Cambridge Institute of Therapeutic Immunology and Infectious Disease, and the Department of Medicine, University of Cambridge, Cambridge, UK.
Molecular Development of the Immune System Section, Laboratory of Immune System Biology and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
J Exp Med. 2019 Jun 3;216(6):1311-1327. doi: 10.1084/jem.20182304. Epub 2019 Apr 30.
Interleukin-2, which conveys essential signals for immunity, operates through a heterotrimeric receptor. Here we identify human interleukin-2 receptor (IL-2R) β chain () gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rβ and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2Rβ expression and function. IL-2Rβ loss of function was recapitulated in a recombinant system in which mutations caused reduced surface expression and IL-2 binding. Stem cell transplant ameliorated clinical symptoms in one patient; forced expression of wild-type IL-2Rβ also increased the IL-2 responsiveness of patient T lymphocytes in vitro. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.
白细胞介素-2 通过异源三聚体受体传递免疫必需信号。在这里，我们确定人类白细胞介素-2 受体（IL-2R）β链（）基因缺陷是导致危及生命的免疫失调的原因。我们报道了来自四个近亲家庭的八个人的 基因中的三个纯合突变，这些突变通过不同的机制引起疾病。几乎所有患者均出现自身抗体、高丙种球蛋白血症、肠道炎症、皮肤异常、淋巴结病和巨细胞病毒病。患者的 T 淋巴细胞缺乏表面 IL-2Rβ 的表达，并且无法对 IL-2 刺激作出反应。相比之下，自然杀伤细胞保留了部分 IL-2Rβ 的表达和功能。在重组系统中， 突变导致表面表达和 IL-2 结合减少，从而再现了 IL-2Rβ 功能丧失。干细胞移植改善了一名患者的临床症状；野生型 IL-2Rβ 的强制表达也增加了患者 T 淋巴细胞在体外对 IL-2 的反应性。这些患者的见解可以为基于白细胞介素-2 的免疫疾病和癌症治疗方法的开发提供信息。
