T Cells Encountering Myeloid Cells Programmed for Amino Acid-dependent Immunosuppression Use Rictor/mTORC2 Protein for Proliferative Checkpoint Decisions
| Autor: | Thomas A. Wynn, Joseph E. Qualls, Charles O. Rock, Luke Barron, Suzanne Jackowski, Geoffrey Neale, Peter J. Murray, Adolfo Alfonso-Pecchio, Lee-Ann Van de Velde, Chitra Subramanian, Amber M. Smith |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cell cycle checkpoint Arginine T-Lymphocytes T cell Immunology Mechanistic Target of Rapamycin Complex 2 mTORC1 Biology Lymphocyte Activation Biochemistry 03 medical and health sciences Interleukin 21 Immune Tolerance medicine Animals Cytotoxic T cell Myeloid Cells IL-2 receptor Molecular Biology Cells Cultured Cell Proliferation Interleukin 3 Immunosuppression Therapy Mice Knockout Mice Inbred BALB C TOR Serine-Threonine Kinases Cell Cycle Checkpoints Cell Biology Coculture Techniques Cell biology Mice Inbred C57BL Rapamycin-Insensitive Companion of mTOR Protein 030104 developmental biology medicine.anatomical_structure Multiprotein Complexes Carrier Proteins Proto-Oncogene Proteins c-akt |
| Zdroj: | Journal of Biological Chemistry. 292:15-30 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m116.766238 |
| Popis: | 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 G1 block. 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. |
| Databáze: | OpenAIRE |
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