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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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BackgroundLipid metabolism in homeostasis and disease
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“Phenotypically, the mTORC1 positive TH17 subset can be distinguished by a lack of CD27 expression [53] whereas CD27 positive TH17 cells are associated with a memorylike transcriptome, express low levels of mTORC1 and are capable to proliferate and turn into CD27 negative TH17 cells.”
Doss, P. M. I. A., Umair, M., Baillargeon, J., Fazazi, R., Fudge, N., Akbar, I., Yeola, A. P., Williams, J. B., Leclercq, M., Joly-Beauparlant, C., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.108833 · Cited by 39
Stem-like T cells are associated with the pathogenesis of ulcerative colitis in humans
Li, Y., Ramírez-Suástegui, C., Harris, R. J., Castañeda-Castro, F. E., Ascui, G., Pérez-Jeldres, T., Diaz, A., Morong, C., Giles, D. A., Chai, J. N., et al. (2024) · Nature Immunology · doi:10.1038/s41590-024-01860-7 · Cited by 39
“…in animal models of autoimmune disease describe the existence of a stem-like T cell population that exhibits resistance to exhaustion, and importantly, this progenitor population sustains the pool of short-lived proinflammatory effector T cells that drive autoimmune inflammation 10–13 , 16 .”
InfluentialTonic interferon restricts pathogenic IL-17-driven inflammatory disease via balancing the microbiome
Marié, I. J., Brambilla, L., Azzouz, D. F., Chen, Z., Baracho, G. V., Arnett, A., Li, H. S., Liu, W., Cimmino, L., Chattopadhyay, P. K., et al. (2021) · eLife · doi:10.7554/elife.68371 · Cited by 34
Metabolic rewiring: a new master of Th17 cell plasticity and heterogeneity
Papadopoulou, G., & Xanthou, G. (2021) · FEBS Journal · doi:10.1111/febs.15853 · Cited by 39
Fu, S., Chien, M., Hsu, C.-Y., Liu, Y., & Sytwu, H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093379 · Cited by 35
The Ups and Downs of Metabolism during the Lifespan of a T Cell
Balyan, R., Gautam, N., & Gascoigne, N. R. J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21217972 · Cited by 36
Mangani, D., Subramanian, A., Huang, L., Cheng, H., Krovi, S. H., Wu, Y., Yang, D., Moreira, T. G., Escobar, G., Schnell, A., et al. (2024) · Immunity · doi:10.1016/j.immuni.2024.09.017 · Cited by 35
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RORα is critical for mTORC1 activity in T cell-mediated colitis
Chi, X., Jin, W., Bai, X., Zhao, X., Shao, J., Li, J., Sun, Q., Su, B., Wang, X., Yang, X. O., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109682 · Cited by 33
Functional heterogeneity of CD4+ T cells in liver inflammation
Muscate, F., Woestemeier, A., & Gagliani, N. (2021) · Seminars in Immunopathology · doi:10.1007/s00281-021-00881-w · Cited by 32
Qiu, R., Yu, X., Wang, L., Han, Z., Yao, C., Cui, Y., Hou, G., Dai, D., Jin, W., & Shen, N. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.2000060 · Cited by 36
The rapid proximity labeling system PhastID identifies ATP6AP1 as an unconventional GEF for Rheb
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Wang, Y., Liu, M., Zhang, L., Liu, X., Ji, H., Wang, Y., Gui, J., Yan, Y., & Wen, Z. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06336-4 · Cited by 31
Beyond T-cell subsets: stemness and adaptation redefining immunity and immunotherapy
Zou, D., Li, X. C., & Chen, W. (2025) · Cellular and Molecular Immunology · doi:10.1038/s41423-025-01321-7 · Cited by 30
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Metabolic Control of Memory T-Cell Generation and StemnessPreprint
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“CD4+ Tfh stem-cell-like (Lüthje et al. 2012; Hale et al. 2013; Kunzli et al. 2020); CD4+ Th17 stem-cell-like (Muranski et al. 2011; Karmaus et al. 2019); CD8+ Tscm (Gattinoni et al. 2009; Sukumar et al. 2016); CD8+CX3CR1int peripheral memory (Gerlach et al. 2016); CD8+CXCR5+ Tfh-like (He et al.…”
BackgroundInfluentialSelf-citationMeyer, A., Sienes, R. E., Nijim, W., Zanotti, B., Umar, S., Volin, M. V., Raemdonck, K. V., Lewis, M., Pitzalis, C., Arami, S., et al. (2023) · Annals of the Rheumatic Diseases · doi:10.1136/ard-2022-223284 · Cited by 26
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“Driven by key regulators of glycolysis, such as mTOR, pathogenic Th17 cells exhibit increased glycolysis, which may promote proliferation and pro-inflammatory cytokine production by facilitating elevated protein, lipid, and nucleic acid [40].”
BackgroundPolyamines from myeloid-derived suppressor cells promote Th17 polarization and disease progression
Hu, C., Yu, Z., Ma, Z., Zhao, L., Wu, H., Shu, C., Pang, B., Yu, J., Xu, Y., Zhang, X., et al. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.10.013 · Cited by 26
“6,40 Our previous studies of SLE patients and SLE mouse models showed that MDSCs can promote Th17 differentiation and aggravate SLE progression by producing Arg-1.”
BackgroundA diverse proteome is present and enzymatically active in metabolite extracts
House, R. J., Soper-Hopper, M. T., Vincent, M. P., Ellis, A. E., Capan, C. D., Madaj, Z., Wolfrum, E., Isaguirre, C., Castello, C. D., Johnson, A., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-50128-z · Cited by 32
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Self-citationDomizio, J. D., & Gilliet, M. F. (2019) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2019.04.020 · Cited by 24
“However, NET-induced reprogramming of memory T cells into Th17 cells should also be considered, especially in the light of the recent finding that committed memory Th cells contain a subpopulation of cells with functional plasticity (Karmaus et al., 2019).”
BackgroundTargeting Th17 cells in HIV-1 remission/cure interventions
Fert, A., Marchand, L. R., Salinas, T. R. W., & Ancuța, P. (2022) · Trends in Immunology · doi:10.1016/j.it.2022.04.013 · Cited by 21
Metabolic Constrains Rule Metastasis Progression
Roda, N., Gambino, V., & Giorgio, M. (2020) · Cells · doi:10.3390/cells9092081 · Cited by 22
Th17 cells in the liver: balancing autoimmunity and pathogen defense
Taniki, N., Nakamoto, N., Chu, P., Ichikawa, M., Teratani, T., & Kanai∥, T. (2022) · Seminars in Immunopathology · doi:10.1007/s00281-022-00917-9 · Cited by 22
“The glycolytic-lipogenic pathway is not only important to Th17 differentiation, but also controls the pathogenicity, stemness, and plasticity of Th17 cell [143].”
BackgroundByström, J., Taher, T. E. I., Henson, S. M., Gould, D., & Mageed, R. A. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.990794 · Cited by 22
“Furthermore, mice with T cells lacking Raptor produced Th17 cells with low metabolic activity, and expression of TCF1 (Figure 1D) (6).”
BackgroundPIM kinases regulate early human Th17 cell differentiation
Buchacher, T., Shetty, A., Koskela, S. A., Smolander, J., Kaukonen, R., Sousa, A. G. G., Junttila, S., Laiho, A., Rundquist, O., Lönnberg, T., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113469 · Cited by 22
Stem‐like T cells in cancer and autoimmunity
Schnell, A. (2024) · Immunological Reviews · doi:10.1111/imr.13356 · Cited by 22
Lei, X., Xiao, R., Chen, Z., Ren, J., Zhao, W., Tang, W., Wen, K., Zhu, Y., Li, X., Ouyang, S., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2412120121 · Cited by 23
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“Moreover, in an experimental autoimmune encephalomyelitis (EAE) mouse model, a similar subset of TCF1+ cells was able to differentiate into Th17 cells that produced IL17 when the mTORC1 pathway was blocked (72).”
BackgroundFactors impacting the benefits and pathogenicity of Th17 cells in the tumor microenvironment
Xing, J., Man, C., Liu, Y., Zhang, Z., & Peng, H. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1224269 · Cited by 24
“Considering the significant impact of metabolism on the plasticity of Th17 cells, the emerging trend in cancer treatment is the development of suitable antitumor Th17 cells for adoptive cell therapy (88).”
BackgroundMemory like NK cells display stem cell like properties after Zika virus infection
Kujur, W., Murillo, O., Adduri, S., Vankayalapati, R., Konduru, N. V., & Mulik, S. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1009132 · Cited by 22
“Notably, PD1 CXCR5 CD8 T cells in chronic viral infection [11–13,48,49] and progenitor exhausted CD8 T cells from the tumors [14,15] as well as CD27 Th17 cells from autoimmune disease [36] display stemness.”
BackgroundDecoding the crosstalk between mevalonate metabolism and T cell function
Kennewick, K. T., & Bensinger, S. J. (2023) · Immunological Reviews · doi:10.1111/imr.13200 · Cited by 20
Immunometabolism of dendritic cells in health and disease
Guo, C., & Chi, H. (2023) · Advances in immunology · doi:10.1016/bs.ai.2023.10.002 · Cited by 21
Self-citation
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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