Regulatory T cell lineage specification by the forkhead transcription factor FoxP3

Regulatory T cell-mediated dominant tolerance has been demonstrated to play an important role in the prevention of autoimmunity. Here, we present data arguing that the forkhead transcription factor Foxp3 acts as the regulatory T cell lineage specification factor and mediator of the genetic mechanism of dominant tolerance. We show that expression of Foxp3 is highly restricted to the subset up of T cells and, irrespective of CD25 expression, correlates with suppressor activity. Induction of Foxp3 expression in nonregulatory T cells does not occur during pathogen-driven immune responses, and Foxp3 deficiency does not impact the functional responses of nonregulatory T cells. Furthermore, T cell-specific ablation of Foxp3 is sufficient to induce the identical early onset lymphoproliferative syndrome observed in Foxp3-deficient mice. Analysis of Foxp3 expression during thymic development suggests that this mechanism is not hard-wired but is dependent on TCR/MHC ligand interactions.

调节性T细胞介导的显性耐受已被证明在预防自身免疫中起重要作用。在此，我们提供的数据表明，叉头转录因子Foxp3作为调节性T细胞谱系特异性因子以及显性耐受遗传机制的介质发挥作用。我们发现Foxp3的表达高度局限于T细胞亚群，且不论CD25表达情况如何，都与抑制活性相关。在病原体驱动的免疫应答过程中，非调节性T细胞中不会诱导Foxp3表达，并且Foxp3缺失不影响非调节性T细胞的功能应答。此外，T细胞特异性Foxp3缺失足以诱导在Foxp3缺陷小鼠中观察到的相同的早发性淋巴增殖综合征。对胸腺发育过程中Foxp3表达的分析表明，该机制不是固定不变的，而是依赖于TCR/MHC配体相互作用。