Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Nat Commun. 2017 Nov 17;8(1):1592. doi: 10.1038/s41467-017-01687-x.
Plasmacytoid dendritic cells (pDC) sense viral RNA through toll-like receptor 7 (TLR7), form self-adhesive pDC-pDC clusters, and produce type I interferons. This cell adhesion enhances type I interferon production, but little is known about the underlying mechanisms. Here we show that MyD88-dependent TLR7 signaling activates CD11a/CD18 integrin to induce microtubule elongation. TLR7 lysosomes then become linked with these microtubules through the GTPase Arl8b and its effector SKIP/Plekhm2, resulting in perinuclear to peripheral relocalization of TLR7. The type I interferon signaling molecules TRAF3, IKKα, and mTORC1 are constitutively associated in pDCs. TLR7 localizes to mTORC1 and induces association of TRAF3 with the upstream molecule TRAF6. Finally, type I interferons are secreted in the vicinity of cell-cell contacts between clustered pDCs. These results suggest that TLR7 needs to move to the cell periphery to induce robust type I interferon responses in pDCs.
浆细胞样树突状细胞 (pDC) 通过 Toll 样受体 7 (TLR7) 感知病毒 RNA，形成自黏附的 pDC-pDC 簇，并产生 I 型干扰素。这种细胞黏附增强了 I 型干扰素的产生，但对其潜在机制知之甚少。在这里，我们表明 MyD88 依赖性 TLR7 信号激活 CD11a/CD18 整合素以诱导微管伸长。然后，TLR7 溶酶体通过 GTPase Arl8b 和其效应蛋白 SKIP/Plekhm2 与这些微管相连，导致 TLR7 从核周向周边重新定位。I 型干扰素信号分子 TRAF3、IKKα 和 mTORC1 在 pDC 中持续相关。TLR7 定位于 mTORC1 并诱导 TRAF3 与上游分子 TRAF6 结合。最后，I 型干扰素在聚集的 pDC 之间的细胞-细胞接触附近分泌。这些结果表明，TLR7 需要移动到细胞外周才能在 pDC 中诱导强烈的 I 型干扰素反应。
