Pharmacological Activation of Pyruvate Kinase M2 Inhibits CD4 ⁺ T Cell Pathogenicity and Suppresses Autoimmunity

Summary

Pyruvate kinase (PK) catalyzes the conversion of phosphoenolpyruvate to pyruvate during glycolysis. The PK isoform PKM2 has additional roles in regulation of gene transcription and protein phosphorylation. PKM2 has been shown to control macrophage metabolic remodeling in inflammation, but its role in T cell biology is poorly understood. Here, we report PKM2 upregulation, phosphorylation, and nuclear accumulation in murine and human CD4 ⁺ T cells following activation in vitro. Treatment of T cells with TEPP-46, an allosteric activator that induces PKM2 tetramerization and blocks its nuclear translocation, strongly reduces their activation, proliferation, and cytokine production by inhibiting essential signaling pathways and thus preventing the engagement of glycolysis. TEPP-46 limits the development of both T helper 17 (Th17) and Th1 cells in vitro and ameliorates experimental autoimmune encephalomyelitis (EAE) in vivo. Overall, our results suggest that pharmacological targeting of PKM2 may represent a valuable therapeutic approach in T cell-mediated inflammation and autoimmunity.

Graphical Abstract

Highlights

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  PKM2 translocates into the nucleus of CD4 ⁺ T cells upon TCR stimulation

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  TEPP-46 induces PKM2 tetramerization and blocks PKM2 nuclear translocation

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  TEPP-46 limits T cell activation by inhibiting glycolysis in T cells

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  TEPP-46 inhibits Th17 and Th1 polarization and EAE development in vivo

Abstract

Angiari et al. show that the glycolytic enzyme PKM2 translocates into the nucleus of CD4 ⁺ T cells upon TCR stimulation. PKM2 tetramerization by small-molecule PKM2 activators blocks its nuclear translocation and engagement of glycolysis, inhibiting T cell activation, Th17 and Th1 polarization, and development of EAE in vivo.