The CTLA-4 checkpoint regulates the activation of T cells. Individuals with heterozygous mutations in CTLA-4 have a complex phenotype typically characterized by antibody deficiency alongside variable autoimmunity. Despite severe disease in some individuals, others remain largely unaffected with reasons for this variation unknown. We studied a large family carrying a single point mutation in CTLA-4 leading to an amino acid change R75W and compared both unaffected with affected individuals. We measured a variety of features pertaining to T cell and CTLA-4 biology and observed that at the cellular level there was complete penetrance of CTLA-4 mutations. Accordingly, unaffected individuals were indistinguishable from those with disease in terms of level of CTLA-4 expression, percentage of Treg, upregulation of CTLA-4 upon stimulation and proliferation of CD4 T cells. We conclude that the wide variation in disease phenotype is influenced by immune variation outside of CTLA-4 biology.

CTLA-4 检查点调节 T 细胞的激活。CTLA-4 杂合突变的个体具有复杂的表型，通常以抗体缺乏和可变的自身免疫为特征。尽管一些人患有严重疾病，但其他人基本上没有受到影响，这种变异的原因尚不清楚。我们研究了一个在 CTLA-4 中携带单点突变导致氨基酸变化 R75W 的大家族，并将未受影响的个体与受影响的个体进行比较。我们测量了与 T 细胞和 CTLA-4 生物学有关的各种特征，并观察到在细胞水平上 CTLA-4 突变完全外显。因此，就 CTLA-4 表达水平、Treg 百分比、CD4 T 细胞刺激和增殖后 CTLA-4 的上调。我们得出结论，疾病表型的广泛变异受到 CTLA-4 生物学之外的免疫变异的影响。