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

• Published in: Nature immunology Vol. 17; no. 12; p. 1459
• 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: United States 01.12.2016
• Subjects: Animals; Cell Differentiation; Cell Proliferation; Cells, Cultured; Forkhead Transcription Factors - metabolism; Glucose Transporter Type 1 - genetics; Glucose Transporter Type 1 - metabolism; Glycolysis; Immune Tolerance; Mechanistic Target of Rapamycin Complex 1; Metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multiprotein Complexes - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Regulatory - immunology; Toll-Like Receptors - metabolism; TOR Serine-Threonine Kinases - metabolism
• ISSN: 1529-2916
• DOI: 10.1038/ni.3577

CD4 effector T cells (T cells) and regulatory T cells (T 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 cell proliferation and inflammatory function, the mechanisms that regulate T cell metabolism and function remain unclear. We found that Toll-like receptor (TLR) signals that promote T cell proliferation increased PI(3)K-Akt-mTORC1 signaling, glycolysis and expression of Glut1. However, TLR-induced mTORC1 signaling also impaired T 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 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 cells.