| First Author | Michalek RD | Year | 2011 |
| Journal | Proc Natl Acad Sci U S A | Volume | 108 |
| Issue | 45 | Pages | 18348-53 |
| PubMed ID | 22042850 | Mgi Jnum | J:180233 |
| Mgi Id | MGI:5305884 | Doi | 10.1073/pnas.1108856108 |
| Citation | Michalek RD, et al. (2011) Estrogen-related receptor-alpha is a metabolic regulator of effector T-cell activation and differentiation. Proc Natl Acad Sci U S A 108(45):18348-53 |
| abstractText | 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-alpha (ERRalpha) regulates metabolic pathways critical for Teff. Resting CD4(+) T cells expressed low levels of ERRalpha protein that increased on activation. ERRalpha 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, ERRalpha 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 ERRalpha(-/-) T cells and T cells treated with two chemically independent ERRalpha inhibitors or by shRNAi. Acute ERRalpha 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 ERRalpha inhibition. Furthermore, in vivo inhibition of ERRalpha reduced T-cell proliferation and Teff generation in both immunization and experimental autoimmune encephalomyelitis models. Thus, ERRalpha is a selective transcriptional regulator of Teff metabolism that may provide a metabolic means to modulate immunity. |
