Targeting pyruvate kinase M2 (PKM2) reduces T cell pathogenicity in multiple sclerosis

BACKGROUND: Pyruvate kinase M2 (PKM2) is an enzyme with moonlighting activities that controls murine T cell pro-inflammatory potential in a mouse model of multiple sclerosis (MS). However, no study analysed in detail the expression of PKM2 in human T cell subsets, and whether targeting PKM2 may limit the inflammatory potential of T cells from patients with MS is unknown. METHODS: In this observational, case control study we evaluated the expression of PKM2 in circulating T cells of healthy control individuals (HCs) and patients with MS, as well as its isomerisation in peripheral blood mononuclear cells (PBMCs) from HCs and patients. In parallel, we analysed the impact of targeting PKM2 on the inflammatory profile of T cells from HCs and individuals with MS. FINDINGS: Circulating effector and memory T cells express higher PKM2 levels compared to naïve T cells, and PKM2 expression in such T cell subsets may correlate with age and disease duration in individuals with MS. Among effector/memory T cells, the Th17/Tc17 subsets display the highest PKM2 expression. Additionally, we observed a preferential inhibition of interferon-gamma (IFN-γ), interleukin-5 (IL-5), IL-13, and IL-17 production by MS T cells upon PKM2 pharmacological targeting. Finally, we found that PBMCs from patients with MS have a higher percentage of PKM2 monomer compared to PBMCs from HCs, supporting heightened PKM2 moonlighting activity. INTERPRETATION: Our data suggest that PKM2 may represent a therapeutic target to limit T cell-driven inflammation in MS and potentially other human autoimmune diseases. FUNDING: Austrian Multiple Sclerosis Research Society, Kulturamt der Stadt Graz, MEFOGraz and Worldwide Cancer Research.