Regulation of T cell activation and pathogenicity by dimeric pyruvate kinase M2 (PKM2)

Pyruvate kinase (PK) catalyses the conversion of phosphorenolpyruvate to pyruvate during glycolysis. Previous studies suggested that the PK isoform PKM2 also plays moonlighting activities different from its enzymatic one, such are regulation of gene transcription and protein phosphorylation. PKM2 was previously shown to control macrophage metabolic remodelling and pro-inflammatory potential, but its role in CD4+ T cell biology is poorly understood. In the present work, we report that PKM2 is upregulated in both murine and human CD4+ T cells following activation in vitro. In particular, PKM2 is present in equilibrium between a monomeric, dimeric and tetrameric isoform in T cells, with the dimeric one appearing exclusively upon activation. Treatment of T cells with TEPP-46, an allosteric activator that induces PKM2 tetramerisation and blocks dimer formation, strongly reduces their activation, proliferation and cytokine production through alteration of intracellular metabolism. TEPP-46 inhibits the generation of both T helper 17 (Th17) and Th1 cells, while inducing regulatory T cell development in vitro. Finally, in vivo treatment with TEPP-46 ameliorates experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis. Overall, our results suggest that PKM2 induction and dimerisation are essential steps for T cell activation and pathogenicity, and targeting PKM2 dynamics may have therapeutic utility in T cell-mediated inflammation and autoimmunity.