Professor David Thomas; University of Cambridge
My current role I am a Professor of renal medicine at the University of Cambridge and a clinical academic focused on understanding the biology of reactive oxygen species (ROS) in immunity. Working with Professor Ken Smith and Professor Gordon Dougan, I characterised the novel protein EROS and showed that it is a highly selective chaperone protein that is essential for the generation of reactive oxygen species and, therefore, host immunity. We also demonstrated that EROS-deficiency is the basis of a novel human inborn error of immunity and the molecular mechanism by which EROS works. (Thomas et al J. Exp. Med 2017, Thomas et al JACI 2018, Randzavola, Mortimer et al eLife 2022). EROS also controls the levels of some other proteins, including P2X7, which has numerous roles in both innate and adaptive immunity. This work was funded a Wellcome Trust Clinical Research Career Development Fellowship and the Beit Prize. We are currently working on: 1. the role of EROS in T cells and endothelial cells 2. other novel regulators of ROS generation. I have also worked on Covid-19 focusing on understanding the pathogenesis of disease in patients with end stage kidney disease (ESKD). I was a co-principal investigator on the OCTAVE and OCTAVE-DUO trials, which examine vaccine responses in immunosuppressed patients (Barnes et al Nature Medicine 2023). Working with collaborators at Imperial College, I have also worked on the use of multiomics to predict severity in patients with ESKD (Gisby et al eLife 2021, Gisby et al Nature Communications 2022). This includes the observation that, of 7000 serum proteins, the best predictor of disease outcome is the serum level of the alternative SARS-CoV-2 receptor, LRRC15. This work was funded by the MRC. Previous history I am a graduate of the Cambridge MB / PhD programme and trained in renal medicine at Cambridge where I was a clinical lecturer and subsequently a Wellcome-Beit Prize Career Development fellow. I moved to Imperial College, London as a reader in immunology and inflammation and honorary consultant nephrologist in 2019 before returning to Cambridge as a professor in 2023.
My group described EROS (Essential for Reactive Oxygen Species; CYBC1) as a highly selective chaperone that controls both the expression of the gp91phox-p22phox heterodimer of the phagocyte NADPH oxidase and that of the ATP receptor, P2X7. EROS deficiency results in a novel form of chronic granulomatous disease (CGD) driven by the inability to make ROS in innate immune cells. However, EROS is highly expressed in CD4+ T cells, suggesting a role in adaptive immunity. We show that EROS-deficient CD4+ T cells are markedly abnormal. They secrete excess cytokines upon polyclonal stimulation, including 10-fold more IL-4 ad 3-fold more IL-13 than control cells. EROS-/- mice also have more Foxp3+ regulatory T cells than control mice. RNA-seq analysis of EROS-/- CD4+ T cells revealed a Th2-skewed transcriptional profile with up-regulation of GATA3 and RBP-J that is distinct from that seen in isolated gp91phox or P2X7 deficiency. However, abrogation of P2X7 signalling alone in CD4+ T cells could recapitulate some aspects of EROS deficiency such as excess IL-4 production and GATA3 up-regulation. CRISPR-Cas9-mediated deletion of EROS in primary human CD4+ T cells showed conservation of function, with markedly decreased P2X7 levels, impaired surface marker shedding and enhanced IL-4 production. Numerous transcriptional pathways including those relating to the cell cycle and T cell differentiation were abnormal. Our results suggest a conserved role for EROS is involved in negatively regulating Th2 responses through a partially P2X7 dependent process. I will also discuss another previously uncharacterised protein that regulates ROS generation through sequestering EROS away from its target proteins.
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