Foxp3 and Toll-like receptor signaling balance Tregcell anabolic metabolism for suppression.
CD4+effector T cells (Teffcells) and regulatory T cells (Tregcells) 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 Teffcell proliferation and inflammatory function, the mechanisms that regulate Tregcell metabolism and function remain unclear. We found that Toll-like receptor (TLR) signals that promote Tregcell proliferation increased PI(3)K-Akt-mTORC1 signaling, glycolysis and expression of Glut1. However, TLR-induced mTORC1 signaling also impaired Tregcell 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 Tregcells, 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 Tregcells.
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA.
Valerie A
VA
Gerriets
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA.
Rigel J
RJ
Kishton
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA.|Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University, Nashville, Tennessee, USA.
Marc O
MO
Johnson
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA.
Sivan
S
Cohen
Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University, Nashville, Tennessee, USA.
Peter J
PJ
Siska
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA.
Amanda G
AG
Nichols
Center for Environmental and Systems Biochemistry, Department of Toxicology and Cancer Biology and Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
Marc O
MO
Warmoes
Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Aguirre A
AA
de Cubas
Division of Pediatric Endocrinology and Diabetes, Duke University, Durham, North Carolina, USA.
Nancie J
NJ
MacIver
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA.
Jason W
http://orcid.org/0000-0002-7766-3502
JW
Locasale
Massachusetts General Hospital, Center for Transplantation Sciences, Boston, Massachusetts, USA.
Laurence A
LA
Turka
Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Andrew D
AD
Wells
Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University, Nashville, Tennessee, USA.
Jeffrey C
JC
Rathmell
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism*; D006019:Glycolysis; D007108:Immune Tolerance; D000076222:Mechanistic Target of Rapamycin Complex 1; D008660:Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D051272:Glucose Transporter Type 1; D046912:Multiprotein Complexes; C495678:Slc2a1 protein, mouse; D051193:Toll-Like Receptors; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
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