Cytotoxic T lymphocyte antigen-4 (CTLA-4), an inhibitory receptor expressed on T-cells, plays an essential role in regulating immune responses. In healthy individuals, CTLA-4 prevents overstimulation of T-cells and facilitates regulatory T-cell (Treg) suppressive function through competitive binding of CD80/CD86 on antigen-presenting cells.¹ Heterozygous loss-of-function variants in CTLA4 cause the inborn error of immunity (IEI) termed CTLA-4 insufficiency, which has a variable clinical presentation often including combined immunodeficiency, autoimmunity, and lymphoproliferation.^1-3

Since CTLA-4 insufficiency was first described in 2014, over 54 pathogenic variants have been identified.^{1, 3} Herein, we report two novel CTLA4 variants and describe the clinical presentations in two affected families, the differing functional impacts on CTLA-4-mediated transendocytosis, and the influence of prompt access to genetic testing and targeted therapy on clinical outcomes.

细胞毒性 T 淋巴细胞抗原 4 (CTLA-4) 是 T 细胞上表达的一种抑制性受体，在调节免疫反应中发挥着重要作用。在健康个体中，CTLA-4 可防止 T 细胞过度刺激，并通过 CD80/CD86 与抗原呈递细胞竞争性结合，促进调节性 T 细胞 (Treg) 抑制功能。¹ CTLA4杂合功能丧失变异会导致先天性免疫错误 (IEI)，称为 CTLA-4 不足，其临床表现多种多样，通常包括联合免疫缺陷、自身免疫和淋巴细胞增殖。^1-3

自 2014 年首次描述 CTLA-4 缺陷以来，已鉴定出超过 54 种致病变异。^{1, 3}在此，我们报告了两种新的CTLA4变异，并描述了两个受影响家庭的临床表现、对 CTLA-4 介导的转内吞作用的不同功能影响，以及及时进行基因检测和靶向治疗对临床结果的影响。