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The tumor suppressor menin prevents effector CD8 T-cell dysfunction by targeting mTORC1-dependent metabolic

Junpei Suzuki1,2,3, Takeshi Yamada4, Kazuki Inoue5

  • 1Department of Hematology, Clinical Immunology and Infectious Diseases, Graduate School of Medicine, Ehime University, Shitsukawa, Toon City, Ehime, 791-0295, Japan.

Nature Communications
|August 19, 2018
PubMed

Insights

Menin protein prevents T-cell dysfunction by controlling cellular metabolism. Menin deficiency increases mTORC1 signaling and nutrient metabolism, leading to T-cell dysfunction, which can be reversed by rapamycin or limiting glutamine.

Area of Science:

  • Immunology
  • Cellular Metabolism
  • Molecular Biology

Background:

  • Menin protein is crucial for preventing T-cell dysfunction, including senescence and exhaustion.
  • The precise molecular mechanisms underlying menin's regulatory role in T-cell function are not fully understood.

Purpose of the Study:

  • To elucidate the regulatory mechanisms by which menin prevents T-cell dysfunction.
  • To investigate the role of cellular metabolism and mTORC1 signaling in menin-mediated T-cell regulation.

Main Methods:

  • Analysis of activated CD8 T cells with and without menin.
  • Assessment of cellular metabolism, including glycolysis and glutaminolysis.
  • Treatment with rapamycin and manipulation of glutamine availability.
  • Investigation of α-ketoglutarate (α-KG) effects and histone demethylation.

Main Results:

  • Menin deficiency augments mTOR complex 1 (mTORC1) signaling, glycolysis, and glutaminolysis in CD8 T cells.
  • Rapamycin treatment and limited glutamine availability prevent T-cell dysfunction in menin-deficient cells.
  • α-ketoglutarate antagonizes glutamine's inhibitory effect and activates mTORC1-dependent metabolism.
  • α-KG-dependent histone H3K27 demethylation is implicated in menin-deficient CD8 T-cell dysfunction.

Conclusions:

  • Menin maintains T-cell function by restricting mTORC1 activity and cellular metabolism.
  • Dysregulation of cellular metabolism, particularly glutaminolysis and mTORC1 signaling, contributes to T-cell dysfunction in menin deficiency.
  • Targeting cellular metabolism presents a potential therapeutic strategy for enhancing T-cell function.

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