title: Serine Is an Essential Metabolite for Effector T Cell Expansion.
abstract: 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.
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Eric H
authors.initials: EH
authors.lastname: Ma
authors.affiliation: Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland.
authors.forename: Glenn
authors.initials: G
authors.lastname: Bantug
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Takla
authors.initials: T
authors.lastname: Griss
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, QC H3G 1Y6, Canada; Microbiome and Disease Tolerance Centre, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Condotta
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.
authors.forename: Radia M
authors.initials: RM
authors.lastname: Johnson
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Bozena
authors.initials: B
authors.lastname: Samborska
authors.affiliation: Raze Therapeutics, 400 Technology Square, 10th Floor, Cambridge, MA 02139, USA.
authors.forename: Nello
authors.initials: N
authors.lastname: Mainolfi
authors.affiliation: Raze Therapeutics, 400 Technology Square, 10th Floor, Cambridge, MA 02139, USA.
authors.forename: Vipin
authors.initials: V
authors.lastname: Suri
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Hannah
authors.initials: H
authors.lastname: Guak
authors.affiliation: Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Balmer
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Verway
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Raissi
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Harmony
authors.initials: H
authors.lastname: Tsui
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Giselle
authors.initials: G
authors.lastname: Boukhaled
authors.affiliation: MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK.
authors.forename: Sofia
authors.initials: S
authors.lastname: Henriques da Costa
authors.affiliation: MRC Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Frezza
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Connie M
authors.initials: CM
authors.lastname: Krawczyk
authors.affiliation: Raze Therapeutics, 400 Technology Square, 10th Floor, Cambridge, MA 02139, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Friedman
authors.affiliation: Raze Therapeutics, 400 Technology Square, 10th Floor, Cambridge, MA 02139, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Manfredi
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, QC H3G 1Y6, Canada; Microbiome and Disease Tolerance Centre, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Richer
authors.affiliation: Department of Biomedicine, Immunobiology, University of Basel, 4031 Basel, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hess
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada. Electronic address: russell.jones@mcgill.ca.
authors.forename: Russell G
authors.initials: RG
authors.lastname: Jones
mesh_terms: D000818:Animals; D002244:Carbon / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D004032:Diet; D004734:Energy Metabolism; D005110:Extracellular Space / Q000378:metabolism; D005998:Glycine; D008089:Listeria monocytogenes / Q000276:immunology; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D008810:Mice, Inbred C57BL; D011685:Purine Nucleotides / Q000096:biosynthesis; D012694:Serine / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*
chemical_list: D011685:Purine Nucleotides; D012694:Serine; D002244:Carbon; D005998:Glycine
keywords: Phgdh; Shmt; T cell; glycolysis; immunometabolism; immunotherapy; metabolic reprogramming; metabolism; serine; serine biosynthesis