Glycolytic ATP fuels phosphoinositide 3-kinase signaling to support effector T helper 17 cell responses. Academic Article uri icon

Overview

abstract

  • Aerobic glycolysis-the Warburg effect-converts glucose to lactate via the enzyme lactate dehydrogenase A (LDHA) and is a metabolic feature of effector T cells. Cells generate ATP through various mechanisms and Warburg metabolism is comparatively an energy-inefficient glucose catabolism pathway. Here, we examined the effect of ATP generated via aerobic glycolysis in antigen-driven T cell responses. Cd4CreLdhafl/fl mice were resistant to Th17-cell-mediated experimental autoimmune encephalomyelitis and exhibited defective T cell activation, migration, proliferation, and differentiation. LDHA deficiency crippled cellular redox balance and inhibited ATP production, diminishing PI3K-dependent activation of Akt kinase and thereby phosphorylation-mediated inhibition of Foxo1, a transcriptional repressor of T cell activation programs. Th17-cell-specific expression of an Akt-insensitive Foxo1 recapitulated the defects seen in Cd4CreLdhafl/fl mice. Induction of LDHA required PI3K signaling and LDHA deficiency impaired PI3K-catalyzed PIP3 generation. Thus, Warburg metabolism augments glycolytic ATP production, fueling a PI3K-centered positive feedback regulatory circuit that drives effector T cell responses.

publication date

  • May 11, 2021

Research

keywords

  • Adenosine Triphosphate
  • Phosphatidylinositol 3-Kinase
  • Signal Transduction
  • Th17 Cells

Identity

PubMed Central ID

  • PMC8130647

Scopus Document Identifier

  • 85105315187

Digital Object Identifier (DOI)

  • 10.1016/j.immuni.2021.04.008

PubMed ID

  • 33979589

Additional Document Info

volume

  • 54

issue

  • 5