Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, China.
State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
Adv Exp Med Biol. 2021;1278:33-46. doi: 10.1007/978-981-15-6407-9_2.
The FOXP3 transcription factor acts as a master regulator in the development and function of regulatory T cells (Tregs). Insufficient expression or mutation of FOXP3 gene impairs Treg abundancy and function and causes fatal autoimmune lymphoproliferative diseases in mice and humans. The available crystal structures of FOXP3 protein fragments provide insights into understanding details of the FOXP3 work mechanism in Tregs. This chapter consists of four sections. First, we introduce some features of Treg cells indispensable for the establishment of immune tolerance; second, we describe the critical roles of FOXP3 in Treg development and function; third, we summarize the current available crystal structures of FOXP3 functional domains and related pathogenic mutations in autoimmune diseases; finally, we discuss the potential functional and pathological relevance of FOXP3 protein structure modulation, partner interaction, and posttranslation modification based on the clinical significance in IPEX disease. The information presented in this chapter will help to consider therapeutic strategies to enhance FOXP3 activity and Treg function in the settings of autoimmune disease. Targeting Treg suppression based on FOXP3 structure and interactions hold great promises for the therapy of autoimmune diseases.
叉头框蛋白 3（FOXP3）转录因子作为调节性 T 细胞（Tregs）发育和功能的主调控因子。FOXP3 基因表达不足或突变会损害 Treg 的丰度和功能，并导致小鼠和人类致命的自身免疫性淋巴增生性疾病。FOXP3 蛋白片段的现有晶体结构为深入了解 Tregs 中 FOXP3 工作机制的细节提供了线索。本章由四个部分组成。首先，我们介绍了 Treg 细胞的一些特征，这些特征对建立免疫耐受至关重要；其次，我们描述了 FOXP3 在 Treg 发育和功能中的关键作用；第三，我们总结了目前关于自身免疫性疾病中 FOXP3 功能域的晶体结构以及相关致病性突变的情况；最后，我们讨论了基于 IPEX 疾病的临床意义，FOXP3 蛋白结构调节、相互作用和翻译后修饰的潜在功能和病理相关性。本章介绍的信息将有助于考虑在自身免疫性疾病中增强 FOXP3 活性和 Treg 功能的治疗策略。基于 FOXP3 结构和相互作用的 Treg 抑制靶向具有治疗自身免疫性疾病的巨大潜力。
