Naturally arising regulatory CD4+ T (Treg) cells, which specifically express the transcription factor FoxP3 in the nucleus and CD25 and CTLA-4 on the cell surface, are a T-cell subpopulation specialized for immune suppression, playing a key role in maintaining immunological self-tolerance and homeostasis. FoxP3 is required for Treg function, especially for its suppressive activity. However, FoxP3 expression per se is not necessary for Treg cell lineage commitment in the thymus and insufficient for full Treg-type gene expression in mature Treg cells. It is Treg-specific epigenetic changes such as CpG demethylation and histone modification that can confer a stable and heritable pattern of Treg type gene expression on developing Treg cells in a FoxP3-independent manner. Anomalies in the formation of Treg-specific epigenome, in particular, Treg-specific super-enhancers, which largely include Treg-specific DNA demethylated regions, are indeed able to cause autoimmune diseases in rodents. Furthermore, in humans, single nucleotide polymorphisms in Treg-specific DNA demethylated regions associated with Treg signature genes, such as IL2RA (CD25) and CTLA4, can affect the development and function of naïve Treg cells rather than effector T cells. Such genetic variations are therefore causative of polygenic common autoimmune diseases including type 1 diabetes and rheumatoid arthritis via affecting endogenous natural Treg cells. These findings on the transcription factor network with FoxP3 at a key position as well as Treg-specific epigenetic landscape facilitate our understanding of Treg cell development and function, and can be exploited to prepare functionally stable FoxP3-expressing Treg cells from antigen-specific conventional T cells to treat autoimmune diseases.

中文翻译：

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Treg 细胞发育和功能的转录和表观遗传基础：自身免疫性疾病的遗传异常或变异。


天然产生的调节性 CD4+ T (Treg) 细胞，在细胞核中特异性表达转录因子 FoxP3，在细胞表面表达 CD25 和 CTLA-4，是专门用于免疫抑制的 T 细胞亚群，在维持免疫自我方面发挥着关键作用-耐受性和体内平衡。 FoxP3 是 Treg 功能所必需的，尤其是其抑制活性。然而，FoxP3 表达本身对于胸腺中 Treg 细胞谱系定型不是必需的，并且不足以在成熟 Treg 细胞中完全表达 Treg 型基因。 Treg特异性表观遗传变化，如CpG去甲基化和组蛋白修饰，可以以不依赖FoxP3的方式为发育中的Treg细胞赋予稳定且可遗传的Treg型基因表达模式。 Treg特异性表观基因组形成的异常，特别是Treg特异性超级增强子，主要包括Treg特异性DNA去甲基化区域，确实能够引起啮齿类动物的自身免疫性疾病。此外，在人类中，与 Treg 特征基因（例如 IL2RA (CD25) 和 CTLA4）相关的 Treg 特异性 DNA 去甲基化区域中的单核苷酸多态性可以影响初始 Treg 细胞而不是效应 T 细胞的发育和功能。因此，此类遗传变异通过影响内源性天然 Treg 细胞，导致多基因常见自身免疫性疾病，包括 1 型糖尿病和类风湿性关节炎。这些以 FoxP3 为关键位置的转录因子网络以及 Treg 特异性表观遗传景观的发现有助于我们了解 Treg 细胞的发育和功能，并可用于从抗原特异性常规 T 细胞制备功能稳定的表达 FoxP3 的 Treg 细胞。细胞治疗自身免疫性疾病。