Characterisation of the role of different regulatory T cells in bystander suppression

Petkou, Konstantina (2023). Characterisation of the role of different regulatory T cells in bystander suppression. University of Birmingham. Ph.D.

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Abstract

Current treatments for autoimmune diseases do not provide a cure and heavily rely on broad-range immunosuppressive drugs that can compromise the ability of the host to fight infections or cancers. In recent years, antigen-specific immunotherapies have shown promising results in establishing protective immunity towards autoreactive T cells by administrating disease-relevant antigen(s) in a tolerogenic delivery platform. Using a peptide treatment protocol that induces immune tolerance by giving rise to anergic CD4\(^+\)IL-10\(^+\) T cells, we were keen to characterise the role of TIGIT, a co-inhibitory receptor, in the development, stability, and capacity of these cells to maintain central and peripheral tolerance. Importantly, in multi-antigen diseases, such as multiple sclerosis, inducing tolerance to the immunodominant antigen only can provide protection against other antigens that are found within the same tissue, due to the process of bystander suppression. In this thesis, we aimed to dissect the mechanisms underpinning bystander suppression and investigate the role of different peptide-treated regulatory T cell (Treg) populations. Tregs from the transgenic Tg4 mouse model, with a TCR specific for MBP\(_{Ac1-9}\), were tested for suppression of 2D2 responder cells, specific for a different myelin epitope, MOG\(_{35-55}\) both in vitro and in vivo. Finally, we were interested to investigate the impact of peptide immunotherapy on FoxP3\(^+\) Tregs by studying their phenotypic and functional properties. By using RNA sequencing approaches, we characterised the transcriptional signatures that are differentially expressed in peptide-treated Tregs and are essential for the licensing of these cells to acquire a highly tolerogenic phenotype. The work presented here clarifies the mechanism of action of peptide immunotherapy and paves the way for the application of this platform for the effective treatment of autoimmune diseases.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):