Foxp3 occupancy and regulation of key target genes during T-cell stimulation
Foxp3 occupancy and regulation of key target genes during T-cell stimulation
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DOI：
10.1038/nature05478
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发表时间：
2007-02-22
期刊：
影响因子：
64.8
通讯作者：
Young, Richard A.
中科院分区：
文献类型：
--
作者：
Marson, Alexander;Kretschmer, Karsten;Young, Richard A.
Foxp 3（+）CD 4（+）CD 25（+）调节性T（T-reg）细胞对于预防自身免疫至关重要（1，2）。T-reg细胞对T细胞受体刺激具有减弱的细胞因子应答，并且可以抑制邻近T细胞的增殖和效应子功能（3，4）。叉头转录因子Foxp 3（叉头框P3）在T-reg细胞中选择性表达，是T-reg发育和功能所需的，并且足以在常规CD 4（+）CD 25（-）T细胞中诱导Treg表型（5-8）。Foxp 3的突变在人和小鼠中引起严重的多器官自身免疫（9-11）。FOXP 3可以在DNA结合复合物中与NFAT（活化T细胞的核因子）合作以调节几种已知靶基因的转录（12）。然而，由Foxp 3直接调控的基因的全局集合是未知的，因此，该转录因子如何控制T-reg功能的基因表达程序尚不清楚。在这里，我们确定了Foxp 3靶基因，并报告说，其中许多是T细胞活化和功能的关键调节剂。值得注意的是，Foxp 3占据的主要（尽管不是唯一的）作用是抑制靶基因对T细胞刺激的活化。Foxp 3抑制其靶点似乎对T-reg细胞的正常功能至关重要，因为已知某些靶基因的过度活跃变体与自身免疫性疾病相关。
Foxp3(+) CD4(+) CD25(+) regulatory T (T-reg) cells are essential for the prevention of autoimmunity(1,2). T-reg cells have an attenuated cytokine response to T-cell receptor stimulation, and can suppress the proliferation and effector function of neighbouring T cells(3,4). The forkhead transcription factor Foxp3 ( forkhead box P3) is selectively expressed in T-reg cells, is required for T-reg development and function, and is sufficient to induce a Treg phenotype in conventional CD4(+) CD25(-) T cells(5-8). Mutations in Foxp3 cause severe, multi-organ autoimmunity in both human and mouse(9-11). FOXP3 can cooperate in a DNA-binding complex with NFAT ( nuclear factor of activated T cells) to regulate the transcription of several known target genes(12). However, the global set of genes regulated directly by Foxp3 is not known and consequently, how this transcription factor controls the gene expression programme for T-reg function is not understood. Here we identify Foxp3 target genes and report that many of these are key modulators of T-cell activation and function. Remarkably, the predominant, although not exclusive, effect of Foxp3 occupancy is to suppress the activation of target genes on T-cell stimulation. Foxp3 suppression of its targets appears to be crucial for the normal function of T-reg cells, because overactive variants of some target genes are known to be associated with autoimmune disease.