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

Cellular & Molecular Immunology volume 18, pages 1783–1797 (2021)Cite this article

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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 TNaive cell homeostasis in the periphery by intrinsically promoting the growth, proliferation, and activation of TNaive 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.

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Data availability

The RNA-seq data have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (GEO) with the accession number GSE 134322.

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Acknowledgements

This work was supported by grants from the National Science Foundation of China (81974255) and the Public Welfare Scientific Research Project of China (201402012) to X.Z.

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Authors and Affiliations

  1. National Clinical Research for Child Health and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Ministry of Education Key Laboratory of Child Development and Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China

    Yanjun Jia, Qiuyun Yang, Yanping Wang, Wenyan Li, Xuemei Chen, Tao Xu, Zhirui Tian, Minxuan Feng, Liang Zhang, Wenjing Tang, Lina Zhou & Xiaodong Zhao

  2. National Clinical Research for Child Health and Disorders, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China

    Na Tian

  3. Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, USA

    Wenxia Song

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  1. Yanjun Jia
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Contributions

Y.J., Q.Y., and Y.W. designed and performed experiments and analyzed the data; Y.J. wrote the initial paper; Q.Y., Y.W., X.C., and W.T. recruited and managed patients; W.L., X.C., T.X., Z.T., M.F., L.Z., N.T., and L.Z. performed experiments; W.S. contributed to scientific discussion and data interpretation and reviewed and revised the paper. X.Z. designed the research, supervised the study, and reviewed and revised the paper.

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Correspondence to Xiaodong Zhao.

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Jia, Y., Yang, Q., Wang, Y. et al. Hyperactive PI3Kδ predisposes naive T cells to activation via aerobic glycolysis programs. Cell Mol Immunol 18, 1783–1797 (2021). https://doi.org/10.1038/s41423-020-0379-x

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