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Regulation of CD4 + T cell differentiation and function by glucose metabolism

Genes & Immunity volume 26, pages 287–296 (2025)Cite this article

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Abstract

The long-term persistence of naive T lymphocytes is maintained by a state of relative quiescence. Upon antigenic stimulation, these naive T cells undergo rapid activation and proliferation, differentiating into effector cells with specific clonal expansion. Recently, in-depth studies have revealed a fundamental difference in the metabolic requirements of distinct T cell subsets. The fate of CD4 + T cells is influenced by glucose-mediated glycolysis and oxidative phosphorylation (OXPHOS). In this context, key enzymes and various glycolytic intermediates, in conjunction with transcription factors and cytokines, play a crucial role in CD4 + T cell differentiation and function. In our study, we investigated the mechanisms underlying glycolytic reprogramming in CD4 + T cells, with a particular focus on the role of glycolytic enzymes in modulating cytokines and transcription factors that govern T cell differentiation.Our aim is to provide novel insights into the treatment of clinically relevant immune diseases by thoroughly elucidating the characteristics and potential regulatory mechanisms of glucose metabolism in CD4 + T cells.

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Fig. 1: The differentiation of Th1 cells is contingent upon enzymes involved in glycolysis.
Fig. 2: TH17 cells display elevated expression of glycolytic genes and demonstrate increased rates of extracellular acidification [92].
Fig. 3: Elevated lactate levels in Treg cells enhance the activity of LDHA, facilitating the conversation of α-KG to 2-HG.
Fig. 4: Glucose restriction reduces the production of FBP and activates AMPK, which subsequently initiates the SENP1-Sirt3 signaling pathway crucial for T cell memory formation.

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Data availability is not applicable to this article as no new data were created or analyzed in this study.

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Acknowledgements

We would like to thank the other members of the lab for fruitful discussion and feedback during the writing of this manuscript.

Funding

This work was funded by support from the National Natural Science Foundation of China (NSFC 82171787 to LZ, 82371820 to LJ, 32270987 to JZ), from the Natural Science Foundation of Chongqing (CSTB2024NSCQ-KJFZZDX0001to LJ, CSTB2024NSCQ-MSX0622 to JZ) and from Chongqing Natural Science Foundation Innovation Development Joint Fund Project (CSTB2022NSCQ-LZX0066 to LJ).

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Author notes

  1. These authors contributed equally: Yubo Liu, Yiwen Zhou.

Authors and Affiliations

  1. Department of Immunology, Army Medical University, Chongqing, China

    Yubo Liu, Yiwen Zhou, Ji Zhang & Liyun Zou

  2. Department of Infectious Diseases, Southwest Hospital, Army Medical University, Chongqing, China

    Yubo Liu

  3. Department of Rheumatology and Immunology, Southwest Hospital, Army Medical University, Chongqing, China

    Jingyi Li & Liyun Zou

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  1. Yubo Liu
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  2. Yiwen Zhou
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  3. Ji Zhang
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  4. Jingyi Li
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  5. Liyun Zou
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Contributions

LZ and YL performed study concept and design; YL, YZ, JZ wrote the manuscript and created the figures; LZ,JL revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jingyi Li or Liyun Zou.

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Liu, Y., Zhou, Y., Zhang, J. et al. Regulation of CD4 + T cell differentiation and function by glucose metabolism. Genes Immun 26, 287–296 (2025). https://doi.org/10.1038/s41435-025-00340-8

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