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Metabolic modeling of single Th17 cells reveals regulators of autoimmunity
Open accessPublished version of a preprint
Abstract
Metabolism is a major regulator of immune cell function, but it remains difficult to study the metabolic status of individual cells. Here, we present Compass, an algorithm to characterize cellular metabolic states based on single-cell RNA sequencing and flux balance analysis. We applied Compass to associate metabolic states with T helper 17 (Th17) functional variability (pathogenic potential) and recovered a metabolic switch between glycolysis and fatty acid oxidation, akin to known Th17/regulatory T cell (Treg) differences, which we validated by metabolic assays. Compass also predicted that Th17 pathogenicity was associated with arginine and downstream polyamine metabolism. Indeed, polyamine-related enzyme expression was enhanced in pathogenic Th17 and suppressed in Treg cells. Chemical and genetic perturbation of polyamine metabolism inhibited Th17 cytokines, promoted Foxp3 expression, and remodeled the transcriptome and epigenome of Th17 cells toward a Treg-like state. In vivo perturbations of the polyamine pathway altered the phenotype of encephalitogenic T cells and attenuated tissue inflammation in CNS autoimmunity.
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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 [65]
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Metadata
- Authors
- Wagner, A., Wang, C., Fessler, J., DeTomaso, D., Avila-Pacheco, J., Kaminski, J., Zaghouani, S., Christian, E., Thakore, P., Schellhaass, B., Akama-Garren, E., Pierce, K., Singh, V., Ron-Harel, N., Douglas, V. P., Bod, L., Schnell, A., Puleston, D., Sobel, R. A., Haigis, M., Pearce, E. L., Soleimani, M., Clish, C., Regev, A., Kuchroo, V. K., & Yosef, N.
- Affiliations
- University of California, Berkeley (US)
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Massachusetts Eye and Ear Infirmary (US)
- Max Planck Institute of Immunobiology and Epigenetics (DE)
- VA Palo Alto Health Care System (US)
- Harvard University (US)
- University of New Mexico (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- Corresponding author
- Wang, Chao
- Kuchroo, Vijay K.
- Yosef, Nir
- ORCID
- Wagner, Allon
- Wang, Chao
- Fessler, Johannes
- DeTomaso, David
- Zaghouani, Sarah
- Christian, Elena
- Pierce, Kerry
- Singh, Vasundhara
- Douglas, Vivian Paraskevi
- Bod, Lloyd
- Schnell, Alexandra
- Puleston, Daniel
- Sobel, Raymond A.
- Haigis, Marcia
- Pearce, Erika L.
- Soleimani, Manoocher
- Clish, Clary
- Regev, Aviv
- Kuchroo, Vijay K.
- Yosef, Nir
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2021-08
- Volume
- 184
- Issue
- 16
- Pages
- 4168-4185.e21
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC8621950
- OpenAlex
- W3174064560
- Cited by
- 524
- References
- 163
- Citations by year
- 2026: 105 · 2025: 118 · 2024: 111 · 2023: 92 · 2022: 75 · 2021: 18
- FWCI
- 27.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 369 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Chan Zuckerberg Initiative
- Australian Academy of Science
- Österreichischen Akademie der Wissenschaften
- NIH
- Canada First Research Excellence Fund (P01AI039671, P01AI056299, P01AI073748, R01AI144166, R01NS045937, RO1NS30843, TA-1605-08590)
- National Multiple Sclerosis Society
- National Institute of Mental Health (NIH5U19MH114821)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- Th17 cells, cellular metabolism, flux balance analysis, glycolysis, fatty acid oxidation, regulatory T cells, polyamine metabolism, arginine metabolism, Foxp3, central nervous system autoimmunity, multiple sclerosis, encephalitogenic T cells
- MeSH terms
- Epigenome, Diamine N-Acetyltransferase, Acetyltransferases, Adenosine Triphosphate, Aerobiosis, Algorithms, Eflornithine, Animals, Chromatin, Citric Acid Cycle, Encephalomyelitis, Autoimmune, Experimental, Fatty Acids, Glycolysis, Mice, Inbred C57BL, Models, Biological, Oxidation-Reduction, Putrescine, Autoimmunity, Cytokines, Mitochondrial Membrane Transport Proteins, T-Lymphocytes, Regulatory, Mice, Jumonji Domain-Containing Histone Demethylases, Th17 Cells, Single-Cell Analysis, Transcriptome
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