IFN-Stimulated Gene 15 Is an Alarmin that Boosts the CTL Response via an Innate, NK Cell-Dependent Route
IFN-Stimulated Gene 15 Is an Alarmin that Boosts the CTL Response via an Innate, NK Cell-Dependent Route
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DOI：
10.4049/jimmunol.1901410
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发表时间：
2020-04-15
影响因子：
4.4
通讯作者：
Borst, Jannie
中科院分区：
文献类型：
--
作者：
Iglesias-Guimarais, Victoria;Ahrends, Tomasz;Borst, Jannie
I型IFN在感染和组织损伤时产生，并诱导编码宿主保护性蛋白的许多IFN刺激基因（ISG）的表达。ISG15是一种泛素样分子，可以与蛋白质结合，但也可以以游离形式从细胞中释放。基于ISG15缺陷的人和小鼠的疾病表型，游离的细胞外ISG15被认为具有免疫调节作用。然而，游离ISG15将作为"细胞因子"的潜在机制尚不清楚，并且存在很多争议。在这项研究中，我们在治疗性疫苗接种的临床相关小鼠模型中证明，游离ISG15是一种引起组织警报的警报蛋白，其特征在于细胞外基质重塑、骨髓细胞浸润和炎症。此外，游离ISG15是CTL应答的有效佐剂。在疫苗接种部位产生的ISG15通过增强CD8（+）T细胞的扩增、短期效应子和效应子/记忆分化来促进疫苗特异性CTL应答。证明了游离ISG15作为细胞外配体的功能，因为最近涉及人ISG15与LFA-1体外结合的鼠ISG15中的2个aa的等同物是其体内佐剂作用所需的。此外，与人细胞的体外研究结果进一步一致，游离ISG15在没有CD4（+）T细胞帮助的情况下通过NK细胞增强体内CTL应答。因此，游离ISG15是新认识到的促进CTL应答的先天途径的一部分。
Type I IFN is produced upon infection and tissue damage and induces the expression of many IFN-stimulated genes (ISGs) that encode host-protective proteins. ISG15 is a ubiquitin-like molecule that can be conjugated to proteins but is also released from cells in a free form. Free, extracellular ISG15 is suggested to have an immune-regulatory role, based on disease phenotypes of ISG15-deficient humans and mice. However, the underlying mechanisms by which free ISG15 would act as a "cytokine" are unclear and much debated. We, in this study, demonstrate in a clinically relevant mouse model of therapeutic vaccination that free ISG15 is an alarmin that induces tissue alert, characterized by extracellular matrix remodeling, myeloid cell infiltration, and inflammation. Moreover, free ISG15 is a potent adjuvant for the CTL response. ISG15 produced at the vaccination site promoted the vaccine-specific CTL response by enhancing expansion, short-lived effector and effector/memory differentiation of CD8(+) T cells. The function of free ISG15 as an extracellular ligand was demonstrated, because the equivalents in murine ISG15 of 2 aa recently implicated in binding of human ISG15 to LFA-1 in vitro were required for its adjuvant effect in vivo. Moreover, in further agreement with the in vitro findings on human cells, free ISG15 boosted the CTL response in vivo via NK cells in the absence of CD4(+) T cell help. Thus, free ISG15 is part of a newly recognized innate route to promote the CTL response.