Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Immunol Rev. 2019 Jan;287(1):33-49. doi: 10.1111/imr.12721.
Cytotoxic-T-lymphocyte-antigen-4 (CTLA-4) is a negative immune regulator constitutively expressed on regulatory T (Treg) cells and upregulated on activated T cells. CTLA-4 inhibits T cell activation by various suppressive functions including competition with CD28, regulation of the inhibitory function of Treg cells, such as transendocytosis, and the control of adhesion and motility. Intrinsic CTLA-4 signaling has been controversially discussed, but so far no distinct signaling pathway has been identified. The CTLA-4-mediated Treg suppression plays an important role in the maintenance of peripheral tolerance and the prevention of autoimmune diseases. Human CTLA-4 insufficiency is caused by heterozygous germline mutations in CTLA4 and characterized by a complex immune dysregulation syndrome. Clinical studies on CTLA4 mutation carriers showed a reduced penetrance and variable expressivity, suggesting modifying factor(s). One hundred and forty-eight CTLA4 mutation carriers have been reported; patients showed hypogammaglobulinemia, recurrent infectious diseases, various autoimmune diseases, and lymphocytic infiltration into multiple organs. The CTLA-4 expression level in Treg cells was reduced, while the frequency of Treg cells was increased in CTLA-4-insufficient patients. The transendocytosis assay is a specific functional test for the assessment of newly identified CTLA4 gene variants. Immunoglobulin substitution, corticosteroids, immunosuppressive therapy, and targeted therapy such as with CTLA-4 fusion proteins and mechanistic target of rapamycin (mTOR) inhibitors were applied; patients with life-threatening, treatment-resistant symptoms underwent hematopoietic stem cell transplantation. The fact that in humans CTLA-4 insufficiency causes severe disease taught us that the amount of CTLA-4 molecules present in/on T cells matters for immune homeostasis. However, whether the pathology-causing activated T lymphocytes in CTLA-4-insufficient patients are antigen-specific is an unsolved question. CTLA-4, in addition, has a role in autoimmune diseases and cancer. Anti-CTLA-4 drugs are employed as checkpoint inhibitors to target various forms of cancer. Thus, clinical research on human CTLA-4 insufficiency might provide us a deeper understanding of the mechanism(s) of the CTLA-4 molecule and immune dysregulation disorders.
细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4）是一种负性免疫调节剂，在调节性 T（Treg）细胞上持续表达，并在活化的 T 细胞上上调。CTLA-4 通过多种抑制功能抑制 T 细胞激活，包括与 CD28 的竞争、调节 Treg 细胞的抑制功能，如转胞吞作用，以及控制黏附和迁移。CTLA-4 的内在信号转导一直存在争议，但迄今为止尚未确定明确的信号通路。CTLA-4 介导的 Treg 抑制在维持外周耐受和预防自身免疫性疾病方面发挥着重要作用。人类 CTLA-4 功能不全是由 CTLA4 种系突变引起的，其特征是复杂的免疫失调综合征。对 CTLA4 突变携带者的临床研究表明，外显率降低且表现度可变，提示存在修饰因子。目前已报道 148 例 CTLA4 突变携带者；患者表现为低丙种球蛋白血症、复发性传染病、各种自身免疫性疾病以及淋巴细胞浸润多个器官。CTLA-4 功能不全患者的 Treg 细胞 CTLA-4 表达水平降低，而 Treg 细胞频率增加。转胞吞作用测定是评估新发现的 CTLA4 基因突变的特异性功能试验。应用免疫球蛋白替代、皮质类固醇、免疫抑制治疗以及 CTLA-4 融合蛋白和雷帕霉素（mTOR）抑制剂等靶向治疗；对于有生命威胁、治疗抵抗症状的患者进行造血干细胞移植。人类 CTLA-4 功能不全导致严重疾病的事实告诉我们，T 细胞中/上存在的 CTLA-4 分子数量对于免疫稳态很重要。然而，CTLA-4 功能不全患者中导致疾病的活化 T 淋巴细胞是否是抗原特异性的，这仍是一个悬而未决的问题。此外，CTLA-4 在自身免疫性疾病和癌症中也有作用。抗 CTLA-4 药物被用作检查点抑制剂，以靶向各种形式的癌症。因此，对人类 CTLA-4 功能不全的临床研究可能会使我们更深入地了解 CTLA-4 分子和免疫失调紊乱的机制。
