Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.
J Immunol. 2014 Jan 15;192(2):714-21. doi: 10.4049/jimmunol.1302384. Epub 2013 Dec 11.
The endosomal innate receptor CD158d (killer cell Ig-like receptor 2DL4) induces cellular senescence in human NK cells in response to soluble ligand (HLA-G or agonist Ab). These senescent NK cells display a senescence-associated secretory phenotype, and their secretome promotes vascular remodeling and angiogenesis. To understand how CD158d initiates signaling for a senescence response, we mapped the region in its cytoplasmic tail that controls signaling. We identified a conserved TNFR-associated factor 6 (TRAF6) binding motif, which was required for CD158d-induced NF-κB activation and IL-8 secretion, TRAF6 association with CD158d, and TRAF6 recruitment to CD158d(+) endosomes in transfected cells. The adaptor TRAF6 is known to couple proximal signals from receptors such as endosomal TLRs and CD40 through the kinase TGF-β-activated kinase 1 (TAK1) for NF-κB-dependent proinflammatory responses. Small interfering RNA-mediated silencing of TRAF6 and TAK1, and inhibition of TAK1 blocked CD158d-dependent IL-8 secretion. Stimulation of primary, resting NK cells with soluble Ab to CD158d induced TRAF6 association with CD158d, induced TAK1 phosphorylation, and inhibition of TAK1 blocked the CD158d-dependent reprogramming of NK cells that produces the senescence-associated secretory phenotype signature. Our results reveal that a prototypic TLR and TNFR signaling pathway is used by a killer cell Ig-like receptor that promotes secretion of proinflammatory and proangiogenic mediators as part of a unique senescence phenotype in NK cells.
内体先天受体 CD158d（杀伤细胞免疫球蛋白样受体 2DL4）在人 NK 细胞中响应可溶性配体（HLA-G 或激动剂 Ab）诱导细胞衰老。这些衰老的 NK 细胞表现出衰老相关的分泌表型，其分泌组促进血管重塑和血管生成。为了了解 CD158d 如何引发衰老反应的信号，我们绘制了其细胞质尾部控制信号的区域。我们确定了一个保守的 TNFR 相关因子 6（TRAF6）结合基序，该基序对于 CD158d 诱导的 NF-κB 激活和 IL-8 分泌、TRAF6 与 CD158d 的关联以及 TRAF6 向转染细胞中 CD158d(+)内体的募集是必需的。适配器 TRAF6 已知通过 TGF-β激活激酶 1（TAK1）将内体 TLR 和 CD40 等受体的近端信号耦合在一起，用于 NF-κB 依赖性促炎反应。TRAF6 和 TAK1 的小干扰 RNA 介导的沉默以及 TAK1 的抑制阻断了 CD158d 依赖性 IL-8 分泌。用可溶性 Ab 刺激原发性静止 NK 细胞可诱导 TRAF6 与 CD158d 的关联，诱导 TAK1 磷酸化，并且 TAK1 的抑制阻断了 CD158d 依赖性 NK 细胞的重编程，从而产生衰老相关的分泌表型特征。我们的结果表明，一种促炎和促血管生成介质的分泌作为 NK 细胞中独特的衰老表型的一部分，是由一种杀伤细胞免疫球蛋白样受体利用典型的 TLR 和 TNFR 信号通路来实现的。
