Investigation of hypoxia-sensing mechanisms in immune regulation (360G-Wellcome-211122_Z_18_Z)

CD4+CD25+Foxp3+ regulatory T cells (Tregs) are central to immune regulation and are a promising therapy for the treatment of autoimmunity and transplant rejection, where I am currently leading a clinical trial. Adaptive immune responses are regulated by environmental factors including hypoxia which reduces the activity of prolyl hydroxylase domain (PHD) enzymes thereby activating Hypoxia Inducible Factor (HIF) transcription factors. Effects on cytotoxic T cell activity have been reported, but the interplay between hypoxic signalling and Treg function is less clear. We have recently investigated this PHD/HIF axis using novel tetracycline-inducible PHD knockdown mice. Preliminary data suggest a previously unreported role for PHD2 and HIF-2a in the modulation of Treg activity. I now propose to characterise further the relationship between the PHD/HIF pathway and Treg activity, and to identify therapeutic targets that may be harnessed to modulate Treg function. Effects of further genetic (and pharmacological) manipulations will be tested in sensitive Treg functional assays and transplantation models. The cellular and metabolic mechanisms will be investigated in detail through phenotypic, transcriptomic and metabolic profiling. Overall, these data will broaden our understanding of the relationship between oxygen-sensing mechanisms and immune regulation which I am ultimately well placed to translate to the clinical setting.