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Metabolic heterogeneity underlies reciprocal fates of TH17 cell stemness and plasticity
Open accessAbstract
A defining feature of adaptive immunity is the development of long-lived memory T cells to curtail infection. Recent studies have identified a unique stem-like T-cell subset amongst exhausted CD8-positive T cells in chronic infection1–3, but it remains unclear whether CD4-positive T-cell subsets with similar features exist in chronic inflammatory conditions. Amongst helper T cells, TH17 cells have prominent roles in autoimmunity and tissue inflammation and are characterized by inherent plasticity4–7, although how such plasticity is regulated is poorly understood. Here we demonstrate that TH17 cells in a mouse model of autoimmune disease are functionally and metabolically heterogeneous; they contain a subset with stemness-associated features but lower anabolic metabolism, and a reciprocal subset with higher metabolic activity that supports transdifferentiation into TH1-like cells. These two TH17-cell subsets are defined by selective expression of the transcription factors TCF-1 and T-bet, and by discrete levels of CD27 expression. We also identify signalling via the kinase complex mTORC1 as a central regulator of TH17-cell fate decisions by coordinating metabolic and transcriptional programmes. TH17 cells with disrupted mTORC1 signalling or anabolic metabolism fail to induce autoimmune neuroinflammation or to develop into TH1-like cells, but instead upregulate TCF-1 expression and acquire stemness-associated features. Single-cell RNA sequencing and experimental validation reveal heterogeneity in fate-mapped TH17 cells, and a developmental arrest in the TH1 transdifferentiation trajectory upon loss of mTORC1 activity or metabolic perturbation. Our results establish that the dichotomy of stemness and effector function underlies the heterogeneous TH17 responses and autoimmune pathogenesis, and point to previously unappreciated metabolic control of plasticity in helper T cells. Phenotypically, transcriptionally and metabolically diverse subsets of TH17 cells develop in a chronic autoimmune disease: one subset has inferred stemness features and low anabolic metabolism, while a reciprocal subset has higher metabolic activity that supports transdifferentiation into TH1 cells.
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“the non-pathogenic/homeostatic and pathogenic Th17 cell phenotypes studied in the mouse models may mirror the physiological roles of human Th17 cell subsets that are important for immunity against distinct bacteria and fungi”
From TH17 cell heterogeneity and its role in tissue inflammation (2023) · cites this paper as [64]
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“These stem-like T cells give rise to diverse pathogenic subsets depending on the context, including T H 17 cells in encephalomyelitis (73, 74), ulcerative colitis (77), and arthritis (78); T FH cells and cytotoxic CD4 + T cells in vasculitis (76); and cytotoxic CD8 + T cells in type 1 diabetes (75)…”
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Metadata
- Authors
- Karmaus, P. W. F., Chen, X., Lim, S. A., Herrada, A. A., Nguyen, T.-L. M., Xu, B., Dhungana, Y., Rankin, S., Chen, W., Rosencrance, C., Yang, K., Fan, Y., Cheng, Y., Easton, J., Neale, G., Vogel, P., & Chi, H.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Chi, Hongbo
- ORCID
- Venue
- Nature
- Published
- 2018-12-19
- Volume
- 565
- Issue
- 7737
- Pages
- 101-105
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6420879
- OpenAlex
- W2905426112
- Semantic Scholar
- ebe01d7ca54b23c200f359ee77ec3f9d963ffe99
- Cited by
- 215
- References
- 42
- Citations by year
- 2026: 18 · 2025: 30 · 2024: 37 · 2023: 24 · 2022: 21 · 2021: 32 · 2020: 35 · 2019: 17
- FWCI
- 9.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- St. Jude Children's Research Hospital
- National Institutes of Health
- National Cancer Institute (R01CA176624, R01CA221290, P30CA021765)
- National Institute of Allergy and Infectious Diseases (R01AI101407, R01AI105887, R01AI140761, R01AI131703, R37AI105887)
- National Institute of Neurological Disorders and Stroke (R01NS064599)
- 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 › IL-33, ST2, and ILC Pathways
- Keywords
- Th17 cells, T cell stemness, T cell plasticity, mTORC1 signaling, TCF1, T-bet, CD27, anabolic metabolism, autoimmune neuroinflammation, chronic autoimmune disease, single-cell RNA sequencing
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Regulatory-Associated Protein of mTOR, T-bet Transcription Factor, Animals, Autoimmune Diseases, Disease Models, Animal, Female, Immunologic Memory, Inflammation, Male, Stem Cells, Signal Transduction, Sequence Analysis, RNA, Tumor Necrosis Factor Receptor Superfamily, Member 7, T-Box Domain Proteins, Mice, T Cell Transcription Factor 1, Cell Transdifferentiation, Th17 Cells, Single-Cell Analysis
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