Brandstadter Joshua D, Chen Huiyao, Jiang Songfu, Huang Xiaopei, Yang Yiping
Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Department of Hematology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; and.
J Leukoc Biol. 2017 Jun;101(6):1317-1323. doi: 10.1189/jlb.2A0816-342R. Epub 2017 Mar 10.
NK cells are critical for the control of viral infections. Studies have shown that efficient NK cell activation in response to infection with VV in vivo requires multiple pathways, including the NKG2D pathway. We have recently shown that IL-18 is necessary for the activation of NK cells through upregulation of the NKG2D ligand Rae-1 on DCs upon VV infection. However, how IL-18R signaling on the accessory cells contributes to Rae-1 up-regulation remains to be defined. In this study, we found IL-18-mediated Rae-1 up-regulation in accessory cells, including macrophages and DCs, to be dependent on the MyD88-PI3K pathway. We further found that IL-18 signaling through PI3K led to inhibition of GSK-3, which we found to be a negative regulator of Rae-1. Finally, we demonstrated that in vivo inhibition of GSK-3 could restore Rae-1 up-regulation on IL18R DCs and partially rescue NK-cell activation against VV, leading to improved viral control in IL-18R mice. Our results showed that IL18-dependent Rae-1 up-regulation on accessory cells is mediated by the MyD88-PI3K-GSK3 pathway. These observations may provide important insights into the design of effective NK cell-based immunotherapies.
自然杀伤细胞对于控制病毒感染至关重要。研究表明，在体内对痘苗病毒感染作出反应时，自然杀伤细胞的有效激活需要多种途径，包括NKG2D途径。我们最近发现，白细胞介素-18对于在痘苗病毒感染时通过上调树突状细胞上的NKG2D配体Rae-1来激活自然杀伤细胞是必需的。然而，辅助细胞上的白细胞介素-18受体信号传导如何促进Rae-1上调仍有待确定。在本研究中，我们发现白细胞介素-18介导的包括巨噬细胞和树突状细胞在内的辅助细胞中Rae-1的上调依赖于MyD88-PI3K途径。我们进一步发现，通过PI3K的白细胞介素-18信号传导导致糖原合酶激酶-3的抑制，我们发现糖原合酶激酶-3是Rae-1的负调节因子。最后，我们证明在体内抑制糖原合酶激酶-3可以恢复白细胞介素-18受体树突状细胞上Rae-1的上调，并部分挽救自然杀伤细胞对痘苗病毒的激活，从而改善白细胞介素-18受体小鼠中的病毒控制。我们的结果表明，辅助细胞上白细胞介素-18依赖的Rae-1上调是由MyD88-PI3K-糖原合酶激酶-3途径介导的。这些观察结果可能为基于自然杀伤细胞的有效免疫疗法的设计提供重要见解。
