How manipulating oxygen and iron availability affects Tregs and the immune system

Thesis

Regulatory T cells (Tregs) are essential for maintaining immune balance, failure of which can result in infections, cancer, autoimmunity, or chronic inflammation. Hypoxia and hypoferremia are common features of inflammatory microenvironments, but their effect on Tregs is poorly understood. In this thesis, I investigate how manipulating oxygen and iron availability affects Tregs and the immune system. Firstly, I examine how hypoxia and HIF signalling affects Treg and immune biology using hypoxia-treated mice lacking specific genes of the hypoxia pathway to reveal a complex interplay between different HIF isoforms and subunits. I also investigate how hypoxia signalling alters Treg transcription using single cell and bulk RNA sequencing, revealing a role for the p38 MAPK-NFkB signalling pathway and an association between CD25 loss and increased CD22-Notch1 signalling in Tregs. To examine how iron biology impacts Tregs, I use an in vitro iron deprivation model to show that Tregs appear more resistant to hypoferremia than conventional T cells. I show that cell-intrinsically iron-deprived Tregs are suppressive in vitro but not in vivo, and that the Treg:Teff ratio favours Tregs (and consequently tolerance) in models using mixed bone marrow chimeras and malaria infection. Finally, I investigate how iron limitation impacts graft survival in a skin transplantation model, showing that iron deprivation can restrain alloresponses and rejection. The work presented here provides a deeper understanding of the mechanisms that regulate Treg function and uncovers areas for potential therapeutic applications in all diseases arising from immune imbalance.

Authors: Sion, M

• DOI: 10.5287/ora-n68gdmdwq
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: transplantation; immunology; iron; Tregs; hypoxia
• Subjects: Immunology