Modulation of PKM activity affects the differentiation of T H 17 cells

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...

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Bibliographic Details
Published in:Science signaling 2020-10, Vol.13 (655)
Main Authors: Seki, Scott M, Posyniak, Kacper, McCloud, Rebecca, Rosen, Dorian A, Fernández-Castañeda, Anthony, Beiter, Rebecca M, Serbulea, Vlad, Nanziri, Sarah C, Hayes, Nikolas, Spivey, Charles, Gemta, Lelisa, Bullock, Timothy N J, Hsu, Ku-Lung, Gaultier, Alban
Format: Article
Language:English
Subjects:
Animals
Cell Differentiation - drug effects
Cell Differentiation - genetics
Cell Differentiation - immunology
Female
Male
Mice
Mice, Knockout
Multiple Sclerosis - genetics
Multiple Sclerosis - immunology
Pyridazines - pharmacology
Pyrroles - pharmacology
Pyruvate Kinase - genetics
Pyruvate Kinase - immunology
Signal Transduction - drug effects
Signal Transduction - genetics
Signal Transduction - immunology
Th17 Cells - immunology
Transforming Growth Factor beta1 - genetics
Transforming Growth Factor beta1 - immunology
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Summary: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). T 17 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 T 17 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 T 17 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.
ISSN:1945-0877
1937-9145
DOI:10.1126/scisignal.aay9217