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Title: Dissecting the mechanisms of regulatory T cell-derived Extracellular Vesicle (EV)-mediated suppression to facilitate the optimisation of these cells and EVs in the clinic
Author: Tung, Sim Lai
ISNI:       0000 0004 8500 5344
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
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Regulatory T cells (Tregs) are currently being clinically assessed as a means to treat various immune conditions including transplant rejection. Despite their clinical application, Treg suppression mechanisms remain to be fully elucidated. Recently, the host laboratory discovered a novel mechanism of suppression by mouse Tregs; the release of immunomodulatory extracellular vesicles (EVs). These vesicles are released by many cell types and their contents specifically packaged, with bioactive material, to mediate cell-to-cell communication. Transfer of their contents into target cells modulates their functions. The goals of my research was to test whether; 1) mouse Treg EVs modulate bone-marrow derived dendritic cells (BM-DCs) function through the transfer of microRNAs (miRNAs); 2) human Tregs release EVs and investigate their miRNA contents; 3) human Treg EVs modulate T responder cell (Tresps) functions in vitro; 4) human Treg EVs can function in vivo to protect against transplant rejection. My results have shown that mouse Treg EVs specifically contained miR-142-3p and miR-150-5p; and when co-cultured with BM-DCs, the expression levels of these miRNAs were increased in BM-DCs. miR-142-3p and miR-150-5p have been reported to modulate DC cytokine profiles suggesting that Treg EVs can affect the aforementioned. Indeed, mouse Treg EVs reduced IL-6 whilst increased IL-10 production levels by BM-DCs, perhaps to promote an anti-inflammatory milieu. Human Tregs, upon activation released ~120nm sized cup-shaped EVs. These human Treg EVs suppressed Tresps proliferation and modulated their cytokine production profiles by inhibiting pro-inflammatory IFNγ, IL-2 and IL-6 cytokine production levels whilst promoting the release of IL-10 and IL-4 by Tresps. Exclusive miRNAs which were absent in human Tregs but enriched in human Treg EVs included; miR-369-3p, miR-376c-3p and miR-195-3p, which were predicted to target 3'-untranslated regions (3'-UTR) of IFNγ, IL-2 and IL-6 mRNA. Importantly, human Treg EVs functioned in vivo to protect against human skin transplant damage by reducing immune cell infiltration of alloreactive CD3+ T cells, CD45+ and Ki67+ cells within the transplanted allograft. The results generated herein demonstrated that human Treg EVs are functionally immunosuppressive and can protect against transplant rejection, suggesting that Treg EVs may in the future be a clinically applicable cell-free therapy for transplant patients.
Supervisor: Lombardi, Giovanna ; Smyth, Lesley Ann Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available