Upon antigen stimulation, T lymphocytes undergo dramatic changes in metabolism to fulfill the bioenergetic, biosynthetic and redox demands of proliferation and differentiation. Glutathione (GSH) plays an essential role in controlling redox balance and cell fate. While GSH can be recycled from Glutathione disulfide (GSSG), the inhibition of this recycling pathway does not impact GSH content and murine T cell fate. By contrast, the inhibition of the de novo synthesis of GSH, by deleting either the catalytic (Gclc) or the modifier (Gclm) subunit of glutamate–cysteine ligase (Gcl), dampens intracellular GSH, increases ROS, and impact T cell differentiation. Moreover, the inhibition of GSH de novo synthesis dampened the pathological progression of experimental autoimmune encephalomyelitis (EAE). We further reveal that glutamine provides essential precursors for GSH biosynthesis. Our findings suggest that glutamine catabolism fuels de novo synthesis of GSH and directs the lineage choice in T cells.

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Published in eLife, v. 7, e36158, p. 1-28.

© 2018, Lian et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

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This work was supported by R21AI117547 and 1R01AI114581 from National Institute of Health, V2014-001 from the V-Foundation and 128436-RSG-15-180-01-LIB from the American Cancer Society (RW), K01AA025093 (YC), R24AA022057 (VV), the American Lebanese and Syrian Associated Charities (DG), and Natural Science Foundation of Hunan Province Grant 2018JJ2351(GL), NCI 1P01CA163223-01A1 and NIDDK 1U24DK097215-01A1 (TWMF), 130421-RSG-17-071-01-TBG from the American Cancer Society , R03 CA212802-01A1 (JY) and R21 AI113930 (YL).

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Supplementary file 1. List of primer sequences used for RT-PCR analysis. DOI: https://doi.org/10.7554/eLife.36158.025

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All data generated or analysed during this study are included in the manuscript and supporting files.

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Figure 6—figure supplement 2.

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elife-36158-transrepform-v2.pdf (157 kB)
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