2. Academic Validation
  3. Modulation of PKM activity affects the differentiation of TH17 cells

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

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. ag7h@virginia.edu.
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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