Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation

Nat Immunol. 2013 May;14(5):500-8. doi: 10.1038/ni.2556. Epub 2013 Mar 24.


T lymphocytes must regulate nutrient uptake to meet the metabolic demands of an immune response. Here we show that the intracellular supply of large neutral amino acids (LNAAs) in T cells was regulated by pathogens and the T cell antigen receptor (TCR). T cells responded to antigen by upregulating expression of many amino-acid transporters, but a single System L ('leucine-preferring system') transporter, Slc7a5, mediated uptake of LNAAs in activated T cells. Slc7a5-null T cells were unable to metabolically reprogram in response to antigen and did not undergo clonal expansion or effector differentiation. The metabolic catastrophe caused by loss of Slc7a5 reflected the requirement for sustained uptake of the LNAA leucine for activation of the serine-threonine kinase complex mTORC1 and for expression of the transcription factor c-Myc. Control of expression of the System L transporter by pathogens is thus a critical metabolic checkpoint for T cells.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids, Neutral / metabolism*
  • Animals
  • Cell Differentiation / genetics
  • Cell Proliferation
  • Cytotoxicity, Immunologic
  • Interferon-gamma / metabolism
  • Interleukin-2 / metabolism
  • Large Neutral Amino Acid-Transporter 1 / genetics
  • Large Neutral Amino Acid-Transporter 1 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Protein Transport
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism
  • T-Lymphocytes, Cytotoxic / immunology*
  • Up-Regulation


  • Amino Acids, Neutral
  • Interleukin-2
  • Large Neutral Amino Acid-Transporter 1
  • Receptors, Antigen, T-Cell, alpha-beta
  • Interferon-gamma

Associated data

  • GEO/GSE33942