TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis
TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis
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TIPE2，先天性和适应性免疫的负调节因子，可维持免疫稳态。
DOI：
10.1016/j.cell.2008.03.026
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发表时间：
2008-05-02
期刊：
影响因子：
64.5
通讯作者：
Chen, Youhai H.
中科院分区：
文献类型：
--
作者：
Sun, Honghong;Gong, Shunyou;Chen, Youhai H.
免疫动态平衡对免疫系统的正常运作至关重要，它的崩溃会导致致命的炎症性疾病。我们在此报告了肿瘤坏死因子-α诱导蛋白-8(TNFAIP8)家族的一个成员，命名为TIPE2，是维持免疫稳态所必需的。TIPE2在淋巴组织中优先表达，在小鼠中缺失会导致多器官炎症、脾肿大和过早死亡。TIPE2基因缺陷的动物对感染性休克敏感，而TIPE2基因缺陷的细胞对Toll样受体(TLR)和T细胞受体(TCR)激活具有高反应性。重要的是，TIPE2与caspase-8结合，抑制活化蛋白-1和核因子-kappaB的激活，同时促进Fas诱导的细胞凋亡。抑制caspase-8可显著阻断TIPE2缺陷细胞的高反应性。这些结果表明，TIPE2是TLR和TCR功能的重要负调控因子，它在免疫系统中的选择性表达可以防止高反应性，维持免疫平衡。
Immune homeostasis is essential for the normal functioning of the immune system, and its breakdown leads to fatal inflammatory diseases. We report here the identification of a member of the tumor necrosis factor-alpha-induced protein-8 (TNFAIP8) family, designated TIPE2, that is required for maintaining immune homeostasis. TIPE2 is preferentially expressed in lymphoid tissues, and its deletion in mice leads to multiorgan inflammation, splenomegaly, and premature death. TIPE2-deficient animals are hypersensitive to septic shock, and TIPE2-deficient cells are hyper-responsive to Toll-like receptor (TLR) and T cell receptor (TCR) activation. Importantly, TIPE2 binds to caspase-8 and inhibits activating protein-1 and nuclear factor-kappa B activation while promoting Fas-induced apoptosis. Inhibiting caspase-8 significantly blocks the hyper-responsiveness of TIPE2-deficient cells. These results establish that TIPE2 is an essential negative regulator of TLR and TCR function, and its selective expression in the immune system prevents hyperresponsiveness and maintains immune homeostasis.