T cell-specific deletion of Pgam1 reveals a critical role for glycolysis in T cell responses

Koji Toriyama,Nobuaki Takemori,Amane Konishi,Takeshi Yamada,Atsushi Shiraishi,Hiroshi Kondoh,Takumi Mikawa,Makoto Kuwahara,Tomoyoshi Soga,Toshihiro Yorozuya,Masakatsu Yamashita

doi:10.1038/s42003-020-01122-w

Abstract

Although the important roles of glycolysis in T cells have been demonstrated, the regulatory mechanism of glycolysis in activated T cells has not been fully elucidated. Furthermore, the influences of glycolytic failure on the T cell-dependent immune response in vivo remain unclear. We therefore assessed the role of glycolysis in the T cell-dependent immune response using T cell-specific Pgam1-deficient mice. Both CD8 and CD4 T cell-dependent immune responses were attenuated by Pgam1 deficiency. The helper T cell-dependent inflammation was ameliorated in Pgam1-deficient mice. Glycolysis augments the activation of mTOR complex 1 (mTORC1) and the T-cell receptor (TCR) signals. Glutamine acts as a metabolic hub in activated T cells, since the TCR-dependent increase in intracellular glutamine is required to augment glycolysis, increase mTORC1 activity and augment TCR signals. These findings suggest that mTORC1, glycolysis and glutamine affect each other and cooperate to induce T cell proliferation and differentiation.

Highlights

The important roles of glycolysis in T cells have been demonstrated, the regulatory mechanism of glycolysis in activated T cells has not been fully elucidated
The mechanistic target of rapamycin is a crucial regulator of cellular metabolism13,14. mTOR signaling is essential for immune signals and alteration of cellular metabolism for proper differentiation and function of T cells15–17. mTOR exists in two complexes, mTOR complex 1 and mTORC2. mTORC1 and mTORC2 orchestrate metabolic reprograming to exit the quiescent state of T cells18. mTORC1 regulates protein synthesis via phosphorylation of the S6 kinases and the inhibitory eukaryotic initiation factor 4E-binding proteins
The mRNA expression of the regulatory targets of c-Myc and Srebp[1] was attenuated in Pgam[1] KO activated CD8 T cells (Fig. 5d, e). These results suggest that TCRmediated activation of glucose metabolism supports the sustained mTORC1 activation and induces the metabolic reprograming of T cells that is required for clonal expansion and differentiation

Summary

Introduction

The important roles of glycolysis in T cells have been demonstrated, the regulatory mechanism of glycolysis in activated T cells has not been fully elucidated. We assessed the role of glycolysis in the T cell-dependent immune response using T cell-specific Pgam1-deficient mice. Glutamine acts as a metabolic hub in activated T cells, since the TCR-dependent increase in intracellular glutamine is required to augment glycolysis, increase mTORC1 activity and augment TCR signals These findings suggest that mTORC1, glycolysis and glutamine affect each other and cooperate to induce T cell proliferation and differentiation. Effector T cells dominantly use aerobic glycolysis for glucose metabolism, OXPHOS continues to occur[6,8] This change in the metabolic status is termed “metabolic reprogramming” and is believed to play an important role in the regulation of T cell-mediated immune responses[9]. We reported that glutamine activates mTORC1 signaling, partly via supplementation of α-KG27

Methods

Results

Conclusion