De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells
Abstract
Interleukin-17 (IL-17)-secreting T cells of the T helper 17 (TH17) lineage play a pathogenic role in multiple inflammatory and autoimmune conditions and thus represent a highly attractive target for therapeutic intervention. We report that inhibition of acetyl-CoA carboxylase 1 (ACC1) restrains the formation of human and mouse TH17 cells and promotes the development of anti-inflammatory Foxp3(+) regulatory T (Treg) cells. We show that TH17 cells, but not Treg cells, depend on ACC1-mediated de novo fatty acid synthesis and the underlying glycolytic-lipogenic metabolic pathway for their development. Although TH17 cells use this pathway to produce phospholipids for cellular membranes, Treg cells readily take up exogenous fatty acids for this purpose. Notably, pharmacologic inhibition or T cell-specific deletion of ACC1 not only blocks de novo fatty acid synthesis but also interferes with the metabolic flux of glucose-derived carbon via glycolysis and the tricarboxylic acid cycle. In vivo, treatment with the ACC-specific inhibitor soraphen A or T cell-specific deletion of ACC1 in mice attenuates TH17 cell-mediated autoimmune disease. Our results indicate fundamental differences between TH17 cells and Treg cells regarding their dependency on ACC1-mediated de novo fatty acid synthesis, which might be exploited as a new strategy for metabolic immune modulation of TH17 cell-mediated inflammatory diseases.
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Th17 cells engage in de novo fatty acid synthesis necessary for the Th17 phenotype.
“By contrast, Th17 cells engage in de novo fatty acid synthesis that is necessary for the Th17 phenotype.”
From Mitochondria in the Regulation of Innate and Adaptive Immunity (2015) · cites this paper as Berod et al., 2014
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- Authors
- Berod, L., Friedrich, C., Nandan, A., Freitag, J., Hagemann, S., Harmrolfs, K., Sandouk, A., Hesse, C., Castro, C. N., Bähre, H., Tschirner, S. K., Gorinski, N., Gohmert, M., Mayer, C. T., Huehn, J., Ponimaskin, E., Abraham, W.-R., Müller, R., Lochner, M., & Sparwasser, T.
- Affiliations
- Medizinische Hochschule Hannover (DE)
- Helmholtz Centre for Infection Research (DE)
- Corresponding author
- Lochner, Matthias
- Sparwasser, Tim
- ORCID
- Venue
- Nature Medicine
- Published
- 2014-10-05
- Volume
- 20
- Issue
- 11
- Pages
- 1327-1333
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1965671023
- Cited by
- 927
- References
- 35
- Citations by year
- 2026: 65 · 2025: 81 · 2024: 93 · 2023: 91 · 2022: 96 · 2021: 110 · 2020: 94 · 2019: 79 · 2018: 61 · 2017: 63 · 2016: 55 · 2015: 34 · 2014: 4
- FWCI
- 23.74
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-04-07)
- Open access
- closed
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- de novo lipogenesis, acetyl-CoA carboxylase 1, Th17 cells, regulatory T cells, Foxp3, IL-17, T cell metabolism, glycolysis, TCA cycle, phospholipid synthesis, soraphen A, autoimmune disease
- MeSH terms
- Acetyl-CoA Carboxylase, Animals, Cell Differentiation, Fatty Acids, Glycolysis, Humans, Immunization, Mice, Inbred C57BL, Macrolides, Cell Lineage, Cell Proliferation, Lipogenesis, T-Lymphocytes, Regulatory, Metabolic Networks and Pathways, Metabolome, Th17 Cells
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