Ammonia detoxification promotes CD8+ T cell memory development by urea and citrulline cycles

  • Nat Immunol. 2023 Jan;24(1):162-173. doi: 10.1038/s41590-022-01365-1.
Ke Tang  #  1  2 ,  Huafeng Zhang  #  3 ,  Jinghui Deng  #  1 ,  Dianheng Wang  4 ,  Shichuan Liu  1 ,  Shuya Lu  1 ,  Qingfa Cui  1 ,  Chen Chen  1 ,  Jincheng Liu  1 ,  Zhuoshun Yang  1 ,  Yonggang Li  5 ,  Jie Chen  4 ,  Jiadi Lv  4 ,  Jingwei Ma  6 ,  Bo Huang  7  8
Affiliations
  • 1. Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2. Cell Architecture Research Center, Huazhong University of Science and Technology, Wuhan, China.
  • 3. Department of Pathology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4. Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, China.
  • 5. Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, Wuhan, China.
  • 6. Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 7. Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 8. Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 36471170 DOI: 10.1038/s41590-022-01365-1
Abstract

Amino acid metabolism is essential for cell survival, while the byproduct ammonia is toxic and can injure cellular longevity. Here we show that CD8+ memory T (TM) cells mobilize the carbamoyl phosphate (CP) metabolic pathway to clear ammonia, thus promoting memory development. CD8+ TM cells use β-hydroxybutyrylation to upregulate CP synthetase 1 and trigger the CP metabolic cascade to form arginine in the cytosol. This cytosolic arginine is then translocated into the mitochondria where it is split by Arginase 2 to urea and ornithine. Cytosolic arginine is also converted to nitric oxide and citrulline by nitric oxide synthases. Thus, both the urea and citrulline cycles are employed by CD8+ T cells to clear ammonia and enable memory development. This ammonia clearance machinery might be targeted to improve T cell-based Cancer immunotherapies.

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