GOT1 regulates CD8+ effector and memory T cell generation
Wei Xu,
Chirag H. Patel,
Liang Zhao,
Im-Hong Sun,
Min-Hee Oh,
Im-Meng Sun,
Rachel S. Helms,
Jiayu Wen,
Jonathan D. Powell
Affiliations
Wei Xu
Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Chirag H. Patel
Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Calico LLC, South San Francisco, CA 94080, USA
Liang Zhao
Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Im-Hong Sun
Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Min-Hee Oh
Department of Immunobiology, Yale University, New Haven, CT 06520, USA
Im-Meng Sun
Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Rachel S. Helms
Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Jiayu Wen
Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Jonathan D. Powell
Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Calico LLC, South San Francisco, CA 94080, USA; Corresponding author
Summary: T cell activation, proliferation, function, and differentiation are tightly linked to proper metabolic reprogramming and regulation. By using [U-13C]glucose tracing, we reveal a critical role for GOT1 in promoting CD8+ T cell effector differentiation and function. Mechanistically, GOT1 enhances proliferation by maintaining intracellular redox balance and serine-mediated purine nucleotide biosynthesis. Further, GOT1 promotes the glycolytic programming and cytotoxic function of cytotoxic T lymphocytes via posttranslational regulation of HIF protein, potentially by regulating the levels of α-ketoglutarate. Conversely, genetic deletion of GOT1 promotes the generation of memory CD8+ T cells.
