Abstract
Glutamine has been implicated as an immunomodulatory nutrient, but how glutamine uptake is mediated during T cell activation is poorly understood. We have shown that naive T cell activation is coupled with rapid glutamine uptake, which depended on the amino acid transporter ASCT2. ASCT2 deficiency impaired the induction of T helper 1 (Th1) and Th17 cells and attenuated inflammatory T cell responses in mouse models of immunity and autoimmunity. Mechanistically, ASCT2 was required for T cell receptor (TCR)-stimulated activation of the metabolic kinase mTORC1. We have further shown that TCR-stimulated glutamine uptake and mTORC1 activation also required a TCR signaling complex composed of the scaffold protein CARMA1, the adaptor molecule BCL10, and the paracaspase MALT1. This function was independent of IKK kinase, a major downstream target of the CARMA1 complex. These findings highlight a mechanism of T cell activation involving ASCT2-dependent integration of the TCR signal and a metabolic signaling pathway.
Copyright © 2014 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Adoptive Transfer
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Amino Acid Transport System ASC / genetics
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Amino Acid Transport System ASC / immunology*
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Amino Acid Transport System ASC / metabolism
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Animals
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B-Cell CLL-Lymphoma 10 Protein
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Biological Transport
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CARD Signaling Adaptor Proteins / metabolism
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CD28 Antigens / immunology
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Caspases / metabolism
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Cell Differentiation / immunology
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Enzyme Activation / immunology
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Glutamine / metabolism*
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Humans
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Inflammation / immunology
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Interleukin-2 / biosynthesis
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Jurkat Cells
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Leucine / metabolism
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Lymphocyte Activation / immunology
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Minor Histocompatibility Antigens
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
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Multiprotein Complexes / metabolism*
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Neoplasm Proteins / metabolism
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Receptors, Antigen, T-Cell / immunology*
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Signal Transduction / immunology
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TOR Serine-Threonine Kinases / metabolism*
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Th1 Cells / immunology
Substances
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Adaptor Proteins, Signal Transducing
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Amino Acid Transport System ASC
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B-Cell CLL-Lymphoma 10 Protein
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Bcl10 protein, mouse
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CARD Signaling Adaptor Proteins
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CD28 Antigens
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Card11 protein, mouse
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Interleukin-2
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Minor Histocompatibility Antigens
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Multiprotein Complexes
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Neoplasm Proteins
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Receptors, Antigen, T-Cell
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Slc1a5 protein, mouse
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Glutamine
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases
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Caspases
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Malt1 protein, mouse
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Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
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Leucine