The phenotype and function of CD25+[superscript]CD127-[superscript] regulatory T cells in rheumatoid arthritis
Author(s)
Cribbs, Adam
Type
Thesis or dissertation
Abstract
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.
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.
Version
Open Access
Date Issued
2013-03
Online Publication Date
2014-10-29T11:44:13Z
Date Awarded
2013-09
Advisor
Williams, Richard
Gregory, Bernard
Publisher Department
Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)