title: Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation.
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.
authors: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors: Ryan D
authors: RD
authors: Michalek
authors: Valerie A
authors: VA
authors: Gerriets
authors: Amanda G
authors: AG
authors: Nichols
authors: Makoto
authors: M
authors: Inoue
authors: Dmitri
authors: D
authors: Kazmin
authors: Ching-Yi
authors: CY
authors: Chang
authors: Mary A
authors: MA
authors: Dwyer
authors: Erik R
authors: ER
authors: Nelson
authors: Kristen N
authors: KN
authors: Pollizzi
authors: Olga
authors: O
authors: Ilkayeva
authors: Vincent
authors: V
authors: Giguere
authors: William J
authors: WJ
authors: Zuercher
authors: Jonathan D
authors: JD
authors: Powell
authors: Mari L
authors: ML
authors: Shinohara
authors: Donald P
authors: DP
authors: McDonnell
authors: Jeffrey C
authors: JC
authors: Rathmell
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D016133:Polymerase Chain Reaction; D034622:RNA Interference; D011960:Receptors, Estrogen / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D005947:Glucose; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor