Critical Role of AZI2 in GM-CSF-Induced Dendritic Cell Differentiation
Critical Role of AZI2 in GM-CSF-Induced Dendritic Cell Differentiation
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DOI：
10.4049/jimmunol.1203155
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发表时间：
2013-06-01
影响因子：
4.4
通讯作者：
Takeuchi, Osamu
中科院分区：
文献类型：
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作者：
Fukasaka, Masahiro;Ori, Daisuke;Takeuchi, Osamu
TNFR 相关因子家族成员相关的 NF-κ B 激活剂 (TANK) 结合激酶 1 (TBK1) 对于病毒感染时激活 IFN 调节因子 3 和 I 型 IFN 产生至关重要。一组 TBK1 结合蛋白、5-氮杂胞苷诱导基因 2 (AZI2；也称为 NAP1)、TANK 和 TBK1 结合蛋白 1 (TBKBP1) 也与 I 型 IFN 的产生有关。其中，TANK被发现对于应对病毒感染来说是可有可无的。然而，AZI2和TBKBP1的生理作用尚未阐明。在这项研究中，我们发现这些 TBK1 结合蛋白对于小鼠 I 型 IFN 的产生都不是关键的。相比之下，AZI2（而不是 TBKBP1）对于响应 GM-CSF 从骨髓细胞中分化出传统树突状细胞 (cDC) 至关重要。 AZI2 通过 TBK1 控制 GM-CSF 诱导的骨髓细胞细胞周期。来自 AM 缺陷小鼠的 GM-CSF 来源的 DC 在体外和体内均显示出细胞因子产生和 T 细胞激活的严重缺陷。相反，AZI2 的过度表达导致 cDC 的有效生成，并且细胞响应 Ag 刺激而表现出增强的 T 细胞活化。综上所述，AZI2 表达对于 GM-CSF 生成 cDC 至关重要，并且有可能用于提高 cDC 的免疫效率。
TNFR-associated factor family member associated NF-kappa B activator (TANK) binding kinase 1 (TBK1) is critical for the activation of IFN regulatory factor 3 and type I IFN production upon virus infection. A set of TBK1-binding proteins, 5-azacytidine-induced gene 2 (AZI2; also known as NAP1), TANK, and TBK1-binding protein 1 (TBKBP1), have also been implicated in the production of type I IFNs. Among them, TANK was found to be dispensable for the responses against virus infection. However, physiological roles of AZI2 and TBKBP1 have yet to be clarified. In this study, we found that none of these TBK1-binding proteins is critical for type I IFN production in mice. In contrast, AZI2, but not TBKBP1, is critical for the differentiation of conventional dendritic cells (cDCs) from bone marrow cells in response to GM-CSF. AZI2 controls GM-CSF induced cell cycling of bone marrow cells via TBK1. GM-CSF derived DCs from AM-deficient mice show severe defects in cytokine production and T cell activation both in vitro and in vivo. Reciprocally, overexpression of AZI2 results in efficient generation of cDCs, and the cells show enhanced T cell activation in response to Ag stimulation. Taken together, AZI2 expression is critical for the generation of cDCs by GM-CSF and can potentially be used to increase the efficiency of immunization by cDCs.