T Cell Activation Depends on Extracellular Alanine

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alanine / pharmacology*
  • Animals
  • Immunologic Memory / drug effects*
  • Lymphocyte Activation / drug effects*
  • Mice
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*

Substances

  • Alanine