Open AccessModulation of PKM activity affects the differentiation of T H 17 cells
Author(s) -
Shinsuke Seki,
Kacper Posyniak,
Rebecca L. McCloud,
Dorian A. Rosen,
Anthony Fernández-Castañeda,
Rebecca M. Beiter,
Vlad Serbulea,
Sarah C. Nanziri,
Nikolas W. Hayes,
Charles Spivey,
Lelisa Gemta,
Timothy N. J. Bullock,
KuLung Hsu,
Alban Gaultier
Publication year - 2020
Publication title -
science signaling
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.659
H-Index - 154
eISSN - 1937-9145
pISSN - 1945-0877
DOI - 10.1126/scisignal.aay9217
Subject(s) - inflammation , multiple sclerosis , microbiology and biotechnology , spinal cord , chemistry , pkm2 , neuroscience , biology , immunology , biochemistry , enzyme , glycolysis , pyruvate kinase
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 H 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 H 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 H 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.