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Abstract
The maintenance of FOXP3 expression in CD25hi regulatory T cells (Tregs) is crucial to the control of inflammation and essential for successful Treg transfer therapies. Coexpression of CD25 and FOXP3 in combination with a hypomethylated region within the FOXP3 gene, called the Treg-specific demethylated region (TSDR), is considered the hallmark of stable Tregs. The TSDR is an epigenetic motif that is important for stable FOXP3 expression and is used as a biomarker to measure Treg lineage commitment. In this study, we report that, unlike in peripheral blood, CD4+ T cell expression of CD25 and FOXP3 is frequently dissociated at the inflamed site in patients with juvenile idiopathic arthritis, which led us to question the stability of human Tregs in chronic inflammatory environments. We describe a novel CD4+CD127loCD25hi human T cell population that exhibits extensive TSDR and promoter demethylation in the absence of stable FOXP3 expression. This population expresses high levels of CTLA-4 and can suppress T conventional cell proliferation in vitro. These data collectively suggest that this population may represent a chronically activated FOXP3lo Treg population. We show that these cells have defects in IL-2 signaling and reduced expression of a deubiquitinase important for FOXP3 stability. Clinically, the proportions of these cells within the CD25hi T cell subset are increased in patients with the more severe courses of disease. Our study demonstrates, therefore, that hypomethylation at the TSDR can be decoupled from FOXP3 expression in human T cells and that environment-specific breakdown in FOXP3 stability may compromise the resolution of inflammation in juvenile idiopathic arthritis.
Highlights
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We report that, unlike in peripheral blood, CD4+ T cell expression of CD25 and FOXP3 is frequently dissociated at the inflamed site in patients with juvenile idiopathic arthritis, which led us to question the stability of human regulatory T cell (Treg) in chronic inflammatory environments
That hypomethylation at the Treg-specific demethylated region (TSDR) can be decoupled from FOXP3 expression in human T cells and that environment-specific breakdown in FOXP3 stability may compromise the resolution of inflammation in juvenile idiopathic arthritis
Summary
Both P1 and P2 Treg populations had a significantly higher rate of turnover compared with CD127hi T cells (median frequencies: P1, 21.00%; P2, 23.60%; CD127hi, 3.65%) whereas P3 exhibited intermediate turnover (median frequency, 9.28%), which was not significantly different from Tcons (Fig. 7E), suggesting that defects in IL-2 sensitivity may result in a failure to maintain FOXP3 expression and reduced proliferative potential for P3 Tregs. It has been previously demonstrated that the milder form of oligoarticular JIA (O-JIA), called persistent O-JIA, is associated with an increased frequency and number of Tregs in the inflamed compartment [5, 6] compared with the more severe forms of disease; these studies did not stratify according to FOXP3 high or low expression.
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