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Functional reprogramming of regulatory T cells in the absence of Foxp3
Open accessAbstract
Regulatory T cells (T reg cells) deficient in the transcription factor Foxp3 lack suppressor function and manifest an effector T (T eff) cell-like phenotype. We demonstrate that Foxp3 deficiency dysregulates metabolic checkpoint kinase mammalian target of rapamycin (mTOR) complex 2 (mTORC2) signaling and gives rise to augmented aerobic glycolysis and oxidative phosphorylation. Specific deletion of the mTORC2 adaptor gene Rictor in Foxp3-deficient T reg cells ameliorated disease in a Foxo1 transcription factor-dependent manner. Rictor deficiency re-established a subset of T reg cell genetic circuits and suppressed the T eff cell-like glycolytic and respiratory programs, which contributed to immune dysregulation. Treatment of T reg cells from patients with FOXP3 deficiency with mTOR inhibitors similarly antagonized their T eff cell-like program and restored suppressive function. Thus, regulatory function can be re-established in Foxp3-deficient T reg cells by targeting their metabolic pathways, providing opportunities to restore tolerance in T reg cell disorders.
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“AKT/mTOR/HIF1α signaling has been suggested to play critical roles in promoting glycolysis and lactate production and thus in the “metabolic reprogramming” of cancer cells24–28.”
From RETRACTED ARTICLE: Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression (2020) · cites this paper as [26]
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Metadata
- Authors
- Charbonnier, L.-M., Cui, Y., Stephen-Victor, E., Harb, H., Lopez, D., Bleesing, J. J., Garcia-Lloret, M. I., Chen, K., Ozen, A., Carmeliet, P., Li, M. O., Pellegrini, M., & Chatila, T. A.
- Affiliations
- Boston Children's Hospital (US)
- University of California, Los Angeles (US)
- Cincinnati Children's Hospital Medical Center (US)
- University of Utah (US)
- Marmara University (TR)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Chatila, Talal A.
- ORCID
- Venue
- Nature Immunology
- Published
- 2019-08-05
- Volume
- 20
- Issue
- 9
- Pages
- 1208-1219
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC6707855
- OpenAlex
- W2966678440
- Cited by
- 145
- References
- 55
- Citations by year
- 2026: 14 · 2025: 12 · 2024: 14 · 2023: 16 · 2022: 26 · 2021: 24 · 2020: 32 · 2019: 7
- FWCI
- 8.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Dspace Repository (Marmara Üniversitesi) (submittedVersion, other-oa)
- Lirias (KU Leuven) (submittedVersion)
- Dspace Repository (Marmara Üniversitesi) (submittedVersion)
- Funders
- National Institutes of Health (5r01ai085090-10)
- National Cancer Institute (P30CA008748, P30CA016042)
- National Institute of Allergy and Infectious Diseases (R01-AI-085090, R01AI102888, R01AI065617)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK034854)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Keywords
- regulatory T cells, mTORC2 signaling, Rictor, aerobic glycolysis, oxidative phosphorylation, FOXO1, mTOR inhibitors, immune tolerance, immune dysregulation
- MeSH terms
- Mechanistic Target of Rapamycin Complex 2, Rapamycin-Insensitive Companion of mTOR Protein, Animals, Cells, Cultured, Female, Gene Expression Regulation, Glycolysis, Humans, Male, Mice, Inbred C57BL, Oxidative Phosphorylation, Signal Transduction, Mice, Knockout, T-Lymphocytes, Regulatory, Mice, Forkhead Transcription Factors, Cellular Reprogramming
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