The metabolite BH4 controls T cell proliferation in autoimmunity and cancer.
The metabolite BH4 controls T cell proliferation in autoimmunity and cancer.
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DOI：
10.1038/s41586-018-0701-2
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发表时间：
2018-11
期刊：
影响因子：
64.8
通讯作者：
Penninger JM
中科院分区：
文献类型：
--
作者：
Cronin SJF;Seehus C;Weidinger A;Talbot S;Reissig S;Seifert M;Pierson Y;McNeill E;Longhi MS;Turnes BL;Kreslavsky T;Kogler M;Hoffmann D;Ticevic M;da Luz Scheffer D;Tortola L;Cikes D;Jais A;Rangachari M;Rao S;Paolino M;Novatchkova M;Aichinger M;Barrett L;Latremoliere A;Wirnsberger G;Lametschwandtner G;Busslinger M;Zicha S;Latini A;Robson SC;Waisman A;Andrews N;Costigan M;Channon KM;Weiss G;Kozlov AV;Tebbe M;Johnsson K;Woolf CJ;Penninger JM
遗传调节剂和环境刺激调节自身免疫和癌症中的T细胞活化。酶辅因子四氢生物蝶呤（BH 4）参与单胺神经递质的产生，一氧化氮的产生和疼痛。在这里，我们发现了这些过程之间的联系，确定了BH4在T细胞生物学中的基本作用。我们发现，GTP环化水解酶1（GCH 1，BH 4合成的限速酶）的基因失活和sepiapterin还原酶（SPR，其合成途径中的末端酶）的抑制严重损害了成熟小鼠和人类T细胞的增殖。活化T细胞中的BH4产生与铁代谢和线粒体生物能量学的改变有关。在体内阻断BH4的合成消除了T细胞介导的自身免疫和过敏性炎症，而通过GCH 1过表达增强BH4水平，增强了表达CD4和CD8的T细胞的反应，增加了它们在体内的抗肿瘤活性。向小鼠施用BH4显著降低肿瘤生长并扩大肿瘤内效应T细胞的群体。犬尿氨酸是一种色氨酸代谢物，它可以阻断抗肿瘤免疫，以一种可以被BH4拯救的方式抑制T细胞增殖。最后，我们报告了一个潜在的SPR拮抗剂的发展，为可能的临床应用。我们的数据揭示了GCH 1，SPR及其下游代谢产物BH 4作为T细胞生物学的关键调节因子，可以很容易地操纵以阻断自身免疫或增强抗癌免疫。
Genetic regulators and environmental stimuli modulate T-cell activation in autoimmunity and cancer. The enzyme co-factor tetrahydrobiopterin (BH4) is involved in the production of monoamine neurotransmitters, the generation of nitric oxide, and pain. Here we uncover a link between these processes, identifying a fundamental role for BH4 in T-cell biology. We find that genetic inactivation of GTP cyclohydrolase 1 (GCH1, the rate-limiting enzyme in the synthesis of BH4) and inhibition of sepiapterin reductase (SPR, the terminal enzyme in its synthetic pathway) severely impair the proliferation of mature mouse and human T cells. BH4 production in activated T cells is linked to alterations in iron metabolism and mitochondrial bioenergetics. In vivo blockade of BH4 synthesis abrogates T-cell-mediated autoimmunity and allergic inflammation, while enhancing BH4 levels through GCH1 overexpression augments responses by CD4- and CD8-expressing T cells, increasing their antitumour activity in vivo. Administration of BH4 to mice markedly reduces tumour growth and expands the population of intratumoral effector T cells. Kynurenine—a tryptophan metabolite that blocks antitumour immunity—inhibits T-cell proliferation in a manner that can be rescued by BH4. Finally, we report the development of a potent SPR antagonist for possible clinical use. Our data uncover GCH1, SPR and their downstream metabolite BH4 as critical regulators of T-cell biology that can be readily manipulated to either block autoimmunity or enhance anticancer immunity.
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影响因子：
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通讯作者：
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四氢生物蝶呤的生物合成是犬尿氨酸途径代谢物黄腐酸的潜在靶标
影响因子：
4.8
作者：
Haruki, Hirohito;Hovius, Ruud;Johnsson, Kai
通讯作者：
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影响因子：
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Martin, Stefan F.;Dudda, Jan C.;Bachtanian, Eva;Lembo, Annalisa;Liller, Stefanie;Duerr, Christoph;Heimesaat, Markus M.;Bereswill, Stefan;Fejer, Gyoergy;Vassileva, Ralitsa;Jakob, Thilo;Freudenberg, Nikolaus;Termeer, Christian C.;Johner, Caroline;Galanos, Chris;Freudenberg, Marina A.
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Freudenberg, Marina A.