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eUREkA! T cells answer nature’s call

Cellular & Molecular Immunology volume 20, pages 692–693 (2023)Cite this article

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Nitrogen is critical for cell growth, proliferation, and function. Amino acid (AA) catabolism is a major source of intracellular nitrogen for biosynthesis but also generates the nitrogen-containing molecule ammonia (NH3+), which can accumulate to toxic levels in a cell if not exported to the circulation and detoxified by the urea cycle in the liver. In a recent paper in Nature Immunology, Tang et al. [1] discovered a functional urea cycle in memory T cells, which metabolizes ammonia, prevents its toxic accumulation, and consequently promotes the maintenance of this long-lived cell type critical for recall responses to infection and cancer.

Pharmacological or genetic inhibition of CP synthetase-1 (CPS1) elevated intracellular ammonia levels in Tmem cells, showing that these cells do indeed metabolize ammonia. Restoring ammonia levels decreased Tmem cell numbers, suggesting that CPS1 has a role in Tmem cell formation or persistence. Furthermore, the transfer of CPS1-deficient OT-I CD8+ T cells into mice prior to Lm-OVA infection resulted in the generation of fewer Tmem cells in vivo and increased cell death compared to transfer of control cells. As CPS1 was needed to protect Tmem cells from excess ammonia-induced cell death in vitro, it will be important to measure ammonia in the extracellular fluid in vivo, to investigate what levels of ammonia are sufficient to cause death. The urea cycle may therefore maintain Tmem cell populations both by enhancing their formation and by improving their survival.

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References

  1. Tang K, Zhang H, Deng J, Wang D, Liu S, Lu S, et al. Ammonia detoxification promotes CD8+ T cell memory development by urea and citrulline cycles. Nat Immunol. 2023;24:162–73.

    Article  CAS  PubMed  Google Scholar 

  2. Kurmi K, Haigis MC. Nitrogen metabolism in cancer and immunity. Trends Cell Biol. 2020;30:408–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Carlström M. Nitric oxide signalling in kidney regulation and cardiometabolic health. Nat Rev Nephrol 2021;17:575–90.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Zhang H, Tang K, Ma J, Zhou L, Liu J, Zeng L, et al. Ketogenesis-generated β-hydroxybutyrate is an epigenetic regulator of CD8+ T-cell memory development. Nat Cell Biol. 2020;22:18–25.

    Article  CAS  PubMed  Google Scholar 

  5. Bell HN, Huber AK, Singhal R, Korimerla N, Rebernick RJ, Kumar R, et al. Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer. Cell Metab. 2023;35:134–49.

    Article  CAS  PubMed  Google Scholar 

  6. Spinelli JB, Yoon H, Ringel AE, Jeanfavre S, Clish CB, Haigis MC. Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass. Science. 2017;358:941–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Inoue Y, Hayhurst GP, Inoue J, Mori M, Gonzalez FJ. Defective ureagenesis in mice carrying a liver-specific disruption of hepatocyte nuclear factor 4α (HNF4α) regulates ornithine transcarbamoylase in vivo. J Biol Chem. 2002;277:25257–65.

    Article  CAS  PubMed  Google Scholar 

  8. Geiger R, Rieckmann JC, Wolf T, Basso C, Feng Y, Fuhrer T, et al. L-Arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell. 2016;167:829–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lundberg JO, Weitzberg E. Nitric oxide signaling in health and disease. Cell. 2022;185:2852–78.

    Article  Google Scholar 

  10. Puleston DJ, Baixauli F, Sanin DE, Edwards-Hicks J, Villa M, Kabat AM, et al. Polyamine metabolism is a central determinant of helper T cell lineage fidelity. Cell. 2021;184:4186–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. Bloomberg-Kimmel Institute of Immunotherapy, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Beth Kelly & Erika L. Pearce

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  1. Beth Kelly
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Correspondence to Beth Kelly or Erika L. Pearce.

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Kelly, B., Pearce, E.L. eUREkA! T cells answer nature’s call. Cell Mol Immunol 20, 692–693 (2023). https://doi.org/10.1038/s41423-023-00994-2

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