期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 45, 页码 18348-18353出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1108856108
关键词
glycolysis; fatty acid; oxidative metabolism; mammalian target of rapamycin; AMPK
资金
- Cancer Research Institute
- National Institutes of Health [R01 AI063345, R01 HL108006]
- American Asthma Foundation
- Lupus Research Institute
- Leukemia and Lymphoma Society
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 (ERR alpha) regulates metabolic pathways critical for Teff. Resting CD4(+) T cells expressed low levels of ERR alpha protein that increased on activation. ERR alpha 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, ERR alpha 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 ERR alpha(-/-) T cells and T cells treated with two chemically independent ERR alpha inhibitors or by shRNAi. Acute ERR alpha 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 ERR alpha inhibition. Furthermore, in vivo inhibition of ERR alpha reduced T-cell proliferation and Teff generation in both immunization and experimental autoimmune encephalomyelitis models. Thus, ERR alpha is a selective transcriptional regulator of Teff metabolism that may provide a metabolic means to modulate immunity.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据