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

Stefano Angiari1, Marah C Runtsch2, Caroline E Sutton2, Eva M Palsson-McDermott2, Beth Kelly3, Nisha Rana3, Harry Kane2, Gina Papadopoulou4, Erika L Pearce3, Kingston H G Mills2, Luke A J O'Neill5

  1. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin D02 R590, Ireland. Electronic address: angiaris@tcd.ie.
  2. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin D02 R590, Ireland.
  3. Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
  4. Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens 115 27, Athens, Greece.
  5. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin D02 R590, Ireland. Electronic address: laoneill@tcd.ie.

Abstract

Pyruvate kinase (PK) catalyzes the conversion of phosphoenolpyruvate to pyruvate during glycolysis. The PK isoform PKM2 has additional roles in regulation of gene transcription and protein phosphorylation. PKM2 has been shown to control macrophage metabolic remodeling in inflammation, but its role in T cell biology is poorly understood. Here, we report PKM2 upregulation, phosphorylation, and nuclear accumulation in murine and human CD4+ T cells following activation in vitro. Treatment of T cells with TEPP-46, an allosteric activator that induces PKM2 tetramerization and blocks its nuclear translocation, strongly reduces their activation, proliferation, and cytokine production by inhibiting essential signaling pathways and thus preventing the engagement of glycolysis. TEPP-46 limits the development of both T helper 17 (Th17) and Th1 cells in vitro and ameliorates experimental autoimmune encephalomyelitis (EAE) in vivo. Overall, our results suggest that pharmacological targeting of PKM2 may represent a valuable therapeutic approach in T cell-mediated inflammation and autoimmunity.

Presented By Stefano Angiari

Immunology & Microbiology, MetabolismNicholas Liao2020-02 (Feb)