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

Linda V Sinclair, Julia Rolf, Elizabeth Emslie, Yun-Bo Shi, Peter M Taylor, Doreen A Cantrell (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    300 Citations (Scopus)

    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.
    Original languageEnglish
    Pages (from-to)500-508
    Number of pages9
    JournalNature Immunology
    Volume14
    Issue number5
    DOIs
    Publication statusPublished - May 2013

    Fingerprint

    Antigen Receptors
    Cell Differentiation
    Neutral Amino Acids
    T-Lymphocytes
    Amino Acids
    Leucine
    Amino Acid Transport System L
    Amino Acid Transport Systems
    Antigens
    Null Lymphocytes
    Protein-Serine-Threonine Kinases
    T-Cell Antigen Receptor
    Transcription Factors

    Keywords

    • LYMPHOCYTE ACTIVATION
    • GENERATION
    • GENE-EXPRESSION
    • MEMORY
    • MTOR
    • MAMMALIAN TARGET
    • KINASE
    • IN-VIVO
    • TRANSFER-RNA SYNTHETASE
    • 4F2 HEAVY-CHAIN

    Cite this

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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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    author = "Sinclair, {Linda V} and Julia Rolf and Elizabeth Emslie and Yun-Bo Shi and Taylor, {Peter M} and Cantrell, {Doreen A}",
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    T1 - Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation

    AU - Sinclair, Linda V

    AU - Rolf, Julia

    AU - Emslie, Elizabeth

    AU - Shi, Yun-Bo

    AU - Taylor, Peter M

    AU - Cantrell, Doreen A

    PY - 2013/5

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    N2 - 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.

    AB - 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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    KW - GENERATION

    KW - GENE-EXPRESSION

    KW - MEMORY

    KW - MTOR

    KW - MAMMALIAN TARGET

    KW - KINASE

    KW - IN-VIVO

    KW - TRANSFER-RNA SYNTHETASE

    KW - 4F2 HEAVY-CHAIN

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    JF - Nature Immunology

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