A5062931831- Immune Cell Function and Interaction
- CAR-T cell therapy research
- Reproductive Biology and Fertility
- T-cell and B-cell Immunology
- Nuclear Receptors and Signaling
- Assisted Reproductive Technology and Twin Pregnancy
- Cancer Immunotherapy and Biomarkers
- Reproductive Health and Technologies
- Signaling Pathways in Disease
- Macrophage Migration Inhibitory Factor
- Sperm and Testicular Function
- Immunotherapy and Immune Responses
- Cytokine Signaling Pathways and Interactions
University of Birmingham
2019-2025
Reproductive Biology Associates
2008-2012
Does the selection of sperm for ICSI based on their ability to bind hyaluronan improve clinical pregnancy rates (CPR) (primary end-point), implantation (IR) and loss (PLR)? In couples where ≤65% bound hyaluronan, hyaluronan-bound (HB) led a statistically significant reduction in PLR. HB demonstrate enhanced developmental parameters which have been associated with successful fertilization embryogenesis. Sperm selected using liquid source achieved an improvement IR. A pilot study by primary...
Nr4a receptors are activated by T cell receptor (TCR) signaling and play key roles in differentiation. Which TCR pathways regulate their sensitivities to signal strength duration remains unclear. Using Nr4a1/Nur77-GFP Nr4a3-Timer of kinetics activity (Tocky) mice, we elucidate the governing expression. We reveal that Nr4a1-Nr4a3 Src family kinase dependent. Moreover, Nr4a2 Nr4a3 attenuated calcineurin inhibitors bind nuclear factor cells 1 (NFAT1), highlighting a necessary sufficient role...
How T cell receptor (TCR) signal strength modulates function and to what extent this is modified by immune checkpoint blockade (ICB) are key questions in immunology. Using Nr4a3-Tocky mice, we characterized early quantitative qualitative changes that occur CD4+ cells relation TCR signaling strength. We captured how dose- time-dependent programming of distinct co-inhibitory receptors rapidly recalibrates activation thresholds visualized the immediate effects ICB on re-activation. Our findings...
Abstract In lymphocytes, Nr4a gene expression is specifically regulated by antigen receptor signalling, making them ideal targets for use as distal T cell (TCR) reporters. Nr4a3-Timer of kinetics and activity (Tocky) mice are a ground-breaking tool to report TCR-driven Nr4a3 using Fluorescent Timer protein (FT). FT undergoes time-dependent shift in its emission spectrum following translation, allowing the temporal reporting transcriptional events. Our recent work suggested that Nr4a1/Nur77...
Lag3 and PD-1 are immune checkpoints that regulate T cell responses current immunotherapy targets. Yet how they function to control early stages of CD4+ activation remains unclear. Here, we show the pathways exhibit layered process, with effects more pronounced in presence pathway co-blockade (CB). RNA sequencing revealed CB drove an NFAT-dependent transcriptional profile, including promotion ICOShi follicular helper differentiation. NFAT inhibition abolished CB-induced upregulation...
TIGIT is an immune checkpoint receptor that can signal via cytoplasmic ITT-like and ITIM motifs to regulate T cell function. The signalling molecules mediate inhibitory in cells remain poorly defined, it not clear how activation regulated. Here, proximity proteomics was employed Jurkat identify TIGIT-associating proteins upon engagement with its ligand CD155. This identified several ligation-specific interactors, including involved (Grb2 SOS1), cytoskeletal regulation (CD2AP SdcBP),...
Summary Nr4a receptors are activated by T cell receptor (TCR) and B (BCR) signalling play key roles in differentiation promoting exhaustion. How TCR pathways regulate their sensitivities to different physiological types of (e.g. tonic versus activating) remains unknown. Here we utilise Nr4a1/Nur77-GFP Nr4a3 -Tocky mice elucidate the that govern expression CD4 + CD8 cells. Our findings reveal Nr4a1-3 Src family kinase-dependent. Moreover, Nr4a2 abolished calcineurin inhibitors bind NFAT1,...
Abstract Anti-Lag3 and anti-PD-1 combination immunotherapy for melanoma has received recent regulatory approval, yet its mechanism of action is unclear, particularly CD4 + T cells. Here, we determined the roles Lag3 PD-1/PD-L1 pathways during cell activation in vivo . During primary immune responses, played a redundant role with PD1/PD-L1 axis dominant regulating early activation. By exploiting an adaptive tolerance model, reveal that PD-L1 co-blockade (CB) drove major changes cells,...
Summary How T cell receptor (TCR) signal strength modulates function and to what extent this is modified by immune checkpoint blockade (ICB) are key questions in immunology. Using Nr4a3-Tocky mice as a digital read-out of NFAT pathway activity, we identify the rapid quantitative qualitative changes that occur CD4 + cells response range TCR signalling strengths. We demonstrate time dose dependent programming distinct co-inhibitory receptors rapidly re-calibrates activation thresholds. By...