Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency
Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency
复制标题
DOI：
10.1016/j.jaci.2019.03.002
复制
发表时间：
2019-08-01
影响因子：
14.2
通讯作者：
Geha, Raif S.
中科院分区：
文献类型：
--
作者：
Alosaimi, Mohammed F.;Hoenig, Manfred;Geha, Raif S.
背景：肿瘤 TNF 受体家族成员 4-1BB (CD137) 由 TNFRSF9 编码并在活化的 T 细胞上表达。 4-1BB 提供共刺激信号，增强 CD8(+) T 细胞的存活、细胞毒性和线粒体活性，从而促进针对病毒和肿瘤的免疫力。 4-1BB 配体在抗原呈递细胞和 EBV 转化的 B 细胞上表达。目的：我们研究了 2 名无关患者反复鼻肺感染、持续 EBV 病毒血症和 EBV 诱导的淋巴细胞增殖的遗传基础。方法：进行全外显子组测序、免疫印迹、免疫表型分析以及淋巴细胞和线粒体功能的体外检测。结果：这 2 名患者共有一个4-1BB 中的纯合 G109S 错义突变导致蛋白质表达和配体结合失效。患者的CD8(+) T细胞增殖减少，IFN-γ和穿孔素表达受损，并且针对同种异体和HLA匹配的EBV-B细胞的细胞毒性减弱。患者激活的 T 细胞中的线粒体生物发生、膜电位和功能显着降低。针对 4-1BB 的抑制性抗体在体外再现了患者缺陷的 CD8(+) T 细胞激活和针对 EBV 感染的 B 细胞的细胞毒性。结论：这种新型免疫缺陷表明 4-1BB 共刺激在宿主针对 EBV 感染的免疫中发挥着关键作用。
Background: The tumor TNF receptor family member 4-1BB (CD137) is encoded by TNFRSF9 and expressed on activated Tcells. 4-1BB provides a costimulatory signal that enhances CD8(+) T-cell survival, cytotoxicity, and mitochondrial activity, thereby promoting immunity against viruses and tumors. The ligand for 4-1BB is expressed on antigen-presenting cells and EBV-transformed B cells.Objective: We investigated the genetic basis of recurrent sinopulmonary infections, persistent EBV viremia, and EBV-induced lymphoproliferation in 2 unrelated patients.Methods: Whole-exome sequencing, immunoblotting, immunophenotyping, and in vitro assays of lymphocyte and mitochondrial function were performed.Results: The 2 patients shared a homozygous G109S missense mutation in 4-1BB that abolished protein expression and ligand binding. The patients' CD8(+) T cells had reduced proliferation, impaired expression of IFN-gamma and perforin, and diminished cytotoxicity against allogeneic and HLA-matched EBV-B cells. Mitochondrial biogenesis, membrane potential, and function were significantly reduced in the patients' activated T cells. An inhibitory antibody against 4-1BB recapitulated the patients' defective CD8(+) T-cell activation and cytotoxicity against EBV-infected B cells in vitro.Conclusion: This novel immunodeficiency demonstrates the critical role of 4-1BB costimulation in host immunity against EBV infection.