Glutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function.,Cell Metabolism

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Glutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function.
Cell Metabolism ( IF 27.7 ) Pub Date : 2020-03-25 , DOI: 10.1016/j.cmet.2020.03.004
Henry Kurniawan ₁ , Davide G Franchina ₁ , Luana Guerra ₁ , Lynn Bonetti ₁ , Leticia Soriano -Baguet ₁ , Melanie Grusdat ₁ , Lisa Schlicker ₂ , Oliver Hunewald ₃ , Catherine Dostert ₁ , Myriam P Merz ₄ , Carole Binsfeld ₁ , Gordon S Duncan ₅ , Sophie Farinelle ₁ , Yannic Nonnenmacher ₂ , Jillian Haight ₅ , Dennis Das Gupta ₆ , Anouk Ewen ₁ , Rabia Taskesen ₇ , Rashi Halder ₈ , Ying Chen ₉ , Christian Jäger ₈ , Markus Ollert ₁₀ , Paul Wilmes ₈ , Vasilis Vasiliou ₉ , Isaac S Harris ₁₁ , Christiane B Knobbe-Thomsen ₇ , Jonathan D Turner ₄ , Tak W Mak ₁₂ , Michael Lohoff ₆ , Johannes Meiser ₁₃ , Karsten Hiller ₂ , Dirk Brenner ₁₄

Affiliation

Experimental & Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, 29 Rue Henri Koch, Esch-sur-Alzette, Luxembourg.
Braunschweig Integrated Center of Systems Biology (BRICS), Technische Universität Braunschweig, Rebenring 56, 38106 Braunschweig; Computational Biology of Infection Research, Helmholtz Centre for Infection Research, Inhoffenstraße 7, 38124 Braunschweig, Germany.
Allergy and Clinical Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, 29 Rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg.
Immune Endocrine Epigenetics Research Group, Department of Infection and Immunity, Luxembourg Institute of Health, 29 Rue Henri Koch, L-4354 Esch-sur-Alzette, Grand Duchy of Luxembourg.
The Campbell Family Cancer Research Institute, Ontario Cancer Institute University Health Network, Toronto, ON, Canada.
Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, Marburg, Germany.
Departments of Medical Biophysics and Immunology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg.
Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA.
Allergy and Clinical Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, 29 Rue Henri Koch, L-4354 Esch-sur-Alzette, Luxembourg; Odense Research Center for Anaphylaxis (ORCA), Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
Department of Biomedical Genetics and Wilmot Cancer Institute, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, New York, USA.
The Campbell Family Cancer Research Institute, Ontario Cancer Institute University Health Network, Toronto, ON, Canada; Departments of Medical Biophysics and Immunology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; The University of Hong Kong, Hong Kong SAR, China.
Cancer Metabolism Group, Department of Oncology, 84 Val Fleuri, Luxembourg, Luxembourg.
Experimental & Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, 29 Rue Henri Koch, Esch-sur-Alzette, Luxembourg; Odense Research Center for Anaphylaxis (ORCA), Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark; Immunology & Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg.

Regulatory T cells (Tregs) maintain immune homeostasis and prevent autoimmunity. Serine stimulates glutathione (GSH) synthesis and feeds into the one-carbon metabolic network (1CMet) essential for effector T cell (Teff) responses. However, serine's functions, linkage to GSH, and role in stress responses in Tregs are unknown. Here, we show, using mice with Treg-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that GSH loss in Tregs alters serine import and synthesis and that the integrity of this feedback loop is critical for Treg suppressive capacity. Although Gclc ablation does not impair Treg differentiation, mutant mice exhibit severe autoimmunity and enhanced anti-tumor responses. Gclc-deficient Tregs show increased serine metabolism, mTOR activation, and proliferation but downregulated FoxP3. Limitation of cellular serine in vitro and in vivo restores FoxP3 expression and suppressive capacity of Gclc-deficient Tregs. Our work reveals an unexpected role for GSH in restricting serine availability to preserve Treg functionality.

中文翻译：

谷胱甘肽限制丝氨酸代谢以保护调节性 T 细胞功能。

调节性 T 细胞 (Treg) 维持免疫稳态并预防自身免疫。丝氨酸刺激谷胱甘肽 (GSH) 合成，并馈入效应 T 细胞 (Teff) 反应所必需的一碳代谢网络 (1CMet)。然而，丝氨酸的功能、与 GSH 的联系以及在 Tregs 应激反应中的作用尚不清楚。在这里，我们使用对谷氨酸半胱氨酸连接酶 (Gclc) 催化亚基进行 Treg 特异性消融的小鼠证明，Treg 中 GSH 的丢失会改变丝氨酸的输入和合成，并且该反馈环路的完整性对于 Treg 抑制能力至关重要。尽管 Gclc 消融不会损害 Treg 分化，但突变小鼠表现出严重的自身免疫和增强的抗肿瘤反应。 Gclc 缺陷的 Tregs 表现出丝氨酸代谢、mTOR 激活和增殖增加，但 FoxP3 下调。体外和体内细胞丝氨酸的限制可恢复 FoxP3 的表达和 Gclc 缺陷的 Tregs 的抑制能力。我们的工作揭示了 GSH 在限制丝氨酸可用性以保留 Treg 功能方面的意想不到的作用。

更新日期：2020-03-25

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