Serine Is an Essential Metabolite for Effector T Cell Expansion

• Published in: Cell metabolism Vol. 25; no. 2; pp. 345 - 357
• Main Authors: Ma, Eric H., Bantug, Glenn, Griss, Takla, Condotta, Stephanie, Johnson, Radia M., Samborska, Bozena, Mainolfi, Nello, Suri, Vipin, Guak, Hannah, Balmer, Maria L., Verway, Mark J., Raissi, Thomas C., Tsui, Harmony, Boukhaled, Giselle, Henriques da Costa, Sofia, Frezza, Christian, Krawczyk, Connie M., Friedman, Adam, Manfredi, Mark, Richer, Martin J., Hess, Christoph, Jones, Russell G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.02.2017
• Subjects: Animals; Carbon - metabolism; Cell Cycle Checkpoints; Cell Proliferation; Diet; Energy Metabolism; Extracellular Space - metabolism; Glycine; glycolysis; immunometabolism; immunotherapy; Listeria monocytogenes - immunology; Metabolic Networks and Pathways; metabolic reprogramming; metabolism; Metabolome; Mice, Inbred C57BL; Phgdh; Purine Nucleotides - biosynthesis; serine; Serine - metabolism; serine biosynthesis; Shmt; T cell; T-Lymphocytes - cytology; T-Lymphocytes - metabolism; serine; immunometabolism; T cell; glycolysis; immunotherapy; serine biosynthesis; metabolism; Shmt; Phgdh; metabolic reprogramming
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2016.12.011

During immune challenge, T lymphocytes engage pathways of anabolic metabolism to support clonal expansion and the development of effector functions. Here we report a critical role for the non-essential amino acid serine in effector T cell responses. Upon activation, T cells upregulate enzymes of the serine, glycine, one-carbon (SGOC) metabolic network, and rapidly increase processing of serine into one-carbon metabolism. We show that extracellular serine is required for optimal T cell expansion even in glucose concentrations sufficient to support T cell activation, bioenergetics, and effector function. Restricting dietary serine impairs pathogen-driven expansion of T cells in vivo, without affecting overall immune cell homeostasis. Mechanistically, serine supplies glycine and one-carbon units for de novo nucleotide biosynthesis in proliferating T cells, and one-carbon units from formate can rescue T cells from serine deprivation. Our data implicate serine as a key immunometabolite that directly modulates adaptive immunity by controlling T cell proliferative capacity. [Display omitted] •Enzymes of SGOC metabolism are upregulated upon T cell activation•Serine is required for optimal T cell proliferation in vitro and in vivo•Serine supports de novo purine biosynthesis in proliferating T cells•One-carbon units from formate can bypass serine starvation Activated lymphocytes reprogram their metabolism to support rapid growth and proliferation. Ma et al. reveal an essential role for the non-essential amino acid serine in T cell-mediated immune responses and show that serine metabolism is required for optimal T cell proliferation by fueling one-carbon metabolism and nucleotide biosynthesis.