Phosphatase PP2A is requisite for the function of regulatory T cells
Open accessAbstract
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.
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Aα-deficient regulatory T-cells showed increased proliferation and an altered metabolic profile, characterized by higher glycolytic and oxidative-phosphorylation rates.
“Aα-deficient T reg cells showed increased proliferation and an altered metabolic profile, characterized by higher glycolytic and oxidative-phosphorylation rates.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [81]
This was accompanied by an increased number of activated CD4+ and CD8+ T-cells and increased production of several cytokines in these cells.
“This was accompanied by an increased number of activated CD4 + and CD8 + T-cells, and increased production of several cytokines in these cells [81].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [81]
Biochemically, this was associated with upregulated mTORC1 activity and increased S6 phosphorylation, while AKT activity was unaltered.
“Biochemically, this was associated with upregulated mTORC1 activity and increased S6 phosphorylation, while AKT activity was unaltered.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [81]
Regulatory T-cell-specific knockout of the Aα subunit caused severe, progressive, multi-organ autoimmunity and a lymphoproliferative disorder.
“A severe, progressive, multi-organ autoimmunity and lymphoproliferative disorder was also observed in regulatory T-cell (T reg )-specific KO mice of the Aα subunit [81].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [81]
Addition of the mTORC1 inhibitor rapamycin normalized the regulatory T-cell phenotypes.
“Addition of the mTORC1 inhibitor rapamycin normalized the T reg phenotypes [81].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [81]
By 10-14 weeks, these mice showed dermatitis, scaly tails and ears, eyelid crusting, skin rash, ulcerations, extensive inflammatory and lymphocytic infiltrates in multiple organs, and enlarged secondary lymphoid organs.
“By 10-14 weeks, these mice showed dermatitis, scaly tails and ears, eyelid crusting, skin rash, ulcerations, extensive inflammatory and lymphocytic infiltrates in multiple organs, and enlarged secondary lymphoid organs.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [81]
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References 57 · Cited by 238
- Authors
- Apostolidis, S. A., Rodríguez-Rodríguez, N., Suárez-Fueyo, A., Dioufa, N., Ozcan, E., Crispín, J. C., Tsokos, M. G., & Tsokos, G. C.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Tsokos, George C
- Venue
- Nature Immunology
- Published
- 2016-03-14
- Volume
- 17
- Issue
- 5
- Pages
- 556-564
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC4837024
- OpenAlex
- W2301336892
- Cited by
- 238
- References
- 57
- Citations by year
- 2026: 13 · 2025: 17 · 2024: 22 · 2023: 19 · 2022: 24 · 2021: 37 · 2020: 26 · 2019: 24 · 2018: 26 · 2017: 24 · 2016: 6
- FWCI
- 16.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI068787)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- protein phosphatase 2A, regulatory T cells, mTORC1, ceramide, Foxp3, autoimmunity, immune homeostasis, suppressive function, lymphoproliferative disorders, cytokine profile
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Autoimmune Diseases, Cells, Cultured, Ceramides, Female, Flow Cytometry, Humans, Lymphoproliferative Disorders, Male, Mice, Inbred C57BL, Mice, Transgenic, Phosphorylation, Immunoblotting, Signal Transduction, Autoimmunity, Mice, Knockout, Jurkat Cells, Multiprotein Complexes, T-Lymphocytes, Regulatory, Protein Phosphatase 2, TOR Serine-Threonine Kinases
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