Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan; Department of Experimental Pathology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
Immunity. 2021 May 11;54(5):947-961.e8. doi: 10.1016/j.immuni.2021.04.005. Epub 2021 Apr 29.
The transcription factor Foxp3 plays crucial roles for Treg cell development and function. Conserved non-coding sequences (CNSs) at the Foxp3 locus control Foxp3 transcription, but how they developmentally contribute to Treg cell lineage specification remains obscure. Here, we show that among Foxp3 CNSs, the promoter-upstream CNS0 and the intergenic CNS3, which bind distinct transcription factors, were activated at early stages of thymocyte differentiation prior to Foxp3 promoter activation, with sequential genomic looping bridging these regions and the promoter. While deletion of either CNS0 or CNS3 partially compromised thymic Treg cell generation, deletion of both completely abrogated the generation and impaired the stability of Foxp3 expression in residual Treg cells. As a result, CNS0 and CNS3 double-deleted mice succumbed to lethal systemic autoimmunity and inflammation. Thus, hierarchical and coordinated activation of Foxp3 CNS0 and CNS3 initiates and stabilizes Foxp3 gene expression, thereby crucially controlling Treg cell development, maintenance, and consequently immunological self-tolerance.
转录因子 Foxp3 对于调节性 T 细胞（Treg）的发育和功能起着至关重要的作用。Foxp3 基因座上的保守非编码序列（CNS）控制 Foxp3 的转录，但它们在发育过程中如何有助于 Treg 细胞谱系的特化仍不清楚。在这里，我们表明，在 Foxp3 CNS 中，启动子上游 CNS0 和基因间 CNS3 在 Foxp3 启动子激活之前，在胸腺细胞分化的早期就被激活，这些区域和启动子之间通过顺序的基因组环化桥接。虽然 CNS0 或 CNS3 的缺失部分削弱了胸腺 Treg 细胞的生成，但两者的缺失完全消除了生成，并损害了残留 Treg 细胞中 Foxp3 表达的稳定性。结果，CNS0 和 CNS3 双缺失的小鼠死于致命的全身自身免疫和炎症。因此，Foxp3 CNS0 和 CNS3 的分级和协调激活启动并稳定 Foxp3 基因表达，从而对 Treg 细胞的发育、维持以及免疫的自身耐受起着至关重要的作用。
