title: T Cells Encountering Myeloid Cells Programmed for Amino Acid-dependent Immunosuppression Use Rictor/mTORC2 Protein for Proliferative Checkpoint Decisions.
abstract: Modulation of T cell proliferation and function by immunoregulatory myeloid cells are an essential means of preventing self-reactivity and restoring tissue homeostasis. Consumption of amino acids such as arginine and tryptophan by immunoregulatory macrophages is one pathway that suppresses local T cell proliferation. Using a reduced complexity in vitro macrophage-T cell co-culture system, we show that macrophage arginase-1 is the only factor required by M2 macrophages to block T cells in G1, and this effect is mediated by l-arginine elimination rather than metabolite generation. Tracking how T cells adjust their metabolism when deprived of arginine revealed the significance of macrophage-mediated arginine deprivation to T cells. We found mTORC1 activity was unaffected in the initial G1block. After 2 days of arginine deprivation, mTORC1 activity declined paralleling a selective down-regulation of SREBP target gene expression, whereas mRNAs involved in glycolysis, gluconeogenesis, and T cell activation were unaffected. Cell cycle arrest was reversible at any point by exogenous arginine, suggesting starved T cells remain poised awaiting nutrients. Arginine deprivation-induced cell cycle arrest was mediated in part by Rictor/mTORC2, providing evidence that this nutrient recognition pathway is a central component of how T cells measure environmental arginine.
authors.affiliation: From the Departments of Infectious Diseases.|Immunology, and.
authors.forename: Lee-Ann
authors.initials: LA
authors.lastname: Van de Velde
authors.affiliation: From the Departments of Infectious Diseases.
authors.forename: Chitra
authors.initials: C
authors.lastname: Subramanian
authors.affiliation: From the Departments of Infectious Diseases.|Immunology, and.
authors.forename: Amber M
authors.initials: AM
authors.lastname: Smith
authors.affiliation: the Laboratory of Parasitic Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Luke
authors.initials: L
authors.lastname: Barron
authors.affiliation: From the Departments of Infectious Diseases.|Immunology, and.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Qualls
authors.affiliation: Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105 and.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.affiliation: From the Departments of Infectious Diseases.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Alfonso-Pecchio
authors.affiliation: From the Departments of Infectious Diseases.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jackowski
authors.affiliation: From the Departments of Infectious Diseases.
authors.forename: Charles O
authors.initials: CO
authors.lastname: Rock
authors.affiliation: the Laboratory of Parasitic Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wynn
authors.affiliation: From the Departments of Infectious Diseases, peter.murray@stjude.org.|Immunology, and.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Murray
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D008213:Lymphocyte Activation; D000076225:Mechanistic Target of Rapamycin Complex 2; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D046912:Multiprotein Complexes; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C525637:rictor protein, mouse; D001120:Arginine; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: T cell; T helper cells; amino acid; arginine; cellular immune response; immune response; immunosuppression; mTOR complex (mTORC); macrophage