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Hyperactive PI3Kδ predisposes naive T cells to activation via aerobic glycolysis programs.

ABSTRACT: Activated phosphoinositide 3-kinase δ 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 PI3Kδ 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.

SUBMITTER: Jia Y

PROVIDER: S-EPMC8245563 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Hyperactive PI3Kδ predisposes naive T cells to activation via aerobic glycolysis programs.

Jia Yanjun Y Yang Qiuyun Q Wang Yanping Y Li Wenyan W Chen Xuemei X Xu Tao T Tian Zhirui Z Feng Minxuan M Zhang Liang L Tang Wenjing W Tian Na N Zhou Lina L Song Wenxia W Zhao Xiaodong X

Cellular & molecular immunology 20200225 7

Activated phosphoinositide 3-kinase δ 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 ...[more]

PMID: 32099075

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Hyperactive PI3Kδ predisposes naive T cells to activation via aerobic glycolysis programs.

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Hyperactive PI3Kδ predisposes naive T cells to activation via aerobic glycolysis programs.

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