Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital, Boston, MA 02115, USA.
Immunity. 2011 Apr 22;34(4):479-91. doi: 10.1016/j.immuni.2011.02.017. Epub 2011 Mar 31.
The transcription factor FOXP3 is essential for the suppressive function of regulatory T cells that are required for maintaining self-tolerance. We have solved the crystal structure of the FOXP3 forkhead domain as a ternary complex with the DNA-binding domain of the transcription factor NFAT1 and a DNA oligonucleotide from the interleukin-2 promoter. A striking feature of this structure is that FOXP3 forms a domain-swapped dimer that bridges two molecules of DNA. Structure-guided or autoimmune disease (IPEX)-associated mutations in the domain-swap interface diminished dimer formation by the FOXP3 forkhead domain without compromising FOXP3 DNA binding. These mutations also eliminated T cell-suppressive activity conferred by FOXP3, both in vitro and in a murine model of autoimmune diabetes in vivo. We conclude that FOXP3-mediated suppressor function requires dimerization through the forkhead domain and that mutations in the dimer interface can lead to the systemic autoimmunity observed in IPEX patients.
转录因子 FOXP3 对于调节性 T 细胞的抑制功能至关重要，而调节性 T 细胞对于维持自身耐受是必需的。我们已经解决了 FOXP3 叉头结构域与转录因子 NFAT1 的 DNA 结合域以及来自白细胞介素-2 启动子的 DNA 寡核苷酸形成三元复合物的晶体结构。该结构的一个显著特征是，FOXP3 形成了一个结构域交换二聚体，该二聚体桥接了两个 DNA 分子。结构导向或自身免疫疾病（IPEX）相关突变使 FOXP3 叉头结构域的二聚体形成减少，而不影响 FOXP3 的 DNA 结合。这些突变还消除了 FOXP3 赋予的 T 细胞抑制活性，无论是在体外还是在体内自身免疫性糖尿病的小鼠模型中。我们得出结论，FOXP3 介导的抑制功能需要通过叉头结构域进行二聚化，而二聚体界面的突变可导致 IPEX 患者中观察到的全身性自身免疫。
