Abstract
CD4+CD25+ regulatory T (Treg) cells play a pivotal role in the maintenance of immune homeostasis, where the X-linked master transcription factor forkhead box P3 (FOXP3) determines Treg cell development and function. Genetic deficiency of foxp3 induces dysfunction of Treg cells and immuno-dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome in humans. Functionally deficient Treg cells or the development of exTreg cells positively correlate with autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), and ankylosing spondylitis (AS). In general, females are more susceptible to SLE and MS but less susceptible to AS, where the expression of FOXP3 and its protein complex are perturbed by multiple factors, including hormonal fluctuations, inflammatory cytokines, and danger signals. Therefore, it is critical to explore the potential molecular mechanisms involved and these differences linked to gender. Here, we review recent findings on the regulation of FOXP3 activity in Treg cells and also discuss gender difference in the determination of Treg cell function in autoimmune diseases.
Highlights
Regulatory T (Treg) cells, via their immune suppressive capability, play an indispensable role in maintaining immune homeostasis and preventing autoimmunity induced by excessive, misdirected, or unnecessary immune activation
In Nur77GFP mice, the mean fluorescence intensity (MFI) of GFP revealed that the T cell receptor (TCR) signal strength in thymus-derived Treg (tTreg) and peripherally derived Treg (pTreg) cells was almost two-fold compared with conventional CD4+ T cells [38]
Gene expression profile analysis in FOXP3non-expressing T cells that lacked methylation of the Treg-specific demethylation region (TSDR), and forkhead box P3 (FOXP3)-expressing T cells that retained methylation of the TSDR, showed higher similarity to tTreg cells in the former in gene expression but lack of repression in the expression of il2, ifng, and zap70; the latter cells exhibited normal il2, ifng, and zap70 repression but upregulated a set of genes that were not expressed in tTreg cells. These results indicated that FOXP3 expression and the demethylation of the TSDR are both vital to establish Treg lineage commitment, but neither of them alone is sufficient [49]
Summary
Regulatory T (Treg) cells, via their immune suppressive capability, play an indispensable role in maintaining immune homeostasis and preventing autoimmunity induced by excessive, misdirected, or unnecessary immune activation. Treg cells can reduce T cell activation and proliferation through CD39–CD73-mediated production of metabolic adenosine [5]. Anti-inflammatory cytokines that are secreted by Treg cells can induce immune tolerance [6, 7]. Under pathogenic conditions, such as systemic lupus erythematosus (SLE) and multiple sclerosis (MS), Treg cells exhibit plasticity to some extent and may mimic T helper-like phenotypes. Recent studies have provided insight into the understanding of the stability and activity of forkhead box P3 (FOXP3) in Treg cells regulated by T cell receptor (TCR) signaling, inflammatory cytokines, and danger signals. We discuss the cellular and molecular mechanisms underlying FOXP3mediated regulation of Treg cells and the possible effect that gender difference has on Treg cells and autoimmune diseases
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