Pyruvate kinase M2 is requisite for Th1 and Th17 differentiation

Area of Science:

• Immunology
• Cellular Metabolism
• Molecular Biology

Background:

• T helper 1 (Th1) and T helper 17 (Th17) cells are implicated in autoimmune disease pathogenesis.
• These T cell subsets rely on glycolysis for energy.
• T cell receptor signaling activates calcium/calmodulin-dependent protein kinase IV (CaMK4), which enhances glycolysis.

Purpose of the Study:

• To investigate the role of CaMK4 in promoting glycolysis.
• To identify the molecular mechanisms by which CaMK4 influences glycolysis.
• To explore the therapeutic potential of targeting this pathway in T cell-dependent autoimmune diseases.

Main Methods:

• Utilized CaMK4-deficient CD4+ T cells and CaMK4 inhibitors.
• Employed pull-down assays, mass spectrometry, co-immunoprecipitation, and Western blotting to identify protein interactions.
• Assessed glycolysis, pyruvate kinase activity, and T cell differentiation in vitro and in vivo models.

Main Results:

• CaMK4-deficient cells and cells treated with CaMK4 inhibitors exhibited reduced glycolysis.
• Pyruvate kinase M2 (PKM2) was identified as a direct binding partner of CaMK4.
• CaMK4 directly interacts with and promotes PKM2 activity, which is essential for Th1 and Th17 differentiation.
• PKM2 inhibition reduced glycolysis and Th1/Th17 differentiation, ameliorating experimental autoimmune encephalomyelitis (EAE).

Conclusions:

• CaMK4 promotes glycolysis by binding to and activating PKM2.
• The CaMK4-PKM2 axis is critical for Th1 and Th17 cell differentiation.
• Targeting PKM2 offers a potential therapeutic strategy for autoimmune diseases.