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

Nature Immunology volume 14, pages 500–508 (2013)Cite this article

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A Corrigendum to this article was published on 18 December 2013

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Abstract

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.

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Figure 1: Transport of amino acid by System L transporter in CD8+ T cells.
Figure 2: Amino acids and mTORC1 in CD8+ T cells.
Figure 3: Regulation of System L amino-acid transporters in T cells.
Figure 4: Characterization of Slc7a5fl/flCD4-Cre mice.
Figure 5: Effector differentiation of Slc7a5fl/flCD4-Cre T cells.
Figure 6: Activation and proliferation of Slc7a5fl/flCD4-Cre T cells.
Figure 7: Metabolic consequences of the deletion of Slc7a5 in T cells.

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Change history

  • 25 June 2013

    In the version of this article initially published, the legend for Figure 7b incorrectly included mutant cells. The correct legend should read "...OT-I lymph node T cells...." The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank G. Holman (University of Bath) for anti-Glut1; H. Shen (University of Pennsylvania) for L. monocytogenes; L. Chen for help in the initial characterization of amino-acid transporters expressed by CTLs; members of the Biological Services Unit; R. Clarke of the Flow Cytometry Facility; and members of the D.A.C. laboratory and S. Arthur for critical reading of the manuscript. Supported by the Wellcome Trust (065975/Z/01/A and 097418/Z/11Z to D.A.C., and WT094226 to P.M.T.) and the Intramural Research Program of the National Institute Child Health and Human Development of the US National Institutes of Health.

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Authors and Affiliations

  1. Division of Cell Signalling and Immunology, University of Dundee, Dundee, UK

    Linda V Sinclair, Julia Rolf, Elizabeth Emslie, Peter M Taylor & Doreen A Cantrell

  2. Program in Cellular Regulation and Metabolism, Eunice Kennedy Shriver National Institute Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

    Yun-Bo Shi

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Contributions

L.V.S., all in vitro and most in vivo experiments; J.R., in vivo immunization with NP-OVA and infection with L. monocytogenes; E.E., genomic PCR analysis of Slc7a5fl/flCD4-Cre mice; Y.-B.S., generation of Slc7a5fl/fl mice; P.M.T., conceptual design; and D.A.C., conceptual design and manuscript authorship.

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Correspondence to Doreen A Cantrell.

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Sinclair, L., Rolf, J., Emslie, E. et al. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol 14, 500–508 (2013). https://doi.org/10.1038/ni.2556

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