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

• Published in: Cellular & molecular immunology 2021-07, Vol.18 (7), p.1783-1797
• Main Authors: Jia, Yanjun, Yang, Qiuyun, Wang, Yanping, Li, Wenyan, Chen, Xuemei, Xu, Tao, Tian, Zhirui, Feng, Minxuan, Zhang, Liang, Tang, Wenjing, Tian, Na, Zhou, Lina, Song, Wenxia, Zhao, Xiaodong
• Format: Article
• Language: English
• Subjects: 631/250/248; 631/250/249/2512; 631/80/304; Animals; Antibodies; Biomedical and Life Sciences; Biomedicine; Cell activation; Cell proliferation; Class I Phosphatidylinositol 3-Kinases - genetics; CRISPR; Gene expression; Glycolysis; Hereditary diseases; Homeostasis; Humans; Immunodeficiency; Immunology; Kinases; Lymphocytes; Lymphocytes T; Medical Microbiology; Mice; Microbiology; Mitochondria; Mutation; Phenotypes; Phosphatidylinositol 3-Kinases; Primary Immunodeficiency Diseases; Spleen; T-Lymphocytes; Vaccine
• ISSN: 1672-7681; 2042-0226
• DOI: 10.1038/s41423-020-0379-x

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.