Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation
Open accessAbstract
Stimulation of resting CD4 + T lymphocytes leads to rapid proliferation and differentiation into effector (Teff) or inducible regulatory (Treg) subsets with specific functions to promote or suppress immunity. Importantly, Teff and Treg use distinct metabolic programs to support subset specification, survival, and function. Here, we describe that the orphan nuclear receptor estrogen-related receptor-α (ERRα) regulates metabolic pathways critical for Teff. Resting CD4 + T cells expressed low levels of ERRα protein that increased on activation. ERRα deficiency reduced activated T-cell numbers in vivo and cytokine production in vitro but did not seem to modulate immunity through inhibition of activating signals or viability. Rather, ERRα broadly affected metabolic gene expression and glucose metabolism essential for Teff. In particular, up-regulation of Glut1 protein, glucose uptake, and mitochondrial processes were suppressed in activated ERRα −/− T cells and T cells treated with two chemically independent ERRα inhibitors or by shRNAi. Acute ERRα inhibition also blocked T-cell growth and proliferation. This defect appeared as a result of inadequate glucose metabolism, because provision of lipids, but not increased glucose uptake or pyruvate, rescued ATP levels and cell division. Additionally, we have shown that Treg requires lipid oxidation, whereas Teff uses glucose metabolism, and lipid addition selectively restored Treg—but not Teff—generation after acute ERRα inhibition. Furthermore, in vivo inhibition of ERRα reduced T-cell proliferation and Teff generation in both immunization and experimental autoimmune encephalomyelitis models. Thus, ERRα is a selective transcriptional regulator of Teff metabolism that may provide a metabolic means to modulate immunity.
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TCR-mediated up-regulation of the transcription factors c-Myc and estrogen-related receptor α (ERRα) enhances the expression of genes involved in intermediary metabolism.
“TCR-mediated up-regulation of the transcription factors c-Myc (9) and estrogen-related receptor α (ERRα) (10) enhances the expression of genes involved in intermediary metabolism.”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [10]
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- Authors
- Michalek, R. D., Gerriets, V. A., Nichols, A. G., Inoue, M., Kazmin, D., Chang, C.-Y., Dwyer, M. A., Nelson, E. R., Pollizzi, K. N., Ilkayeva, O., Giguere, V., Zuercher, W. J., Powell, J. D., Shinohara, M. L., McDonnell, D. P., & Rathmell, J. C.
- Affiliations
- Department of Pharmacology and Cancer Biology,
- Department of Immunology, and
- Johns Hopkins University (US)
- Duke Medical Center (US)
- Goodman Cancer Research Centre and Department of Biochemistry, McGill University, Montreal, QC, Canada H3A 1A3; and
- GlaxoSmithKline (United States) (US)
- Duke University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-10-31
- Volume
- 108
- Issue
- 45
- Pages
- 18348-18353
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3215012
- OpenAlex
- W2160328993
- Cited by
- 216
- References
- 34
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 9 · 2023: 14 · 2022: 6 · 2021: 16 · 2020: 9 · 2019: 13 · 2018: 17 · 2017: 15 · 2016: 20 · 2015: 23 · 2014: 18 · 2013: 15 · 2012: 23
- FWCI
- 8.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL108006)
- National Institute of Allergy and Infectious Diseases (R01AI077610, R01AI063345)
- 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 › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- estrogen-related receptor alpha, T cell metabolism, effector T cells, regulatory T cells, CD4+ T cells, glucose metabolism, GLUT1, mitochondrial metabolism, lipid oxidation, T cell proliferation, experimental autoimmune encephalitis, nuclear receptor transcriptional regulation, immunometabolism
- MeSH terms
- ERRalpha Estrogen-Related Receptor, Animals, Cell Differentiation, Glucose, Homeostasis, Lymphocyte Activation, Mice, Inbred C57BL, Mitochondria, Receptors, Estrogen, T-Lymphocytes, Polymerase Chain Reaction, RNA Interference, Cell Proliferation, Mice
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