Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression

• Published in: Nature immunology Vol. 17; no. 12; pp. 1459 - 1466
• Main Authors: Gerriets, Valerie A, Kishton, Rigel J, Johnson, Marc O, Cohen, Sivan, Siska, Peter J, Nichols, Amanda G, Warmoes, Marc O, de Cubas, Aguirre A, MacIver, Nancie J, Locasale, Jason W, Turka, Laurence A, Wells, Andrew D, Rathmell, Jeffrey C
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 03.10.2016; Nature Publishing Group
• Subjects: 631/250/1619/554/1898/1271; 631/250/2152/1566/1618; Biomedicine; Immunology; Infectious Diseases
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.3577

T cells undergo metabolic reprogramming after they are activated. Rathmell and colleagues show that inflammatory Toll-like receptor signals induce glycolysis and impair the suppression of regulatory T cells, but Foxp3 can promote a switch to oxidative phosphorylation and suppression. CD4 + effector T cells (T eff cells) and regulatory T cells (T reg cells) undergo metabolic reprogramming to support proliferation and immunological function. Although signaling via the lipid kinase PI(3)K (phosphatidylinositol-3-OH kinase), the serine-threonine kinase Akt and the metabolic checkpoint kinase complex mTORC1 induces both expression of the glucose transporter Glut1 and aerobic glycolysis for T eff cell proliferation and inflammatory function, the mechanisms that regulate T reg cell metabolism and function remain unclear. We found that Toll-like receptor (TLR) signals that promote T reg cell proliferation increased PI(3)K-Akt-mTORC1 signaling, glycolysis and expression of Glut1. However, TLR-induced mTORC1 signaling also impaired T reg cell suppressive capacity. Conversely, the transcription factor Foxp3 opposed PI(3)K-Akt-mTORC1 signaling to diminish glycolysis and anabolic metabolism while increasing oxidative and catabolic metabolism. Notably, Glut1 expression was sufficient to increase the number of T reg cells, but it reduced their suppressive capacity and Foxp3 expression. Thus, inflammatory signals and Foxp3 balance mTORC1 signaling and glucose metabolism to control the proliferation and suppressive function of T reg cells.