Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation

Immunity. 2014 May 15;40(5):692-705. doi: 10.1016/j.immuni.2014.04.007. Epub 2014 May 1.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adoptive Transfer
  • Amino Acid Transport System ASC / genetics
  • Amino Acid Transport System ASC / immunology*
  • Amino Acid Transport System ASC / metabolism
  • Animals
  • B-Cell CLL-Lymphoma 10 Protein
  • Biological Transport
  • CARD Signaling Adaptor Proteins / metabolism
  • CD28 Antigens / immunology
  • Caspases / metabolism
  • Cell Differentiation / immunology
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Enzyme Activation / immunology
  • Glutamine / metabolism*
  • Humans
  • Inflammation / immunology
  • Interleukin-2 / biosynthesis
  • Jurkat Cells
  • Leucine / metabolism
  • Lymphocyte Activation / immunology
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Minor Histocompatibility Antigens
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • Multiprotein Complexes / metabolism*
  • Neoplasm Proteins / metabolism
  • Receptors, Antigen, T-Cell / immunology*
  • Signal Transduction / immunology
  • TOR Serine-Threonine Kinases / metabolism*
  • Th1 Cells / immunology

Substances

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Transport System ASC
  • B-Cell CLL-Lymphoma 10 Protein
  • Bcl10 protein, mouse
  • CARD Signaling Adaptor Proteins
  • CD28 Antigens
  • Card11 protein, mouse
  • Interleukin-2
  • Minor Histocompatibility Antigens
  • Multiprotein Complexes
  • Neoplasm Proteins
  • Receptors, Antigen, T-Cell
  • Slc1a5 protein, mouse
  • Glutamine
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Caspases
  • Malt1 protein, mouse
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • Leucine