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FOXP3(+) Treg Cells and Gender Bias in Autoimmune Diseases.

Nie J, Li YY, Zheng SG, Tsun A, Li B - Front Immunol (2015)

Bottom Line: Genetic deficiency of foxp3 induces dysfunction of Treg cells and immuno-dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome in humans.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.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai , China.

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.

No MeSH data available.


Related in: MedlinePlus

The regulation of FOXP3 expression. The foxp3 promoter, three conserved regulatory regions, and the epigenetic modification status of the foxp3 gene. Upon TCR stimulation, NFAT, AP1, Sp1, and CREB-ATF bind to the promoter of the foxp3 gene. STAT5 forms a dimer in response to IL-2 signals and translocates to the foxp3 promoter. In the periphery, TGF-β signals drive SMADs and NFAT occupancy at the CNS2 region and may induce FOXP3 expression. The CpG island within the foxp3 promoter region is demethylated in both tTreg cells and pTreg cells but not in naïve T cells. The histones bound to the foxp3 promoter region are hyperacetylated in both tTreg and pTreg cells. However, CNS2 is demethylated only in tTreg but not in pTreg cells.
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Figure 2: The regulation of FOXP3 expression. The foxp3 promoter, three conserved regulatory regions, and the epigenetic modification status of the foxp3 gene. Upon TCR stimulation, NFAT, AP1, Sp1, and CREB-ATF bind to the promoter of the foxp3 gene. STAT5 forms a dimer in response to IL-2 signals and translocates to the foxp3 promoter. In the periphery, TGF-β signals drive SMADs and NFAT occupancy at the CNS2 region and may induce FOXP3 expression. The CpG island within the foxp3 promoter region is demethylated in both tTreg cells and pTreg cells but not in naïve T cells. The histones bound to the foxp3 promoter region are hyperacetylated in both tTreg and pTreg cells. However, CNS2 is demethylated only in tTreg but not in pTreg cells.

Mentions: The significance of FOXP3 to Treg development and stability is well documented. Direct evidence that has shown FOXP3 protein to be important for Treg function has been provided by experiments that inserted a gene cassette co-expressing luciferase and enhanced green fluorescent protein (eGFP) into the 3′-untranslated region (UTR) of the endogenous foxp3 locus of C57BL/6 mice. This lead to FOXP3 mRNA instability, a 90% decrease of FOXP3 protein expression, and as a consequence these mice succumbed to aggressive lymphoproliferative autoimmune syndrome, indicating that Treg cell function directly correlates with the amount of FOXP3 protein expressed (12). Observations like this make it imperative to explore the molecular mechanisms regulating FOXP3 expression (Figure 2).


FOXP3(+) Treg Cells and Gender Bias in Autoimmune Diseases.

Nie J, Li YY, Zheng SG, Tsun A, Li B - Front Immunol (2015)

The regulation of FOXP3 expression. The foxp3 promoter, three conserved regulatory regions, and the epigenetic modification status of the foxp3 gene. Upon TCR stimulation, NFAT, AP1, Sp1, and CREB-ATF bind to the promoter of the foxp3 gene. STAT5 forms a dimer in response to IL-2 signals and translocates to the foxp3 promoter. In the periphery, TGF-β signals drive SMADs and NFAT occupancy at the CNS2 region and may induce FOXP3 expression. The CpG island within the foxp3 promoter region is demethylated in both tTreg cells and pTreg cells but not in naïve T cells. The histones bound to the foxp3 promoter region are hyperacetylated in both tTreg and pTreg cells. However, CNS2 is demethylated only in tTreg but not in pTreg cells.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585344&req=5

Figure 2: The regulation of FOXP3 expression. The foxp3 promoter, three conserved regulatory regions, and the epigenetic modification status of the foxp3 gene. Upon TCR stimulation, NFAT, AP1, Sp1, and CREB-ATF bind to the promoter of the foxp3 gene. STAT5 forms a dimer in response to IL-2 signals and translocates to the foxp3 promoter. In the periphery, TGF-β signals drive SMADs and NFAT occupancy at the CNS2 region and may induce FOXP3 expression. The CpG island within the foxp3 promoter region is demethylated in both tTreg cells and pTreg cells but not in naïve T cells. The histones bound to the foxp3 promoter region are hyperacetylated in both tTreg and pTreg cells. However, CNS2 is demethylated only in tTreg but not in pTreg cells.
Mentions: The significance of FOXP3 to Treg development and stability is well documented. Direct evidence that has shown FOXP3 protein to be important for Treg function has been provided by experiments that inserted a gene cassette co-expressing luciferase and enhanced green fluorescent protein (eGFP) into the 3′-untranslated region (UTR) of the endogenous foxp3 locus of C57BL/6 mice. This lead to FOXP3 mRNA instability, a 90% decrease of FOXP3 protein expression, and as a consequence these mice succumbed to aggressive lymphoproliferative autoimmune syndrome, indicating that Treg cell function directly correlates with the amount of FOXP3 protein expressed (12). Observations like this make it imperative to explore the molecular mechanisms regulating FOXP3 expression (Figure 2).

Bottom Line: Genetic deficiency of foxp3 induces dysfunction of Treg cells and immuno-dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome in humans.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.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai , China.

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.

No MeSH data available.


Related in: MedlinePlus