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Cell Rep. 2019 Sep 17;28(12):3011-3021.e4. doi: 10.1016/j.celrep.2019.08.034.

T Cell Activation Depends on Extracellular Alanine.

Author information

1
Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address: nogaronharel@technion.ac.il.
2
The Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
3
Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
4
Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
5
Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Pharmacology Research Department, Teijin Institute for Bio-Medical Research, Teijin Pharma Limited, Tokyo 1918512, Japan.
6
Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: Arlene_Sharpe@hms.harvard.edu.
7
The Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA. Electronic address: joshr@Princeton.EDU.
8
Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address: marcia_haigis@hms.harvard.edu.

Abstract

T cell stimulation is metabolically demanding. To exit quiescence, T cells rely on environmental nutrients, including glucose and the amino acids glutamine, leucine, serine, and arginine. The expression of transporters for these nutrients is tightly regulated and required for T cell activation. In contrast to these amino acids, which are essential or require multi-step biosynthesis, alanine can be made from pyruvate by a single transamination. Here, we show that extracellular alanine is nevertheless required for efficient exit from quiescence during naive T cell activation and memory T cell restimulation. Alanine deprivation leads to metabolic and functional impairments. Mechanistically, this vulnerability reflects the low expression of alanine aminotransferase, the enzyme required for interconverting pyruvate and alanine, whereas activated T cells instead induce alanine transporters. Stable isotope tracing reveals that alanine is not catabolized but instead supports protein synthesis. Thus, T cells depend on exogenous alanine for protein synthesis and normal activation.

KEYWORDS:

T cell activation; T cells; alanine; metabolism; protein synthesis

PMID:
31533027
DOI:
10.1016/j.celrep.2019.08.034
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