Distinct Glycolytic and Lipid Oxidative Metabolic Programs Are Essential for Effector and Regulatory CD4+ T Cell Subsets
Ryan D. Michalek,*,†,‡ Valerie A. Gerriets,* Sarah R. Jacobs,*,†,‡ Andrew N. Macintyre,*,†,‡ Nancie J. MacIver,*,x Emily F. Mason,* Sarah A. Sullivan,† Amanda G. Nichols,* and Jeffrey C. Rathmell*,†,‡
Stimulated CD4+ T lymphocytes can differentiate into effector T cell (Teff) or inducible regulatory T cell (Treg) subsets with speciﬁc immunological roles. We show that Teff and Treg require distinct metabolic programs to support these functions. Th1, Th2, and Th17 cells expressed high surface levels of the glucose transporter Glut1 and were highly glycolytic. Treg, in contrast, expressed low levels of Glut1 and had high lipid oxidation rates. Consistent with glycolysis and lipid oxidation promoting Teff and Treg, respectively, Teff were selectively increased in Glut1 transgenic mice and reliant on glucose metabolism, whereas Treg had activated AMP-activated protein kinase and were dependent on lipid oxidation. Importantly, AMP-activated protein kinase stimulation was sufﬁcient to decrease Glut1 and increase Treg generation in an asthma model. These data demonstrate that CD4+ T cell subsets require distinct metabolic programs that can be manipulated in vivo to control Treg and Teff development in inﬂammatory diseases. The Journal of Immunology, 2011, 186: 3299¨C3303.
The balance between protective immunity and suppression of inappropriate inﬂammation requires that CD4+ T cells properly activate and differentiate into effector or regulatory subsets (1). However, cell growth and function require sufﬁcient energy generation and biosynthesis (2, 3). To meet these requirements, activated T cells decrease lipid oxidation and undergo a rapid increase in glycolysis (4). At the conclusion of an immune response, decreased glycolysis and increased lipid oxidation can favor the enrichment of long-lived CD8+ memory cells (5, 6). For CD4+ T cells, however, it has been unclear how metabolism may supporteffector T cells (Teff) Th1, Th2, and Th17 and inducible regulatory T cells (Treg). The mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) pathways play important and opposing roles in metabolism and immunity. T cell activation stimulates mTOR to increase glycolysis and diminish lipid oxidation (7). This pathway is also essential for CD4+ T cell subset differentiation, as mTOR-deﬁcient mice generate Treg, but are severely inhibited in the differentiation of the Teff subsets (8, 9). In contrast, the AMPK pathway acts to inhibit mTOR by suppressing mTOR signaling and to promote mitochondrial oxidative metabolism rather than glycolysis (10). Although AMPK activation can be anti-inﬂammatory (11), its role in T cell metabolism and CD4+ T cell subset differentiation is uncertain. In this study, we demonstrate that cell metabolism is critical to regulate CD4+ T cell fate. Direct manipulation of cell metabolism showed that distinct metabolic programs were essential for the survival and speciﬁcation of Teff and Treg, as Teffs required a glycolytic metabolism with active mTOR, whereas Treg had high levels of activated AMPK and required lipid oxidation.