title: Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation.
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.
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX 77030, USA.
authors.forename: Mako
authors.initials: M
authors.lastname: Nakaya
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX 77030, USA.
authors.forename: Yichuan
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX 77030, USA.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX 77030, USA; College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Chang
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX 77030, USA.
authors.forename: Mikyoung
authors.initials: M
authors.lastname: Chang
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX 77030, USA.
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX 77030, USA.
authors.forename: Marzenna
authors.initials: M
authors.lastname: Blonska
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA. Electronic address: ssun@mdanderson.org.
authors.forename: Shao-Cong
authors.initials: SC
authors.lastname: Sun
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D019264:Adoptive Transfer; D026962:Amino Acid Transport System ASC / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D001692:Biological Transport; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D004789:Enzyme Activation / Q000276:immunology; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis; D019169:Jurkat Cells; D007930:Leucine / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D046912:Multiprotein Complexes / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D026962:Amino Acid Transport System ASC; D000074018:B-Cell CLL-Lymphoma 10 Protein; C488088:Bcl10 protein, mouse; D053468:CARD Signaling Adaptor Proteins; D018106:CD28 Antigens; C496467:Card11 protein, mouse; D007376:Interleukin-2; D015778:Minor Histocompatibility Antigens; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; C498850:Slc1a5 protein, mouse; D005973:Glutamine; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D007930:Leucine