Lactate Limits T Cell Proliferation via the NAD(H) Redox State.
Lactate Limits T Cell Proliferation via the NAD(H) Redox State.
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DOI：
10.1016/j.celrep.2020.108500
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发表时间：
2020-12-15
期刊：
影响因子：
8.8
通讯作者：
Beier UH
中科院分区：
文献类型：
--
作者：
Quinn WJ 3rd;Jiao J;TeSlaa T;Stadanlick J;Wang Z;Wang L;Akimova T;Angelin A;Schäfer PM;Cully MD;Perry C;Kopinski PK;Guo L;Blair IA;Ghanem LR;Leibowitz MS;Hancock WW;Moon EK;Levine MH;Eruslanov EB;Wallace DC;Baur JA;Beier UH
Immune cell function is influenced by metabolic conditions. Low-glucose, high-lactate environments, such as the placenta, gastrointestinal tract, and the tumor microenvironment, are immunosuppressive, especially for glycolysis-dependent effector T cells. We report that nicotinamide adenine dinucleotide (NAD+), which is reduced to NADH by lactate dehydrogenase in lactate-rich conditions, is a key point of metabolic control in T cells. Reduced NADH is not available for NAD+-dependent enzymatic reactions involving glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and 3-phosphoglycerate dehydrogenase (PGDH). We show that increased lactate leads to a block at GAPDH and PGDH, leading to the depletion of post-GAPDH glycolytic intermediates, as well as the 3-phosphoglycerate derivative serine that is known to be important for T cell proliferation. Supplementing serine rescues the ability of T cells to proliferate in the presence of lactate-induced reductive stress. Directly targeting the redox state may be a useful approach for developing novel immunotherapies in cancer and therapeutic immunosuppression. Quinn et al. report that lactate has an acidity-independent suppressive effect on effector T cell proliferation mediated through a shift from NAD+ to NADH (lactate-induced reductive stress). This impairs glycolysis and glucose-derived serine production, which is required for effector T cell proliferation.
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影响因子：
19.6
作者：
Levine MH;Wang Z;Xiao H;Jiao J;Wang L;Bhatti TR;Hancock WW;Beier UH
通讯作者：
Beier UH
影响因子：
29
作者：
Frederick DW;Loro E;Liu L;Davila A Jr;Chellappa K;Silverman IM;Quinn WJ 3rd;Gosai SJ;Tichy ED;Davis JG;Mourkioti F;Gregory BD;Dellinger RW;Redpath P;Migaud ME;Nakamaru-Ogiso E;Rabinowitz JD;Khurana TS;Baur JA
通讯作者：
Baur JA
影响因子：
64.5
作者：
Chang CH;Curtis JD;Maggi LB Jr;Faubert B;Villarino AV;O'Sullivan D;Huang SC;van der Windt GJ;Blagih J;Qiu J;Weber JD;Pearce EJ;Jones RG;Pearce EL
通讯作者：
Pearce EL
影响因子：
12.4
作者：
Amelio I;Melino G;Frezza C
通讯作者：
Frezza C
影响因子：
64.5
作者：
Ho PC;Bihuniak JD;Macintyre AN;Staron M;Liu X;Amezquita R;Tsui YC;Cui G;Micevic G;Perales JC;Kleinstein SH;Abel ED;Insogna KL;Feske S;Locasale JW;Bosenberg MW;Rathmell JC;Kaech SM
通讯作者：
Kaech SM