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Updated: Dec 3, 2025
Author Spotlight: Achieving High-Purity In Vitro Differentiation of Th17 Cells Using Cytokine Concentration Modulation
Published on: October 25, 2024
Modulation of PKM activity affects the differentiation of TH17 cells
Scott M Seki1,2,3, Kacper Posyniak1, Rebecca McCloud4
1Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA.
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.
Insights
Small molecules activating pyruvate kinase M2 (PKM2) limit inflammation. In a mouse model of multiple sclerosis (MS), these compounds altered T helper 17 (TH17) cell function, shifting disease pathology.
Area of Science:
- Immunology
- Metabolic pathways
- Neuroinflammation
Background:
- T helper 17 (TH17) cells and their cytokines, interleukin-17 (IL-17) and GM-CSF, are implicated in multiple sclerosis (MS) pathogenesis.
- Pyruvate kinase M2 (PKM2) is a key metabolic enzyme that regulates cell proliferation and immune responses.
- Small molecules that activate PKM2 have shown potential in limiting tumorigenesis and inflammation.
Purpose of the Study:
- To investigate the therapeutic effects of PKM2 activators (TEPP-46 and DASA-58) on T cell-mediated autoimmunity mimicking MS.
- To elucidate how these PKM2 activators modulate TH17 cell differentiation and cytokine production.
Main Methods:
- Utilized a mouse model of T cell-mediated autoimmunity resembling MS.
- Administered TEPP-46 and DASA-58 to assess their impact on T cell populations and cytokine profiles.
- Analyzed the effects of PKM2 activation on transforming growth factor-beta 1 (TGF-β1) signaling.
Main Results:
- TEPP-46 and DASA-58 suppressed the development of IL-17-producing TH17 cells.
- These PKM2 activators enhanced the generation of GM-CSF-producing TH17 cells.
- PKM2 activation disrupted TGF-β1 signaling, affecting TH17 and regulatory T cell differentiation.
- Disease pathology was redirected from the spinal cord to the brain.
Conclusions:
- PKM2 activators demonstrate therapeutic potential in MS-like disease by altering T cell responses.
- Modulation of TH17 cell subsets and cytokine profiles by PKM2 activators influences disease localization.
- Understanding the interplay between PKM2, TGF-β1 signaling, and T cell differentiation is crucial for developing novel MS therapies.
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