Glycolytic ATP fuels phosphoinositide 3-kinase signaling to support effector T helper 17 cell responses Journal Article

Authors: Xu, K.; Yin, N.; Peng, M.; Stamatiades, E. G.; Chhangawala, S.; Shyu, A.; Li, P.; Zhang, X.; Do, M. H.; Capistrano, K. J.; Chou, C.; Leslie, C. S.; Li, M. O.
Article Title: Glycolytic ATP fuels phosphoinositide 3-kinase signaling to support effector T helper 17 cell responses
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. © 2021 Elsevier Inc.
Keywords: autoimmunity; th17 cell; glycolysis; pi3k; atp; ldha; redox balance
Journal Title: Immunity
Volume: 54
Issue: 5
ISSN: 1074-7613
Publisher: Cell Press  
Date Published: 2021-05-11
Start Page: 976
End Page: 987.e7
Language: English
DOI: 10.1016/j.immuni.2021.04.008
PUBMED: 33979589
PROVIDER: scopus
PMCID: PMC8130647
Notes: Article -- Export Date: 1 June 2021 -- Source: Scopus
Citation Impact
MSK Authors
  1. Min Peng
    8 Peng
  2. Christina Leslie
    162 Leslie
  3. Ming Li
    97 Li
  4. Na Yin
    6 Yin
  5. Ke   Xu
    9 Xu
  6. Mytrang   Do
    14 Do
  7. Chun Chou
    9 Chou
  8. Xian Zhang
    9 Zhang
  9. Amy Shyu
    5 Shyu
  10. Peng Li
    4 Li