Modulation of PKM activity affects the differentiation of TH17 cells

  • Sci Signal. 2020 Oct 27;13(655):eaay9217. doi: 10.1126/scisignal.aay9217.
Scott M Seki  1  2  3 ,  Kacper Posyniak  1 ,  Rebecca McCloud  4 ,  Dorian A Rosen  1  5 ,  Anthony Fernández-Castañeda  1  2 ,  Rebecca M Beiter  1  2 ,  Vlad Serbulea  5 ,  Sarah C Nanziri  1 ,  Nikolas Hayes  1 ,  Charles Spivey  1 ,  Lelisa Gemta  6  7 ,  Timothy N J Bullock  6  7 ,  Ku-Lung Hsu  4 ,  Alban Gaultier  8
Affiliations
  • 1. Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA.
  • 2. Graduate Program in Neuroscience, University of Virginia, Charlottesville, VA 22908, USA.
  • 3. Medical Scientist Training Program, University of Virginia, Charlottesville, VA 22908, USA.
  • 4. Department of Chemistry, University of Virginia, Charlottesville, VA 22908, USA.
  • 5. Graduate Program in Pharmacological Sciences, University of Virginia, Charlottesville, VA 22908, USA.
  • 6. Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA.
  • 7. Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
  • 8. Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA. [email protected].
PMID: 33109748 DOI: 10.1126/scisignal.aay9217
Abstract

Small molecules that promote the metabolic activity of the Pyruvate Kinase isoform PKM2, such as TEPP-46 and DASA-58, limit tumorigenesis and inflammation. To understand how these compounds alter T cell function, we assessed their therapeutic activity in a mouse model of T cell-mediated autoimmunity that mimics multiple sclerosis (MS). TH17 cells are believed to orchestrate MS pathology, in part, through the production of two proinflammatory cytokines: interleukin-17 (IL-17) and GM-CSF. We found that both TEPP-46 and DASA-58 suppressed the development of IL-17-producing TH17 cells but increased the generation of those producing GM-CSF. This switch redirected disease pathology from the spinal cord to the brain. In addition, we found that activation of PKM2 interfered with TGF-β1 signaling, which is necessary for the development of TH17 and regulatory T cells. Collectively, our data clarify the therapeutic potential of PKM2 activators in MS-like disease and how these agents alter T cell function.

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