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糖皮质激素诱导的肿瘤坏死因子受体相关蛋白及其配体在肝脏疾病中的作用
DOI: 10.3969/j.issn.1001-5256.2021.07.051
利益冲突声明：所有作者均声明不存在利益冲突。
作者贡献声明：何宇负责收集文献, 分析文献, 撰写论文; 王萍、贾继东负责拟定写作思路, 指导撰写文章并最后定稿。
Research advances in the role of the glucocorticoid-induced tumor necrosis factor receptor-related protein and its ligand in liver diseases
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摘要: 糖皮质激素诱导的肿瘤坏死因子受体(GITR)属于肿瘤坏死因子受体家族, 与其特异性配体GITRL结合后, 所介导的下游信号既可以作为协同刺激分子, 促进效应T淋巴细胞增殖与细胞因子分泌; 还可以影响调节性T淋巴细胞增殖和抑制效应T淋巴细胞的功能, 从而调控效应T淋巴细胞的炎症反应与杀伤肿瘤细胞的作用。GITRL主要表达于抗原递呈细胞且有胞内结构域, 与GITR结合后, 可以通过受体/配体逆向信号从而影响抗原递呈细胞的功能。在肝脏疾病中, GITRL/GITR信号不仅与肝移植术后和基因治疗中免疫排异反应有关, 也与肿瘤免疫微环境形成、肿瘤的免疫逃逸有关。GITRL/GITR在其他肝脏疾病发生和进展中的作用仍有待进一步研究。
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关键词:
- 肝疾病 /
- 糖皮质激素类诱导TNFR相关蛋白质 /
- 糖皮质激素类诱导TNFR相关配体 /
- 免疫调节 /
- T淋巴细胞, 调节性
Abstract: Glucocorticoid-induced tumor necrosis factor receptor (GITR) is a member of the tumor necrosis factor receptor superfamily, and after it specifically binds to GITR ligand (GITRL), the downstream signals mediated by them can not only serve as a costimulatory molecule to promote the proliferation and cytokine secretion of effector T cells, but also affect the proliferation of regulatory T cells and inhibit the function of effector T cells, thereby regulating the inflammatory response and tumor cell-killing effect of effector T cells. GITRL is mainly expressed in antigen- presenting cells and has an intracellular domain, and the binding of GITRL to GITR can affect the function of antigen-presenting cells via receptor/ligand reverse signaling. In liver diseases, GITRL/GITR signal is not only involved in immune rejection after liver transplantation and gene therapy, but also associated with the formation of tumor immune microenvironment and the immune escape of tumor. Further studies are needed to explore the role of GITRL/GITR in the development and progression of other liver diseases. -
表 1 GITRL/GITR配体-受体信号在不同的免疫细胞亚群中的表达和功能
细胞类型 表达水平 功能 CD4+ T淋巴细胞 静息状态GITR表达水平很低, 活化后高表达GITR GITRL与CD3协同刺激T淋巴细胞的活化与增殖, 发挥促炎作用 CD8+ T淋巴细胞 静息状态GITR表达水平很低, 活化后高表达GITR GITRL与CD28协同刺激T淋巴细胞的活化与增殖, 发挥促炎作用 Treg 高表达GITR GITRL抑制Treg增殖, 降低Treg抑制效应T淋巴细胞的功能, 可以诱发自身免疫性疾病, 也能够发挥抑制肿瘤生长的抗肿瘤作用 Th17 表达GITR 促进Th17增殖, 发挥促炎作用 滤泡Th(Tfh) 表达GITR 活化GITR信号可增加Tfh数量和比例, 增强Tfh应答反应与辅助抗体合成功能, 增强肿瘤特异性细胞毒性T淋巴细胞的杀伤肿瘤细胞的功能 Th9 表达GITR 活化GITR信号增强肿瘤特异性细胞毒性T淋巴细胞的应答反应 NK细胞 静息状态中等程度表达GITR, 活化后高表达GITR GITRL与IL-2、IFNα和NKG2D协同活化NK细胞
GITRL通过GITR抑制NK细胞活化与促炎因子分泌DC 静息状态不表达GITR, 活化后中/低表达GITR GITRL促进T淋巴细胞增殖, 抑制Treg形成, 发挥促炎作用 巨噬细胞 静息状态GITR表达水平很低, 活化后中/低表达GITR GITRL刺激巨噬细胞表达一氧化氮合成酶并增加一氧化氮合成, 发挥促炎作用 
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表 2 GITR/GITRL受体-配体逆向信号在抗原递呈细胞中的表达和功能
细胞类型 表达水平 功能 内皮细胞 静息状态高表达GITRL, 活化后GITRL表达进一步升高 GITR增加内皮细胞ICAM-1和VCAM-1的表达, 促进炎症细胞的黏附和迁移 DC 静息状态中/低表达GITRL, 活化后高表达GITRL GITR抑制DC促炎因子IL-12表达, 促进具有抑炎作用的吲哚胺2, 3-二氧化酶表达, 发挥免疫抑制作用 巨噬细胞 静息状态中/低表达GITRL, 活化后高表达GITRL GITR促进巨噬细胞促炎因子、基质金属蛋白酶9和ICAM的表达, 促进巨噬细胞的聚集和与细胞外基质的黏附 注：ICAM-1, 细胞间黏附分子; VCAM-1, 血管细胞黏附分子。
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