Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Lokey Stem Cell Research Building 265 Campus Drive, West Stanford, CA, 94305, USA.
Center for Definitive and Curative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Semin Immunopathol. 2021 Feb;43(1):65-83. doi: 10.1007/s00281-020-00835-8. Epub 2021 Feb 2.
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.
在其胸腺内发育过程中，新生 T 细胞被赋予了抵御病原体和终生接受自身的能力。虽然自身反应性效应 T（Teff）细胞前体通过克隆删除而被消除，但胸腺调节性 T 细胞（tTreg）前体在维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仍知之甚少。tTreg 和 Teff 的发育和选择都源于其克隆型 T 细胞受体（TCR）与抗原呈递细胞（如胸腺上皮细胞和胸腺树突状细胞）表达的肽/MHC 复合物之间的精细协调相互作用。tTreg 的功能依赖于 FOXP3 转录因子的表达，并且 tTreg 在其胸腺内发育过程中发生 FOXP3 基因的诱导表达，特别是在胸腺髓质内。虽然 FOXP3 的初始表达是 TCR 激活的下游事件，但通过与其他细胞外信号（如 TCR 和细胞因子）调节的各种转录因子的相互作用，FOXP3 基因的组成型表达被固定下来，导致 FOXP3 基因的表观遗传修饰。对 tTreg 生成的分子事件的大部分理解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非常具有挑战性。在这篇综述中，我们将阐明先天免疫缺陷如何阐明 tTreg 发育过程中某些分子的关键非冗余作用，阐明它们的异常发育和功能如何导致具有自身免疫但与免疫缺陷和自身炎症状态相关的明确疾病。
