FOXP3 controls regulatory T cell function through cooperation with NFAT
FOXP3 controls regulatory T cell function through cooperation with NFAT
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DOI：
10.1016/j.cell.2006.05.042
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发表时间：
2006-07-28
期刊：
影响因子：
64.5
通讯作者：
Rao, Anjana
中科院分区：
文献类型：
--
作者：
Wu, Yongqing;Borde, Madhuri;Rao, Anjana
免疫细胞的抗原刺激激活了转录因子NFAT，这是T细胞激活和无能的关键调节因素。NFAT与AP-1转录因子家族形成协同复合体，调节T细胞激活相关基因。在这里，我们证明了调节性T细胞(Treg)的功能是由NFAT和叉头转录因子FOXP3的类似合作复合体介导的，FOXP3是Tregs的谱系指定因子。NFAT：FOXP2：DNA复合体的晶体结构揭示了NFAT和FOXP2之间广泛的蛋白质-蛋白质相互作用界面。FOXP3的结构导向突变预计会逐渐破坏其与NFAT的相互作用，以一种分级的方式干扰FOXP3抑制细胞因子IL2的表达，上调Treg标记CTLA4和CD25的表达，并在自身免疫性糖尿病小鼠模型中赋予抑制功能。因此，通过转换转录伙伴，NFAT将急性T细胞激活程序转换为Tregs的抑制程序。
Antigen stimulation of immune cells activates the transcription factor NFAT, a key regulator of T cell activation and anergy. NFAT forms cooperative complexes with the AP-1 family of transcription factors and regulates T cell activation-associated genes. Here we show that regulatory T cell (Treg) function is mediated by an analogous cooperative complex of NFAT with the forkhead transcription factor FOXP3, a lineage specification factor for Tregs. The crystal structure of an NFAT:FOXP2:DNA complex reveals an extensive protein-protein interaction interface between NFAT and FOXP2. Structure-guided mutations of FOXP3, predicted to progressively disrupt its interaction with NFAT, interfere in a graded manner with the ability of FOXP3 to repress expression of the cytokine IL2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function in a murine model of autoimmune diabetes. Thus by switching transcriptional partners, NFAT converts the acute T cell activation program into the suppressor program of Tregs.