Pan Yi-Gen, Yu Yen-Ling, Lin Chi-Chien, Lanier Lewis L, Chu Ching-Liang
Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli County, Taiwan.
Front Immunol. 2017 Oct 27;8:1424. doi: 10.3389/fimmu.2017.01424. eCollection 2017.
The inhibitory effect of immunoreceptor tyrosine-based activation motif (ITAM)-containing adapters DAP12 and FcεRI γ-chain (FcRγ) has been found in many immune functions. Herein, we have further explored the role of these adapters in C-type lectin receptors response. We identified that FcRγ, but not DAP12, could negatively regulate the Dectin-1 responses in dendritic cells (DCs). Loss of FcRγ or both DAP12 and FcRγ enhanced the maturation and cytokine production in DCs upon Dectin-1 activation compared to normal cells, whereas DCs lacking only DAP12 showed little changes. In addition, increments of T cell activation and T helper 17 polarization induced by FcRγ-deficient DCs were observed both and . Examining the Dectin-1 signaling, we revealed that the activations of several signaling molecules were augmented in FcRγ-deficient DCs stimulated with Dectin-1 ligands. Furthermore, we demonstrated that the association of phosphatases SHP-1 and PTEN with FcRγ may contribute to the negative regulation of FcRγ in Dectin-1 activation in DCs. These results extend the inhibitory effect of ITAM-containing adapters to Dectin-1 response in immune functions, even though Dectin-1 contains an ITAM-like intracellular domain. According to the role of Dectin-1 in responding to microbes and tumor cells, our finding may have applications in the development of vaccine and cancer therapy.
含免疫受体酪氨酸激活基序（ITAM）的接头蛋白DAP12和FcεRIγ链（FcRγ）在许多免疫功能中发挥抑制作用。在此，我们进一步探究了这些接头蛋白在C型凝集素受体反应中的作用。我们发现FcRγ而非DAP12能够负向调节树突状细胞（DCs）中Dectin-1的反应。与正常细胞相比，FcRγ缺失或DAP12和FcRγ均缺失时，Dectin-1激活后DCs的成熟和细胞因子产生增强，而仅缺失DAP12的DCs变化不大。此外，在体内和体外均观察到FcRγ缺陷型DCs诱导的T细胞激活增加和辅助性T细胞17极化。检测Dectin-1信号传导，我们发现用Dectin-1配体刺激FcRγ缺陷型DCs时，几种信号分子的激活增强。此外，我们证明磷酸酶SHP-1和PTEN与FcRγ的结合可能有助于FcRγ对DCs中Dectin-1激活的负向调节。这些结果将含ITAM接头蛋白的抑制作用扩展到免疫功能中Dectin-1的反应，尽管Dectin-1含有一个类似ITAM的细胞内结构域。根据Dectin-1在应对微生物和肿瘤细胞中的作用，我们的发现可能在疫苗开发和癌症治疗中具有应用价值。
