid Metabolism
Trinity College Dublin
2016-2025
University of Dundee
2005-2024
Ninewells Hospital
2005-2024
Bridge University
2022
Karolinska Institutet
2022
Rutgers Sexual and Reproductive Health and Rights
2022
University of California, San Diego
2022
The University of Texas at Arlington
2022
University of San Francisco
2022
University of Ulster
2022
Regulatory T (Treg) cells safeguard against autoimmunity and immune pathology. Because determinants of the Treg cell fate are not completely understood, we have delineated signaling events that control de novo expression Foxp3 in naive peripheral CD4 thymocytes. We report premature termination TCR inibition phosphatidyl inositol 3-kinase (PI3K) p110alpha, p110delta, protein kinase B (Akt), or mammalian target rapamycin (mTOR) conferred Treg-like gene profiles. Conversely, continued...
mTORC1 (mammalian target of rapamycin complex 1) controls transcriptional programs that determine CD8+ cytolytic T cell (CTL) fate. In some systems, couples phosphatidylinositol-3 kinase (PI3K) and Akt to the control glucose uptake glycolysis. However, PI3K–Akt-independent mechanisms metabolism in cells, role has not been explored. The present study now demonstrates activity cells is dependent on PI3K or but critical sustain glycolysis cells. We also show PI3K- Akt-independent pathways...
Blocking TGF-β signaling in natural killer cells enhances their metabolism and ability to kill tumor cells.
Abstract The mammalian target of rapamycin complex 1 (mTORC1) is a key regulator cellular metabolism and also has fundamental roles in controlling immune responses. Emerging evidence suggests that these two functions mTORC1 are integrally linked. However, little known regarding function the NK cells, lymphocytes play antiviral antitumor immunity. This study investigated hypothesis mTORC1-controlled underpins normal cell proinflammatory function. We demonstrate robustly stimulated cells...
Natural killer (NK) cells are lymphocytes with important anti-tumour functions. Cytokine activation of NK cell glycolysis and oxidative phosphorylation (OXPHOS) essential for robust responses. However, the mechanisms leading to this metabolic phenotype unclear. Here we show that transcription factor cMyc is IL-2/IL-12-induced functional responses in mice. protein levels acutely regulated by amino acids; lost rapidly when glutamine withdrawn or system L-amino acid transport blocked. We...
Abstract Human NK cells can be classified into phenotypically and functionally distinct subsets based on levels of CD56 receptor. CD56dim are generally considered more cytotoxic, whereas the CD56bright potent producers IFN-γ. In this study, we define metabolic changes that occur in peripheral blood response to cytokine. Metabolic analysis showed upregulate glycolysis oxidative phosphorylation either IL-2 or IL-12/15 cytokine combinations. Despite fact both these combinations robustly...
The adenosine monophosphate-activated protein kinase (AMPK) is activated by antigen receptor signals and energy stress in T cells. In many cell types, AMPK can maintain homeostasis enforce quiescence to limit demands. We consequently evaluated the importance of for controlling transition metabolically active effector CD8 lymphocytes quiescent catabolic memory cells during contraction phase immune response. show that AMPKα1 activates rapidly response metabolic caused glucose deprivation...
Abstract Fructose intake has increased substantially throughout the developed world and is associated with obesity, type 2 diabetes non-alcoholic fatty liver disease. Currently, our understanding of metabolic mechanistic implications for immune cells, such as monocytes macrophages, exposed to elevated levels dietary fructose limited. Here, we show that reprograms cellular pathways favour glutaminolysis oxidative metabolism, which are required support inflammatory cytokine production in both...
Abstract Mitochondria are important regulators of macrophage polarisation. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the mitochondria in inflammatory macrophages, critical for IL-10-induced modulation mitochondrial dynamics oxidative respiration. Mechanistically, catalytic activity presence Arg2 crucial phosphorylation. We further mediates this process by increasing complex II (succinate dehydrogenase)....
Augmented T cell function leading to host damage in autoimmunity is supported by metabolic dysregulation, making targeting immunometabolism an attractive therapeutic avenue. Canagliflozin, a type 2 diabetes drug, sodium glucose co-transporter (SGLT2) inhibitor with known off-target effects on glutamate dehydrogenase and complex I. However, the of SGLT2 inhibitors human have not been extensively explored. Here, we show that canagliflozin-treated cells are compromised their ability activate,...
Abstract Metformin, a widely used first-line treatment for type 2 diabetes (T2D), is known to reduce blood glucose levels and suppress appetite. Here we report significant elevation of the appetite-suppressing metabolite N -lactoyl phenylalanine (Lac-Phe) in individuals treated with metformin across seven observational interventional studies. Furthermore, Lac-Phe were found rise response acute administration post-prandially patients T2D or metabolically healthy volunteers.
Abstract Glucose and glycolysis are important for the proinflammatory functions of many immune cells, depletion glucose in pathological microenvironments is associated with defective responses. Here we show a contrasting function dendritic cells (DCs), as represses output LPS-stimulated DCs inhibits DC-induced T-cell A glucose-sensitive signal transduction circuit involving mTOR complex 1 (mTORC1), HIF1α inducible nitric oxide synthase (iNOS) coordinates DC metabolism to limit DC-stimulated...
Abstract Cytokines stimulate rapid metabolic changes in human NK cells, including increases both glycolysis and oxidative phosphorylation pathways. However, how these are subsequently regulated is not known. In this study, we demonstrate that TGF-β can inhibit many of changes, phosphorylation, glycolytic capacity, respiratory capacity. also inhibited cytokine-induced expression the transferrin nutrient receptor CD71. contrast to a recent report on murine TGF-β–mediated suppression responses...
Childhood obesity is a major global concern, with over 50 million children now classified as obese. Obesity has been linked to the development of numerous chronic inflammatory diseases, including type 2 diabetes and multiple cancers. NK cells are subset innate effector cells, which play an important role in regulation adipose tissue antitumor immunity. can spontaneously kill transformed coordinate subsequent immune responses through their production cytokines. We investigated effect on...
Natural killer (NK) cells provide important immune protection from cancer and are a key requirement for particular immunotherapies. There is accumulating evidence that NK become dysfunctional during cancer. Overcoming cell exhaustion would be an step to allow them function optimally in range of therapies, including those depend on autologos circulating cells. We have previously demonstrated undergo normal metabolic reprogramming response cytokine activation this required optimal function....