Hyperactive PI3Kδ predisposes naive T cells to activation via aerobic glycolysis programs
Hyperactive PI3Kδ predisposes naive T cells to activation via aerobic glycolysis programs
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DOI：
10.1038/s41423-020-0379-x
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发表时间：
2020-02-25
影响因子：
24.1
通讯作者：
Zhao, Xiaodong
中科院分区：
文献类型：
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作者：
Jia, Yanjun;Yang, Qiuyun;Zhao, Xiaodong
活化磷酸肌肽3-激酶δ综合征（APDS）是一种常染色体显性联合免疫缺陷疾病，由PIK3CD基因的致病性功能获得（GOF）突变引起。APDS患者表现出异常的T细胞稳态。然而，PIK3CD GOF促成这一特征的机制尚不清楚。在这里，我们研究了来自中国多个地区的PIK3CD GOF突变儿童队列和相应的CRISPR/Cas9基因编辑小鼠模型，报告了过度活跃的PI3K δ通过内在地促进T-Naive细胞的生长、增殖和激活来破坏T-Naive细胞的外周稳态。我们的研究结果表明，PIK3CD GOF导致初始T细胞中静止相关基因表达谱的缺失，并促进初始T细胞过度生长、过度增殖并获得激活的功能状态。初始PIK3CD GOF T细胞在静息或激活状态下表现出增强的糖酵解能力和减少的线粒体呼吸。阻断糖酵解可消除异常脾T细胞池，在体内和体外逆转PIK3CD - GOF诱导的过度激活表型。这些结果表明，PIK3CD gof诱导的幼稚T细胞过度激活需要增强的有氧糖酵解，并为靶向糖酵解治疗APDS和其他免疫疾病患者提供了潜在的治疗方法。
Activated phosphoinositide 3-kinase delta syndrome (APDS) is an autosomal-dominant combined immunodeficiency disorder resulting from pathogenic gain-of-function (GOF) mutations in the PIK3CD gene. Patients with APDS display abnormal T cell homeostasis. However, the mechanisms by which PIK3CD GOF contributes to this feature remain unknown. Here, with a cohort of children with PIK3CD GOF mutations from multiple regions of China and a corresponding CRISPR/Cas9 gene-edited mouse model, we reported that hyperactive PI3K delta disrupted T-Naive cell homeostasis in the periphery by intrinsically promoting the growth, proliferation, and activation of T-Naive cells. Our results showed that PIK3CD GOF resulted in loss of the quiescence-associated gene expression profile in naive T cells and promoted naive T cells to overgrow, hyperproliferate and acquire an activated functional status. Naive PIK3CD GOF T cells exhibited an enhanced glycolytic capacity and reduced mitochondrial respiration in the resting or activated state. Blocking glycolysis abrogated the abnormal splenic T cell pool and reversed the overactivated phenotype induced by PIK3CD GOF in vivo and in vitro. These results suggest that enhanced aerobic glycolysis is required for PIK3CD GOF-induced overactivation of naive T cells and provide a potential therapeutic approach for targeting glycolysis to treat patients with APDS as well as other immune disorders.