Cited by 229T-cell and B-cell ImmunologyPsoriasis: Treatment and PathogenesisIL-33, ST2, and ILC Pathways

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Metabolic heterogeneity underlies reciprocal fates of TH17 cell stemness and plasticity

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Karmaus, Peer W. F., Chen, Xiang, Lim, Seon Ah, Herrada, Andrés A., Nguyen, Thanh-Long M., Xu, Beisi, Dhungana, Yogesh, Rankin, Sherri, Chen, Wenan, Rosencrance, Celeste, Yang, Kai, Fan, Yiping, Cheng, Yong, Easton, John, Neale, Geoffrey, Vogel, Peter, Chi, Hongbo·2019·Nature

DOI 10.1038/s41586-018-0806-7PMC PMC6420879

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Abstract

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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Background
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Background
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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: Karmaus, Peer W. F.
Chen, Xiang
Lim, Seon Ah
Herrada, Andrés A.
Xu, Beisi
Dhungana, Yogesh
Chen, Wenan
Rosencrance, Celeste
Yang, Kai
Fan, Yiping
Cheng, Yong
Easton, John
Neale, Geoffrey
Vogel, Peter
Chi, Hongbo
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2018-12-19
Volume: 565
Issue: 7737
Pages: 101-105
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-018-0806-7
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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Metabolic heterogeneity underlies reciprocal fates of TH17 cell stemness and plasticity

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