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Title: The phenotype and function of CD²⁵⁺CD¹²⁷⁻ regulatory T cells in rheumatoid arthritis
Author: Cribbs, Adam
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Regulatory T cells control many aspects of the immune system by enforcing dominant negative responses on other immune cells. Defective regulatory T cell function has been linked to many autoimmune diseases, including rheumatoid arthritis. Cytotoxic T lymphocyte antigen 4 (CTLA-4) plays a critical role in the development and function of regulatory T cells. Moreover, CTLA-4 function has been shown to be defective in rheumatoid arthritis; however the exact mechanism by which reduced expression of CTLA-4 leads to an inability of regulatory T cells to suppress effector T cells is still not clear. In this thesis I show that regulatory T cells isolated from peripheral blood of patients with rheumatoid arthritis are unable to suppress the proliferation and IFN-γ cytokine secretion of effector T cells in vitro. This lack of suppression was associated with reduced expression of total and surface CTLA-4. The mechanism underlying this reduction was found to be through methylation of a key CpG in an NFAT binding site within the CTLA-4 promoter. Methylation of this site resulted in reduced NFAT binding, and hence a reduction in CTLA-4 transcription. The observation that epigenetic changes could be responsible, in part, for defective Treg function raises the possibility for therapeutic intervention using methylation inhibitors. CTLA-4 is a known inducer of the immunoregulatory enzyme, indolamine 2,3- dioxygenase (IDO), and in this study it was shown that regulatory T cells from patients with rheumatoid arthritis were unable to induce the expression and enzymatic activity of IDO-1 in co-cultures with antigen presenting cells. CTLA-4 blockade was found to impair the ability of Tregs in co-culture to induce the expression of IDO-1, thereby mimicking the phenotype of a RA Treg. These findings suggest that one of the consequences of the reduced CTLA-4 expression displayed by regulatory T cells in rheumatoid arthritis is a failure to induce IDO expression in antigen presenting cells. This could explain, at least in part, the reduced suppressive capacity of regulatory T cells in rheumatoid arthritis. In addition to CTLA-4, a number of other molecules associated with regulatory T cell suppression such as CREM, CREB, IL-10 and CXCL10 were also found to be dysregulated in regulatory T cells isolated from patients with rheumatoid arthritis. These results suggest that other molecules associated with regulatory T cell suppression may also be epigenetically controlled and provide an insight into the inability of regulatory T cells to maintain immunological homeostasis in patients with RA.
Supervisor: Williams, Richard ; Gregory, Bernard Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available