Abstract
Homeostasis of the immune system depends on the proper function of regulatory T cells (T(reg) cells). Compromised suppressive activity of T(reg) cells leads to autoimmune disease and graft rejection and promotes anti-tumor immunity. Here we report a previously unrecognized requirement for the serine-threonine phosphatase PP2A in the function of T(reg) cells. T(reg) cells exhibited high PP2A activity, and T(reg) cell-specific ablation of the PP2A complex resulted in a severe, multi-organ, lymphoproliferative autoimmune disorder. Mass spectrometry revealed that PP2A associated with components of the mTOR metabolic-checkpoint kinase pathway and suppressed the activity of the mTORC1 complex. In the absence of PP2A, T(reg) cells altered their metabolic and cytokine profile and were unable to suppress effector immune responses. Therefore, PP2A is required for the function of T(reg) cells and the prevention of autoimmunity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autoimmune Diseases / genetics
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Autoimmune Diseases / immunology*
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Autoimmune Diseases / metabolism
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Autoimmunity / genetics
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Autoimmunity / immunology
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Cells, Cultured
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Ceramides / immunology
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Ceramides / metabolism
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Female
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Flow Cytometry
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Humans
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Immunoblotting
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Jurkat Cells
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Lymphoproliferative Disorders / genetics
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Lymphoproliferative Disorders / immunology*
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Lymphoproliferative Disorders / metabolism
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Male
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Mechanistic Target of Rapamycin Complex 1
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Multiprotein Complexes / immunology
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Multiprotein Complexes / metabolism
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Phosphorylation / immunology
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Protein Phosphatase 2 / genetics
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Protein Phosphatase 2 / immunology*
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Protein Phosphatase 2 / metabolism
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Signal Transduction / genetics
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Signal Transduction / immunology
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism
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TOR Serine-Threonine Kinases / immunology
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TOR Serine-Threonine Kinases / metabolism
Substances
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Ceramides
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Multiprotein Complexes
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases
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Protein Phosphatase 2