T Cell Activation Depends on Extracellular Alanine

Noga Ron-Harel, Jonathan M. Ghergurovich, Giulia Notarangelo, Martin W. LaFleur, Yoshiki Tsubosaka, Arlene H. Sharpe, Joshua D. Rabinowitz, Marcia C. Haigis

Research output: Contribution to journalArticlepeer-review

104 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3011-3021.e4
JournalCell Reports
Issue number12
StatePublished - Sep 17 2019

All Science Journal Classification (ASJC) codes

  • General Biochemistry, Genetics and Molecular Biology


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


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