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The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate

Abstract - The malate shuttle is traditionally understood to maintain NAD - + - /NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions is unclear. Here we show that chronic viral infections induce CD8 - + - T cell expression of GOT1, a central enzyme...

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Main Authors: Weisshaar, Nina (Author) , Ma, Sicong (Author) , Ming, Yanan (Author) , Madi, Alaa (Author) , Mieg, Alessa (Author) , Hering, Marvin (Author) , Zettl, Ferdinand (Author) , Mohr, Kerstin (Author) , Ten Bosch, Nora (Author) , Stichling, Diana (Author) , Büttner, Michael (Author) , Poschet, Gernot (Author) , Klinke, Glynis (Author) , Schulz, Michael (Author) , Kunze-Rohrbach, Nina (Author) , Kerber, Carolin (Author) , Klein, Isabel M. (Author) , Wu, Jingxia (Author) , Wang, Xi (Author) , Cui, Guoliang (Author)
Format: Article (Journal)
Language:English
Published: 09 October 2023
In: Nature immunology
Year: 2023, Volume: 24, Issue: 11, Pages: 1921-1949
ISSN:1529-2916
DOI:10.1038/s41590-023-01636-5
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41590-023-01636-5
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41590-023-01636-5
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Author Notes:Nina Weisshaar, Sicong Ma, Yanan Ming, Alaa Madi, Alessa Mieg, Marvin Hering, Ferdinand Zettl, Kerstin Mohr, Nora Ten Bosch, Diana Stichling, Michael Buettner, Gernot Poschet, Glynis Klinke, Michael Schulz, Nina Kunze-Rohrbach, Carolin Kerber, Isabel Madeleine Klein, Jingxia Wu, Xi Wang & Guoliang Cui
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Summary:Abstract - The malate shuttle is traditionally understood to maintain NAD - + - /NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions is unclear. Here we show that chronic viral infections induce CD8 - + - T cell expression of GOT1, a central enzyme in the malate shuttle. - Got1 - deficiency decreased the NAD - + - /NADH ratio and limited antiviral CD8 - + - T cell responses to chronic infection; however, increasing the NAD - + - /NADH ratio did not restore T cell responses. - Got1 - deficiency reduced the production of the ammonia scavenger 2-ketoglutarate (2-KG) from glutaminolysis and led to a toxic accumulation of ammonia in CD8 - + - T cells. Supplementation with 2-KG assimilated and detoxified ammonia in - Got1 - -deficient T cells and restored antiviral responses. These data indicate that the major function of the malate shuttle in CD8 - + - T cells is not to maintain the NAD - + - /NADH balance but rather to detoxify ammonia and enable sustainable ammonia-neutral glutamine catabolism in CD8 - + - T cells during chronic infection.
Item Description:Gesehen am 12.12.2023
Physical Description:Online Resource
ISSN:1529-2916
DOI:10.1038/s41590-023-01636-5

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