Early TCR Signaling Induces Rapid Aerobic Glycolysis Enabling Distinct Acute T Cell Effector Functions
Ashley V. Menk,
Nicole E. Scharping,
Rebecca S. Moreci,
Xue Zeng,
Cliff Guy,
Sonia Salvatore,
Heekyong Bae,
Jianxin Xie,
Howard A. Young,
Stacy Gelhaus Wendell,
Greg M. Delgoffe
Affiliations
Ashley V. Menk
Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA
Nicole E. Scharping
Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA
Rebecca S. Moreci
Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA
Xue Zeng
Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA; Tsinghua Medical University, Beijing, China
Cliff Guy
St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Sonia Salvatore
Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA
Heekyong Bae
Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21701, USA
Jianxin Xie
Cell Signaling Technology, Inc., Danvers, MA 01923, USA
Howard A. Young
Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21701, USA
Stacy Gelhaus Wendell
Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA
Greg M. Delgoffe
Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Corresponding author
Summary: To fulfill bioenergetic demands of activation, T cells perform aerobic glycolysis, a process common to highly proliferative cells in which glucose is fermented into lactate rather than oxidized in mitochondria. However, the signaling events that initiate aerobic glycolysis in T cells remain unclear. We show T cell activation rapidly induces glycolysis independent of transcription, translation, CD28, and Akt and not involving increased glucose uptake or activity of glycolytic enzymes. Rather, TCR signaling promotes activation of pyruvate dehydrogenase kinase 1 (PDHK1), inhibiting mitochondrial import of pyruvate and facilitating breakdown into lactate. Inhibition of PDHK1 reveals this switch is required acutely for cytokine synthesis but dispensable for cytotoxicity. Functionally, cytokine synthesis is modulated via lactate dehydrogenase, which represses cytokine mRNA translation when aerobic glycolysis is disengaged. Our data provide mechanistic insight to metabolic contribution to effector T cell function and suggest that T cell function may be finely tuned through modulation of glycolytic activity.
