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

doi:10.1016/j.celrep.2022.111987

GOT1 regulates CD8⁺ effector and memory T cell generation

Cell Rep. 2023 Jan 31;42(1):111987. doi: 10.1016/j.celrep.2022.111987. Epub 2023 Jan 12.

Authors

Wei Xu¹, Chirag H Patel², Liang Zhao³, Im-Hong Sun³, Min-Hee Oh⁴, Im-Meng Sun³, Rachel S Helms³, Jiayu Wen³, Jonathan D Powell⁵

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Department of Immunobiology, Yale University, New Haven, CT 06520, USA.
⁵ 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. Electronic address: poweljo@jhmi.edu.

Abstract

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.

Keywords: CP: Metabolism; GOT1; HIF; NADH/NAD; effector and memory CD8(+) T cell; glucose; glutamate; serine.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes* / metabolism
Cell Differentiation / genetics
Glucose / metabolism
Immunologic Memory / genetics
Memory T Cells*
T-Lymphocytes, Cytotoxic

Substances

Glucose

Abstract

Publication types

MeSH terms

Substances

Grants and funding