Modulation of PKM Activity Controls Differentiation of Th17 Cells

Abstract

T cells play crucial, and perhaps initiating roles in autoimmune diseases like Multiple Sclerosis (MS). Elucidating the mechanisms that regulate inflammatory T cell responses could reveal novel means of modulation of their pathological role. Small molecules that target specific functions of the pyruvate kinase isoform PKM2, TEPP-46 and DASA-58, have gained attention as potential inhibitors of inflammation. Here, we assessed the therapeutic potential of both molecules in a preclinical mouse model of MS. We found that both compounds suppress the development of IL-17 producing T cells (Th17). However, while TEPP-46 and DASA-58 potently inhibited Th17 cell production of IL-17A, they unexpectedly boosted their GM-CSF production. This surprising switch redirected the disease pathology from the spinal cord to the brain. On a mechanistic level, we found that modulation of PKM2 interferes with TGFβ1 signaling needed for the development of Th17 and regulatory T cells. Collectively, our study addresses a major outstanding question regarding the therapeutic potential of PKM2 modulation in MS and contributes new information to the mechanistic basis of such modulation on T cell functions.

Keywords: PKM, T cells, multiple sclerosis, Metabolism, GMCSF, IL-17