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Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions

Leticia Soriano-Baguet1, Melanie Grusdat1, Henry Kurniawan1

  • 1Experimental and Molecular Immunology, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Immunology and Genetics, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, Avenue des Hauts Fourneaux, Esch-sur-Alzette, Luxembourg.

Cell Reports
|February 27, 2023
PubMed

Insights

Pyruvate dehydrogenase (PDH) is crucial for T helper 17 (Th17) cell function and proliferation. Its deficiency impairs Th17 cell metabolism, offering therapeutic targets for autoimmune diseases.

Area of Science:

  • Immunology
  • Cellular Metabolism
  • Biochemistry

Background:

  • Pyruvate dehydrogenase (PDH) links glycolysis and the TCA cycle.
  • The role of PDH in T helper 17 (Th17) cell function is not well understood.

Purpose of the Study:

  • To investigate the essential role of PDH in Th17 cell metabolism and function.
  • To explore the therapeutic potential of targeting PDH in Th17 cell-driven autoimmunity.

Main Methods:

  • Utilized a mouse model with T cell-specific deletion of PDH.
  • Analyzed Th17 cell proliferation, survival, and effector functions.
  • Investigated metabolic pathways including glycolysis, glutaminolysis, and lipid uptake.
  • Assessed the impact of PDH deficiency on cellular citrate levels, OXPHOS, and histone acetylation.

Main Results:

  • PDH is essential for generating glucose-derived citrate in Th17 cells, supporting their proliferation, survival, and effector functions.
  • Mice with PDH-deficient Th17 cells showed reduced susceptibility to experimental autoimmune encephalomyelitis.
  • PDH absence increased glutaminolysis, glycolysis, and lipid uptake via mTOR signaling, but led to critically low cellular citrate.
  • Low citrate impaired OXPHOS, lipid synthesis, and histone acetylation, hindering Th17 signature gene transcription.

Conclusions:

  • PDH activity is critical for maintaining cellular citrate levels and supporting Th17 cell function.
  • Targeting PDH and the associated metabolic feedback loop presents a potential therapeutic strategy for Th17 cell-mediated autoimmune diseases.

Keywords:
CP: ImmunologyCP: MetabolismIL-17T cellsTh17 cellsacetyl-CoAcitrateepigeneticsexperimental autoimmune encephalomyelitisglucose metabolismhistone acetylationpyruvate dehydrogenase

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