Regulation of NF-κB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a
Regulation of NF-κB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a
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DOI：
10.1016/j.immuni.2004.06.016
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发表时间：
2004-08-01
期刊：
影响因子：
32.4
通讯作者：
Peng, SL
中科院分区：
文献类型：
--
作者：
Lin, L;Hron, JD;Peng, SL
Forkhead (Fox) 转录因子在免疫调节中发挥关键作用。 Foxo 亚家族的成员与细胞周期和/或细胞凋亡的调节有关，但其特定的免疫学背景在很大程度上仍不清楚。我们在此证明 Foxo3a（在外周淋巴器官中表达的主要 Foxo 成员）在淋巴稳态中发挥着关键作用。 Foxo3a 缺陷会导致自发性淋巴细胞增殖，与多个器官的炎症相关，但没有明显的细胞凋亡缺陷。这些发现与过度活跃的辅助性 T 细胞的存在相关，与野生型对应物相比，辅助性 T 细胞增殖更加活跃，产生更多的 Th1 和 Th2 细胞因子。 Foxo3a 抑制 NF-kappaB 激活，其过度激活导致 Foxo3a 缺陷小鼠的 T 细胞过度活跃。因此，Foxo3a 通过抑制 NF-kappaB 活性来调节辅助 T 细胞的激活和耐受性，从而通过抑制炎症转录活性来加强叉头蛋白在维持 T 细胞耐受性中的普遍作用。
Forkhead (Fox) transcription factors play key roles in immunoregulation. Members of the Foxo subfamily have been implicated in the regulation of the cell cycle and/or apoptosis, but their specific immunological contexts remain largely undefined. We demonstrate here that Foxo3a, the predominant Foxo member expressed in peripheral lymphoid organs, plays a critical role in lymphoid homeostasis. Foxo3a deficiency leads to spontaneous lymphoproliferation, associated with inflammation of several organs, in the absence of overt apoptotic defects. These findings correlated with the presence of hyperactivated helper T cells, which proliferated more vigorously and produced more Th1 and Th2 cytokines than their wild-type counterparts. Foxo3a inhibits NF-kappaB activation, whose overactivity was responsible for T cell hyperactivity in Foxo3a-deficient mice. Thus, Foxo3a regulates helper T cell activation and tolerance by inhibiting NF-kappaB activity, reinforcing a generalized role for the forkhead proteins in the maintenance of T cell tolerance through the inhibition of inflammatory transcriptional activities.