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Title: Modulation of regulatory T cell function through specific molecular pathways in transplantation
Author: Kawai, Kento
ISNI:       0000 0004 9355 2903
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2020
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Regulatory T cells (Tregs) are crucial mediators of immune homeostasis that have shown immense promise as a cellular therapy for immune-mediated pathologies such as transplant rejection. Methods to optimise current Treg-based therapies are critical for its successful and widespread translation to the clinical setting. The aim of this study was to investigate the role of two molecular pathways for the modulation of Treg biology and function. In the first part of this study, the role of the interleukin-33 (IL-33)/ST2 axis was interrogated in Tregs. This highly pleiotropic pathway has recently been demonstrated to have an important role in Treg biology. Here, it is shown that IL-33-expanded Tregs have enhanced in vivo suppressive function in a transplantation model. An in-depth characterization of IL-33-expanded Tregs is presented, providing a detailed quantitative transcriptomic and immunophenotypic analysis. Interestingly, this reveals IL-33-expanded Tregs to harbour a phenotypic signature of enhanced potential for graft-homing. In the second part of the study, Treg plasticity and the environmental factors which govern their phenotype and function were examined, with a particular focus on the role of hypoxia and the principal regulators of oxygen homeostasis, the HIF/PHD pathway, in modulating Treg biology. Using an array of HIF/PHD2 transgenic mouse models, the study demonstrates that silencing of the critical prolyl hydroxylase domain-containing enzyme, Phd2, induces an autoimmune-like phenotype in mice. This is driven by upregulated HIF-2a signalling, in which the suppressive function of Treg populations is significantly impaired with loss of ability to control graft rejection. Additionally, evidence is presented to demonstrate that HIF-2a may be inhibited to enhance suppressive function of both mouse and human Tregs. These findings are replicated, at least in part, in mice subjected to chronic hypoxic. While significant progress has been made to unlock the therapeutic potential of Tregs, there remains a great deal more to be learned regarding their behaviour and function for their effective and safe implementation within the clinic. The findings presented in this thesis uncover methods for the molecular manipulation of Tregs to help exploit their versatility for therapeutic use.
Supervisor: Issa, Fadi ; Hester, Joanna Sponsor: Kidney Research UK ; Wellcome Trust ; Horizon 2020
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Immunology ; Transplantation