During their intrathymic development, nascent T cells are empowered to protect against pathogens and to be operative for a life-long acceptance of self. While autoreactive effector T (Teff) cell progenitors are eliminated by clonal deletion, the intrathymic mechanisms by which thymic regulatory T cell (tTreg) progenitors maintain specificity for self-antigens but escape deletion to exert their regulatory functions are less well understood. Both tTreg and Teff development and selection result from finely coordinated interactions between their clonotypic T cell receptors (TCR) and peptide/MHC complexes expressed by antigen-presenting cells, such as thymic epithelial cells and thymic dendritic cells. tTreg function is dependent on expression of the FOXP3 transcription factor, and induction of FOXP3 gene expression by tTreg occurs during their thymic development, particularly within the thymic medulla. While initial expression of FOXP3 is downstream of TCR activation, constitutive expression is fixed by interactions with various transcription factors that are regulated by other extracellular signals like TCR and cytokines, leading to epigenetic modification of the FOXP3 gene. Most of the understanding of the molecular events underlying tTreg generation is based on studies of murine models, whereas gaining similar insight in the human system has been very challenging. In this review, we will elucidate how inborn errors of immunity illuminate the critical non-redundant roles of certain molecules during tTreg development, shedding light on how their abnormal development and function cause well-defined diseases that manifest with autoimmunity alone or are associated with states of immune deficiency and autoinflammation.

在胸腺内发育过程中，新生 T 细胞能够抵御病原体，并终生接受自我。虽然自身反应性效应 T (Teff) 细胞祖细胞通过克隆删除而被消除，但胸腺调节性 T 细胞 (tTreg) 祖细胞保持对自身抗原的特异性但逃避删除以发挥其调节功能的胸腺内机制尚不清楚。 tTreg 和 Teff 的发育和选择都是其克隆型 T 细胞受体 (TCR) 与抗原呈递细胞（例如胸腺上皮细胞和胸腺树突细胞）表达的肽/MHC 复合物之间精细协调的相互作用的结果。 tTreg 功能依赖于 FOXP3 转录因子的表达，tTreg 对FOXP3基因表达的诱导发生在胸腺发育过程中，特别是在胸腺髓质内。虽然FOXP3的初始表达位于 TCR 激活的下游，但组成型表达通过与受其他细胞外信号（如 TCR 和细胞因子）调节的各种转录因子的相互作用而固定，从而导致FOXP3基因的表观遗传修饰。大多数对 tTreg 生成分子事件的理解都是基于对小鼠模型的研究，而在人类系统中获得类似的见解却非常具有挑战性。在这篇综述中，我们将阐明先天性免疫错误如何阐明某些分子在 tTreg 发育过程中的关键非冗余作用，阐明它们的异常发育和功能如何导致明确的疾病，这些疾病仅表现为自身免疫或与状态相关免疫缺陷和自身炎症。