Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA 94143, USA.
Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Immunity. 2019 Feb 19;50(2):362-377.e6. doi: 10.1016/j.immuni.2018.12.016. Epub 2019 Jan 29.
Regulatory T (Treg) cells maintain immune tolerance through the master transcription factor forkhead box P3 (FOXP3), which is crucial for Treg cell function and homeostasis. We identified an IPEX (immune dysregulation polyendocrinopathy enteropathy X-linked) syndrome patient with a FOXP3 mutation in the domain swap interface of the protein. Recapitulation of this Foxp3 variant in mice led to the development of an autoimmune syndrome consistent with an unrestrained T helper type 2 (Th2) immune response. Genomic analysis of Treg cells by RNA-sequencing, Foxp3 chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-sequencing), and H3K27ac-HiChIP revealed a specific de-repression of the Th2 transcriptional program leading to the generation of Th2-like Treg cells that were unable to suppress extrinsic Th2 cells. Th2-like Treg cells showed increased intra-chromosomal interactions in the Th2 locus, leading to type 2 cytokine production. These findings identify a direct role for Foxp3 in suppressing Th2-like Treg cells and implicate additional pathways that could be targeted to restrain Th2 trans-differentiated Treg cells.
调节性 T（Treg）细胞通过主转录因子叉头框 P3（FOXP3）维持免疫耐受，FOXP3 对于 Treg 细胞的功能和稳态至关重要。我们鉴定了一名 IPEX（免疫失调多内分泌腺病肠病 X 连锁）综合征患者，其蛋白的结构域交换界面存在 FOXP3 突变。在小鼠中重现这种 Foxp3 变体导致了一种自身免疫综合征的发展，与不受抑制的辅助性 T 细胞 2（Th2）免疫反应一致。通过 RNA 测序、Foxp3 染色质免疫沉淀 followed by 高通量 DNA 测序（ChIP-seq）和 H3K27ac-HiChIP 对 Treg 细胞进行基因组分析，揭示了 Th2 转录程序的特异性去抑制，导致产生了不能抑制外在 Th2 细胞的 Th2 样 Treg 细胞。Th2 样 Treg 细胞在 Th2 基因座中表现出增加的染色体内相互作用，导致 2 型细胞因子的产生。这些发现确定了 Foxp3 在抑制 Th2 样 Treg 细胞中的直接作用，并暗示了可以靶向的其他途径来抑制 Th2 转分化的 Treg 细胞。
