1. Academic Validation
  2. Ammonia detoxification promotes CD8+ T cell memory development by urea and citrulline cycles

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

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.
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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