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PNAS 108 (45): 18348-18353

Copyright © 2011 by the National Academy of Sciences.


Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation

Ryan D. Michaleka,b, Valerie A. Gerrietsa, Amanda G. Nicholsa, Makoto Inoueb, Dmitri Kazmina, Ching-Yi Changa, Mary A. Dwyera, Erik R. Nelsona, Kristen N. Pollizzic, Olga Ilkayevad, Vincent Gigueree, William J. Zuercherf, Jonathan D. Powellc, Mari L. Shinoharab, Donald P. McDonnella, and Jeffrey C. Rathmella,b,d,1

aDepartment of Pharmacology and Cancer Biology, bDepartment of Immunology, and dThe Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27710; cThe Sidney–Kimmel Comprehensive Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231; eGoodman Cancer Research Centre and Department of Biochemistry, McGill University, Montreal, QC, Canada H3A 1A3; and fDiscovery Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709

Edited by Ruslan Medzhitov, Yale University School of Medicine, New Haven, CT, and approved October 6, 2011 (received for review June 1, 2011)

Abstract: 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.

Key Words: glycolysis • fatty acid • oxidative metabolism • mammalian target of rapamycin • AMPK

Author contributions: R.D.M., V.A.G., C.-Y.C., M.A.D., M.L.S., D.P.M., and J.C.R. designed research; R.D.M., V.A.G., A.G.N., M.I., and O.I. performed research; R.D.M., M.I., C.-Y.C., K.N.P., V.G., W.J.Z., J.D.P., M.L.S., and D.P.M. contributed new reagents/analytic tools; R.D.M., D.K., E.R.N., O.I., and J.C.R. analyzed data; and R.D.M. and J.C.R. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

Data deposition: The microarray data reported in this paper has been deposited in the GenBank database (accession no. GSE33108).

This article contains supporting information online at

1To whom correspondence should be addressed. E-mail: jeff.rathmell{at}

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