跨高尔基网络的 TRAF3IP3 通过 MEK/ERK 信号通路调节 NKT2 的成熟。,Cellular & Molecular Immunology

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跨高尔基网络的 TRAF3IP3 通过 MEK/ERK 信号通路调节 NKT2 的成熟。
Cellular & Molecular Immunology ( IF 21.8 ) Pub Date : 2019-05-10 , DOI: 10.1038/s41423-019-0234-0
Xinwei Zhang ₁ , Ke Wang ₁ , Weijia Zhao ₁ , Li Cao ₁ , Shusong Zhang ₁ , Rong Jin ₁ , Xiuyuan Sun ₁ , Jie Hao ₁ , Xiaojun Huang ₂ , Mingzhao Zhu ₃ , Hounan Wu ₄ , Hongshan Zhao ₁ , Qing Ge _{1,

5}

Affiliation

胸腺自然杀伤 T (NKT)2 细胞是具有 PLZFhiGATA3hiIL-4+ 的不变 NKT 细胞的一个子集。NKT2 细胞的分化尚不完全清楚。在本研究中，我们报告了 TRAF3 相互作用蛋白 3 (TRAF3IP3) 在胸腺髓质中定向 NKT2 的功能成熟和扩增中的重要作用。TRAF3IP3 T 细胞特异性缺失的小鼠胸腺 NKT2 细胞减少，产生 IL-4 的外周 iNKT 减少，以及对 α-半乳糖神经酰胺的反应缺陷。CD24+CD44-和CCR7+CD44-未成熟iNKT中的阳性选择和高PLZF表达不受影响。Traf3ip3-/- 小鼠中只有 CD44hiNK1.1-iNKT 显示 Egr2、PLZF 和 IL-17RB 的表达减少，增殖减少，刺激后 IL-4 产生减少。这种 Egr2 和 IL-4 表达因 iNKT 中的 MEK1/ERK 激活而增强，跨高尔基网络中的 TRAF3IP3 募集 MEK1 并促进 ERK 磷酸化和核转位。MEK/ERK 激活和 NKT2 成熟需要 LTβR 调节的髓质胸腺微环境中的骨髓衍生非淋巴细胞。这些数据证明了 NKT2 分化中一个重要的功能成熟过程，该过程由跨高尔基网络中的 MEK/ERK 信号传导调节。

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TRAF3IP3 at the trans-Golgi network regulates NKT2 maturation via the MEK/ERK signaling pathway.

Thymic natural killer T (NKT)2 cells are a subset of invariant NKT cells with PLZFhiGATA3hiIL-4+. The differentiation of NKT2 cells is not fully understood. In the present study, we report an important role of TRAF3-interacting protein 3 (TRAF3IP3) in the functional maturation and expansion of committed NKT2s in thymic medulla. Mice with T-cell-specific deletion of TRAF3IP3 had decreased thymic NKT2 cells, decreased IL-4-producing peripheral iNKTs, and defects in response to α-galactosylceramide. Positive selection and high PLZF expression in CD24+CD44- and CCR7+CD44- immature iNKTs were not affected. Only CD44hiNK1.1- iNKTs in Traf3ip3-/- mice showed reduced expression of Egr2, PLZF, and IL-17RB, decreased proliferation, and reduced IL-4 production upon stimulation. This Egr2 and IL-4 expression was augmented by MEK1/ERK activation in iNKTs, and TRAF3IP3 at the trans-Golgi network recruited MEK1 and facilitated ERK phosphorylation and nuclear translocation. LTβR-regulated bone marrow-derived nonlymphoid cells in the medullary thymic microenvironment were required for MEK/ERK activation and NKT2 maturation. These data demonstrate an important functional maturation process in NKT2 differentiation that is regulated by MEK/ERK signaling at the trans-Golgi network.

更新日期：2019-05-16

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