Nature immunology, 2019-09, Vol.20 (9), p.1208-1219
2019
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Details
- Autor(en) / Beteiligte
- Titel
- Functional reprogramming of regulatory T cells in the absence of Foxp3
- Ist Teil von
- Nature immunology, 2019-09, Vol.20 (9), p.1208-1219
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Regulatory T cells (T cells) deficient in the transcription factor Foxp3 lack suppressor function and manifest an effector T (T ) 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 cells ameliorated disease in a Foxo1 transcription factor-dependent manner. Rictor deficiency re-established a subset of T cell genetic circuits and suppressed the T cell-like glycolytic and respiratory programs, which contributed to immune dysregulation. Treatment of T cells from patients with FOXP3 deficiency with mTOR inhibitors similarly antagonized their T cell-like program and restored suppressive function. Thus, regulatory function can be re-established in Foxp3-deficient T cells by targeting their metabolic pathways, providing opportunities to restore tolerance in T cell disorders.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1529-2908eISSN: 1529-2916DOI: 10.1038/s41590-019-0442-xTitel-ID: cdi_pubmed_primary_31384057
- Format
- –
- Schlagworte
- Animals, Cells, Cultured, Cellular Reprogramming - immunology, Female, Forkhead Transcription Factors - genetics, Gene Expression Regulation, Glycolysis - physiology, Humans, Male, Mechanistic Target of Rapamycin Complex 2 - antagonists & inhibitors, Mechanistic Target of Rapamycin Complex 2 - metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Oxidative Phosphorylation, Rapamycin-Insensitive Companion of mTOR Protein - genetics, Signal Transduction, T-Lymphocytes, Regulatory - cytology, T-Lymphocytes, Regulatory - immunology