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

Masaki Yasukawa,Junpei Suzuki,Shogo Nabe,Takeshi Yamada,Kazuki Inoue,Yuuki Imai,Seiji Matsuda,Ayako Takemori,Makoto Kanoh,Nobuaki Takemori,Makoto Kuwahara,Masakatsu Yamashita

doi:10.1038/s41467-018-05854-6

Masaki Yasukawa, Junpei Suzuki + Show 10 more

Open Access

https://doi.org/10.1038/s41467-018-05854-6

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Journal: Nature Communications	Publication Date: Aug 17, 2018
Citations: 52	License type: open-access

Affiliation: Ehime University, Ehime University Hospital

Abstract

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.

Highlights

We previously reported that menin knockout (KO; meninflox/flox mice with CD4-Cre transgenic) naive CD4 T cells more rapidly senesced after receiving T-cell receptor (TCR) stimulation than did the wild-type (WT) control cells[10]
In this study, we demonstrated the critical role of menin in regulating the mTORC signaling and cellular metabolism
The menindependent restriction of mechanistic target or rapamycin (mTOR) complex 1 (mTORC1) activity and cellular metabolism during the initial TCR-mediated activation phase seem to be important for preventing the induction of dysfunction in activated CD8 T cells

Summary

Introduction

A major characteristic feature of T-cell senescence is the acquisition of a senescence-associated secretory phenotype (SASP)[10], which is characterized by a striking increase in the secretion of pro-inflammatory cytokines, chemokines, matrix remodeling factors, and pro-angiogenic factors[11,12] These factors deleteriously alter tissue homeostasis, leading to chronic inflammation and cancer[11,13,14,15]. Senescent T cells induce an increased susceptibility to autoimmune diseases such as rheumatoid arthritis through SASP16–19 Another major alteration in senescent T cells is the impaired IL-2 production and memory formation against infection. MTORC1 inhibition is considered a viable strategy for preventing T-cell dysfunction and subsequent increases in the risk of age-related diseases and it was recently reported that mTOR inhibition improves the immune function in the elderly[29].

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