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

Publication ,  Journal Article
Michalek, RD; Gerriets, VA; Nichols, AG; Inoue, M; Kazmin, D; Chang, C-Y; Dwyer, MA; Nelson, ER; Pollizzi, KN; Ilkayeva, O; Giguere, V ...
Published in: Proc Natl Acad Sci U S A
November 8, 2011

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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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

November 8, 2011

Volume

108

Issue

45

Start / End Page

18348 / 18353

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Receptors, Estrogen
  • RNA Interference
  • Polymerase Chain Reaction
  • Mitochondria
  • Mice, Inbred C57BL
  • Mice
  • Lymphocyte Activation
  • Homeostasis
  • Glucose
 

Citation

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Michalek, R. D., Gerriets, V. A., Nichols, A. G., Inoue, M., Kazmin, D., Chang, C.-Y., … Rathmell, J. C. (2011). Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation. Proc Natl Acad Sci U S A, 108(45), 18348–18353. https://doi.org/10.1073/pnas.1108856108
Michalek, Ryan D., Valerie A. Gerriets, Amanda G. Nichols, Makoto Inoue, Dmitri Kazmin, Ching-Yi Chang, Mary A. Dwyer, et al. “Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation.Proc Natl Acad Sci U S A 108, no. 45 (November 8, 2011): 18348–53. https://doi.org/10.1073/pnas.1108856108.
Michalek RD, Gerriets VA, Nichols AG, Inoue M, Kazmin D, Chang C-Y, et al. Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation. Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18348–53.
Michalek, Ryan D., et al. “Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation.Proc Natl Acad Sci U S A, vol. 108, no. 45, Nov. 2011, pp. 18348–53. Pubmed, doi:10.1073/pnas.1108856108.
Michalek RD, Gerriets VA, Nichols AG, Inoue M, Kazmin D, Chang C-Y, Dwyer MA, Nelson ER, Pollizzi KN, Ilkayeva O, Giguere V, Zuercher WJ, Powell JD, Shinohara ML, McDonnell DP, Rathmell JC. Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation. Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18348–18353.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

November 8, 2011

Volume

108

Issue

45

Start / End Page

18348 / 18353

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Receptors, Estrogen
  • RNA Interference
  • Polymerase Chain Reaction
  • Mitochondria
  • Mice, Inbred C57BL
  • Mice
  • Lymphocyte Activation
  • Homeostasis
  • Glucose