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

• Published in: Nature communications Vol. 9; no. 1; pp. 3296 - 12
• Main Authors: Suzuki, Junpei, Yamada, Takeshi, Inoue, Kazuki, Nabe, Shogo, Kuwahara, Makoto, Takemori, Nobuaki, Takemori, Ayako, Matsuda, Seiji, Kanoh, Makoto, Imai, Yuuki, Yasukawa, Masaki, Yamashita, Masakatsu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17-08-2018; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 631/250/2152/1566; 631/45/320; 631/80/509; 64; 64/60; 82/58; 96; 96/106; 96/31; 96/95; Activation, Metabolic - drug effects; Animals; Carbon - metabolism; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell Proliferation - drug effects; Demethylation; Exhaustion; Female; Glutamine; Glutamine - metabolism; Glycolysis; Histones - metabolism; Humanities and Social Sciences; Ketoglutaric acid; Ketoglutaric Acids - metabolism; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Lysine - metabolism; Mechanistic Target of Rapamycin Complex 1 - metabolism; Metabolic activation; Metabolic rate; Metabolism; Metabolites; Metabolomics; Methylation - drug effects; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - metabolism; Rapamycin; Regulatory mechanisms (biology); Science; Science (multidisciplinary); Senescence; Sirolimus - pharmacology; TOR protein; Tumor suppressor genes
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05854-6

While menin plays an important role in preventing T-cell dysfunction, such as senescence and exhaustion, the regulatory mechanisms remain unclear. We found that menin prevents the induction of dysfunction in activated CD8 T cells by restricting the cellular metabolism. mTOR complex 1 (mTORC1) signaling, glycolysis, and glutaminolysis are augmented by menin deficiency. Rapamycin treatment prevents CD8 T-cell dysfunction in
menin
-deficient CD8 T cells. Limited glutamine availability also prevents CD8 T-cell dysfunction induced by
menin
deficiency, and its inhibitory effect is antagonized by α-ketoglutarate (α-KG), an intermediate metabolite of glutaminolysis. α-KG-dependent histone H3K27 demethylation seems to be involved in the dysfunction in
menin
-deficient CD8 T cells. We also found that α-KG activates mTORC1-dependent central carbon metabolism. These findings suggest that menin maintains the T-cell functions by limiting mTORC 1 activity and subsequent cellular metabolism.
T cells can alter their metabolism during activation and differentiation. Here the authors show that the tumor suppressor menin regulates CD8 T-cell fate via the modulation of central carbon metabolism.