Infection of T cells by Epstein-Barr virus (EBV) causes chronic active EBV infection (CAEBV) characterized by T cell lymphoproliferative disorders (T-LPD) of unclear etiology. Here, we identified two homozygous biallelic loss-of-function mutations in PIK3CD and TNFRSF9 in a patient who developed a fatal CAEBV. The mutation in TNFRSF9 gene coding CD137/4-1BB, a costimulatory molecule expressed by antigen-specific activated T cells, resulted in a complete loss of CD137 expression and impaired T cell expansion toward CD137 ligand–expressing cells. Isolated as observed in one sibling, CD137 deficiency resulted in persistent EBV-infected T cells but without clinical manifestations. The mutation in PIK3CD gene that encodes the catalytic subunit p110δ of the PI3K significantly reduced its kinase activity. Deficient T cells for PIK3CD exhibited reduced AKT signaling, while calcium flux, RAS-MAPK activation, and proliferation were increased, suggestive of an imbalance between the PLCγ1 and PI3K pathways. These skewed signals in T cells may sustain accumulation of EBV-infected T cells, a process controlled by the CD137–CD137L pathway, highlighting its critical role in immunity to EBV.

爱泼斯坦-巴尔病毒（EBV）感染T细胞会导致慢性活动性EBV感染（CAEBV），其特征是病因不清楚的T细胞淋巴增生性疾病（T-LPD）。在这里，我们确定了一名致命CAEBV患者的PIK3CD和TNFRSF9中的两个纯合双等位基因功能丧失突变。TNFRSF9基因编码CD137 / 4-1BB（一种由抗原特异性活化T细胞表达的共刺激分子）的突变导致CD137表达完全丧失，并损害了T细胞向表达CD137配体的细胞的扩散。如在同一个兄弟姐妹中观察到的那样，CD137缺乏症可导致持久性EBV感染的T细胞，但无临床表现。PIK3CD中的突变编码PI3K催化亚基p110δ的基因显着降低其激酶活性。缺乏PIK3CD的T细胞表现出降低的AKT信号传导，而钙通量，RAS-MAPK活化和增殖增加，提示PLCγ1和PI3K途径之间存在失衡。T细胞中的这些偏斜信号可能会维持EBV感染的T细胞的积累，这一过程受CD137–CD137L途径控制，突显了其在对EBV免疫中的关键作用。