A5013317014- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Immunotherapy and Immune Responses
- Immune Response and Inflammation
- Immune cells in cancer
- Medical Imaging Techniques and Applications
- Advanced MRI Techniques and Applications
- Cancer, Hypoxia, and Metabolism
- Lymphatic System and Diseases
- Cancer Cells and Metastasis
- Epigenetics and DNA Methylation
- Single-cell and spatial transcriptomics
- Salivary Gland Disorders and Functions
- Inflammasome and immune disorders
- Radiomics and Machine Learning in Medical Imaging
- Peptidase Inhibition and Analysis
- Cancer Immunotherapy and Biomarkers
- Pediatric health and respiratory diseases
- Immune responses and vaccinations
- Advanced NMR Techniques and Applications
- Drug Transport and Resistance Mechanisms
- Genomics and Chromatin Dynamics
- Ubiquitin and proteasome pathways
- Diet and metabolism studies
- Cell Adhesion Molecules Research
Imperial College London
2020-2025
University of Cambridge
2012-2023
Babraham Institute
2017-2022
Cancer Research UK
2013-2019
The University of Melbourne
2007-2017
Cancer Research UK Cambridge Center
2014-2017
Peter Doherty Institute
2014-2017
University Medical Center Utrecht
2014
Centre for Human Genetics
2014
University of Manchester
2014
Fibroblast activation protein-α (FAP) identifies stromal cells of mesenchymal origin in human cancers and chronic inflammatory lesions. In mouse models cancer, they have been shown to be immune suppressive, but studies their occurrence function normal tissues limited. With a transgenic line permitting the bioluminescent imaging FAP+ cells, we find that reside most adult mouse. from three sites, skeletal muscle, adipose tissue, pancreas, highly similar transcriptomes, suggesting shared...
In patients with cancer, the wasting syndrome, cachexia, is associated caloric deficiency. Here, we describe tumor-induced alterations of host metabolic response to deficiency that cause intratumoral immune suppression. pre-cachectic mice transplanted colorectal cancer or autochthonous pancreatic ductal adenocarcinoma (PDA), find IL-6 reduces hepatic ketogenic potential through suppression PPARalpha, transcriptional master regulator ketogenesis. When these are challenged deficiency,...
Ectopic lymphoid structures form in a wide range of inflammatory conditions, including infection, autoimmune disease, and cancer. In the context this response can be beneficial for host: influenza A virus infection–induced pulmonary ectopic germinal centers give rise to more broadly cross-reactive antibody responses, thereby generating cross-strain protection. However, despite ubiquity their role both health little is known about mechanisms by which inflammation able convert peripheral...
Abstract The magnitude and quality of the germinal center (GC) response decline with age, resulting in poor vaccine-induced immunity older individuals. A functional GC requires co-ordination multiple cell types across time space, particular its two functionally distinct compartments: light dark zones. In aged mice, there is CXCR4-mediated mislocalization T follicular helper (T FH ) cells to zone a compressed network dendritic (FDCs) zone. Here we show that localization critical for antibody...
Significance The balance between the retention of lymphocytes in lymph nodes and their exit is a key factor determining clonal burst size, differentiation, efficacy pathogen clearance. Currently, it understood that naïve activated T cells regulate migration using similar system, is, balancing CC chemokine receptor (CCR)7-mediated signals against Sphingosine-1 phosphate receptor-1 (S1PR1)-mediated signals. This study utilizes mouse model to selectively deplete cellular source CCR7 ligands,...
The co-stimulatory molecule CD28 is essential for activation of helper T cells. Despite this critical role, it not known whether has functions in maintaining cell responses following activation. To determine the role after priming, we generated a strain mice where removed from CD4(+) cells priming. We show that continued expression important effector infection; maintained required expansion type 1 cells, and differentiation maintenance follicular during viral infection. Persistent also...
Although the simultaneous engagement of multiple effector mechanisms is thought to characterize optimal CD8 + T-cell immunity and facilitate pathogen clearance, differentiation pathways leading acquisition maintenance such polyfunctional activity are not well understood. Division-dependent profiles molecule expression for virus-specific T cells analyzed here by using a combination carboxyfluorescein succinimidyl ester dilution intracellular cytokine staining subsequent receptor ligation. The...
The failure to generate enduring humoral immunity after vaccination is a hallmark of advancing age. This can be attributed reduction in the germinal center (GC) response, which generates long-lived antibody-secreting cells that protect against (re)infection. Despite intensive investigation, primary cellular defect underlying impaired GCs aging has not been identified. Here, we used heterochronic parabiosis demonstrate GC formation was dictated by age lymph node (LN) microenvironment rather...
The induction of adaptive immunity is dependent on the structural organization LNs, which in turn governed by stromal cells that underpin LN architecture. Using a novel fate-mapping mouse model, we trace developmental origin mesenchymal (mLNSCs) to previously undescribed embryonic fibroblast activation protein-α (FAP)+ progenitor. FAP+ anlagen express lymphotoxin β receptor (LTβR) and vascular cell adhesion molecule (VCAM), but not intercellular (ICAM), suggesting they are early lymphoid...
The germinal center (GC) response is critical for generating high-affinity humoral immunity and immunological memory, which forms the basis of successful immunization. Control GC thought to require follicular regulatory T (Tfr) cells, a subset suppressive Foxp3+ cells located within GCs. Relatively little known about exact role Tfr how they exert their function. A unique feature reported CXCR5-dependent localization GC. Here, we show that lack CXCR5 on results in reduced frequency, but not...
Abstract Metabolic imaging has been widely used to measure the early responses of tumors treatment. Here, we assess abilities PET measurement [18F]FDG uptake and MRI hyperpolarized [1-13C]pyruvate metabolism detect changes in glycolysis following treatment-induced cell death human colorectal (Colo205) breast adenocarcinoma (MDA-MB-231) xenografts mice. A TRAIL agonist that binds but not mouse cells induced tumor-selective death. Tumor was assessed by injecting [1,6-13C2]glucose measuring...
The lymph node (LN) is home to resident macrophage populations that are essential for immune function and homeostasis, but key factors controlling this niche undefined. Here, we show fibroblastic reticular cells (FRCs) an component of the LN niche. Genetic ablation FRCs caused rapid loss macrophages monocytes from LNs across two in vivo models. Macrophages co-localized with human LNs, murine single-cell RNA-sequencing revealed FRC subsets broadly expressed master regulator CSF1. Functional...
The lungs are constantly exposed to the external environment and a myriad of antigenic challenges within air. Chronic exposure allergens other airborne antigens can result in formation lymphocyte aggregates lung, which harbor ectopic germinal centers (GCs). After allergen exposure, GCs that form lung much smaller less densely packed with B cells than lymph node GCs. Despite this, support somatic hypermutation affinity-based maturation as GCs, export memory (MBCs) directly into tissue. This...
High-avidity interactions between TCRs and peptide + class I MHC (pMHCI) epitopes drive CTL activation expansion. Intriguing questions remain concerning the constraints determining optimal TCR/pMHCI binding. The present analysis uses TCR transgenic OT-I model to assess how varying profiles of avidity influence naive proliferation acquisition effector function following exposure cognate H-2K(b)/OVA(257-264) (SIINFEKL) epitope mutants provided as or in engineered influenza A viruses....
The potent innate cytokines IL-12 and IL-18 are considered to be important antigen-independent mediators of IFN-gamma production by NK cells T lymphocytes. present analysis addresses the physiological role in generation virus-specific CD8+ cells. Both wt C57BL/6J (B6) mice with disrupted IL-12p40 (IL-12p40(-/-)) or (IL-18(-/-)) genes were infected an influenza A virus characteristics resultant epitope-specific cell responses compared. While appeared have no notable effect on either growth...
Abstract The role of chromatin remodeling and histone posttranslational modifications how they are integrated to control gene expression during the acquisition cell-specific functions is poorly understood. We show here that following in vitro activation CD4+ CD8+ T lymphocytes, both cell types rapid H3 loss at granzyme B (gzmB) proximal promoter region. However, despite gzmB being remodeled subsets, only cells express high levels display a distinct pattern key epigenetic marks, notably...
Abstract Several tolerance checkpoints exist throughout B cell development to control autoreactive cells and prevent the generation of pathogenic autoantibodies. FcγRIIb is an Fc receptor that inhibits activation and, if defective, associated with autoimmune disease, yet its impact on specific unknown. Here we show reduced expression enhances deletion anergy immature cells, but in contrast promotes expansion germinal center serum autoantibody production, even response exogenous, non-self...
Antibodies secreted within the intestinal tract provide protection from invasion of microbes into host tissues. Germinal center (GC) formation in lymph nodes and spleen strictly requires SLAM-associated protein (SAP)-mediated T cell functions; however, it is not known whether this mechanism plays a similar role mucosal-associated lymphoid Here, we find that Peyer's patches (PPs), SAP-mediated help required for promoting B selection GCs, but clonal diversification. PPs SAP-deficient mice...
TNF is a pro-inflammatory cytokine produced by both lymphoid and non-lymphoid cells. As consequence of the widespread expression its receptors (TNFR1 2), plays role in many important biological processes. In context influenza A virus (IAV) infection, has variably been implicated mediating immunopathology as well suppression immune response. Although number cell types are able to produce TNF, ability CD8+ T cells following viral infection hallmark their effector function. such, regulation...
A cardinal feature of adaptive, cytotoxic T lymphocyte (CTL)-mediated immunity is the ability naïve CTLs to undergo a program differentiation and proliferation upon activation resulting in acquisition lineage-specific cell functions eventual establishment immunological memory. In this review, we examine molecular factors that shape both maintenance effector function virus-specific CTL during memory phases immunity.