Early TCR Signaling Induces Rapid Aerobic Glycolysis Enabling Distinct Acute T Cell Effector Functions

Author:

Menk, Ashley V

Scharping, Nicole E

Moreci, Rebecca S

Zeng, Xue

Guy, Cliff

Salvatore, Sonia

Bae, Heekyong

Xie, Jianxin

Young, Howard

Wendell, Stacy Gelhaus

Delgoffe, Greg M
Author Address

Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA., Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA., Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA; Tsinghua Medical University, Beijing, China., St. Jude Children 39;s Research Hospital, Memphis, TN 38105, USA., Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA., Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21701, USA., Cell Signaling Technology, Inc., Danvers, MA 01923, USA., Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address: gdelgoffe@pitt.edu.,

Abstract:

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. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

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