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Pharmacological Activation of Pyruvate Kinase M2 Inhibits CD4+ T Cell Pathogenicity and Suppresses Autoimmunity

Stefano Angiari1, Marah C Runtsch1, Caroline E Sutton1

  • 1School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin D02 R590, Ireland.

Cell Metabolism
|November 26, 2019
PubMed

Insights

Targeting pyruvate kinase M2 (PKM2) in CD4+ T cells inhibits their activation and proliferation. This approach shows promise for treating T cell-mediated inflammation and autoimmune diseases like experimental autoimmune encephalomyelitis (EAE).

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • Pyruvate kinase (PK) is crucial for glycolysis, with the PKM2 isoform having regulatory roles beyond metabolism.
  • The function of PKM2 in T cell biology remains largely unexplored.
  • PKM2 influences macrophage metabolism during inflammation.

Purpose of the Study:

  • To investigate the role of PKM2 in CD4+ T cell activation and function.
  • To explore the therapeutic potential of targeting PKM2 in T cell-mediated inflammatory diseases.

Main Methods:

  • Studied PKM2 expression, phosphorylation, and localization in activated murine and human CD4+ T cells in vitro.
  • Utilized TEPP-46, a PKM2 activator, to assess its impact on T cell activation, proliferation, and cytokine production.
  • Evaluated the efficacy of TEPP-46 in an in vivo model of experimental autoimmune encephalomyelitis (EAE).

Main Results:

  • PKM2 was upregulated, phosphorylated, and accumulated in the nucleus of activated CD4+ T cells.
  • TEPP-46 treatment inhibited T cell activation, proliferation, and cytokine production by blocking glycolysis.
  • TEPP-46 treatment reduced the development of T helper 17 (Th17) and Th1 cells in vitro and ameliorated EAE in vivo.

Conclusions:

  • PKM2 plays a significant role in CD4+ T cell activation and function.
  • Pharmacological inhibition of PKM2 nuclear translocation via TEPP-46 effectively suppresses T cell-mediated inflammation.
  • Targeting PKM2 represents a potential therapeutic strategy for autoimmune and inflammatory conditions driven by T cells.
Keywords:
PKM2Th1Th17autoimmunityimmunometabolisminflammation

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