Comparative Genomics Reveals Key Gain-of-Function Events in Foxp3 during Regulatory T Cell Evolution.
Comparative Genomics Reveals Key Gain-of-Function Events in Foxp3 during Regulatory T Cell Evolution.
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DOI：
10.3389/fimmu.2012.00113
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发表时间：
2012
影响因子：
7.3
通讯作者：
Betz AG
中科院分区：
文献类型：
--
作者：
Andersen KG;Nissen JK;Betz AG
免疫系统有能力抑制不良反应，如针对胎盘妊娠时的共生细菌、食物和父源抗原的反应。家族特异性转录因子Foxp3协调调节T细胞的发育和功能，这些T细胞是免疫耐受的基础。尽管Foxp3在支持免疫动态平衡方面起着至关重要的作用，但人们对其起源、进化和物种保护知之甚少。我们使用比较基因组学、结构建模和功能分析来探索这些问题。我们的数据显示，在高等脊椎动物中，关键的功能获得事件发生在Foxp3的进化过程中。我们确定了Foxp3叉头区的关键保守残基，并详细分析了Foxp3的N-末端区域，该区域仅在哺乳动物中保守。我们的突变分析表明，这些成分是Foxp3功能所必需的。我们的研究指出了高等脊椎动物免疫耐受中的关键功能适应，并表明在哺乳动物进化过程中，Foxp3介导的转录机制是作为功能结构域的逐步获得而出现的，使Foxp3能够与众多相互作用伙伴相互作用。
The immune system has the ability to suppress undesirable responses, such as those against commensal bacteria, food, and paternal antigens in placenta pregnancy. The lineage-specific transcription factor Foxp3 orchestrates the development and function of regulatory T cells underlying this immunological tolerance. Despite the crucial role of Foxp3 in supporting immune homeostasis, little is known about its origin, evolution, and species conservation. We explore these questions using comparative genomics, structural modeling, and functional analyses. Our data reveal that key gain-of-function events occurred during the evolution of Foxp3 in higher vertebrates. We identify key conserved residues in its forkhead domain and show a detailed analysis of the N-terminal region of Foxp3, which is only conserved in mammals. These components are under purifying selection, and our mutational analyses demonstrate that they are essential for Foxp3 function. Our study points to critical functional adaptations in immune tolerance among higher vertebrates, and suggests that Foxp3-mediated transcriptional mechanisms emerged during mammalian evolution as a stepwise gain of functional domains that enabled Foxp3 to interact with a multitude of interaction partners.