Inhibition of Pyruvate Dehydrogenase Kinase 4 in CD4(+) T Cells Ameliorates Intestinal Inflammation

BACKGROUND & AIMS: Despite recent evidence supporting the metabolic plasticity of CD4(+) T cells, it is uncertain whether the metabolic checkpoint pyruvate dehydrogenase kinase (PDK) in T cells plays a role in the pathogenesis of colitis. METHODS: To investigate the role of PDK4 in colitis, we used dextran sulfate sodium (DSS)-induced colitis and T-cell transfer colitis models based on mice with constitutive knockout (KO) or CD4(+) T-cell–specific KO of PDK4 (Pdk4(fl/fl)CD4(Cre)). The effect of PDK4 deletion on T-cell activation was also studied in vitro. Furthermore, we examined the effects of a pharmacologic inhibitor of PDK4 on colitis. RESULTS: Expression of PDK4 increased during colitis development in a DSS-induced colitis model. Phosphorylated PDHE1α, a substrate of PDK4, accumulated in CD4(+) T cells in the lamina propria of patients with inflammatory bowel disease. Both constitutive KO and CD4(+) T-cell–specific deletion of PDK4 delayed DSS-induced colitis. Adoptive transfer of PDK4-deficient CD4(+) T cells attenuated murine colitis, and PDK4 deficiency resulted in decreased activation of CD4(+) T cells and attenuated aerobic glycolysis. Mechanistically, there were fewer endoplasmic reticulum–mitochondria contact sites, which are responsible for interorganelle calcium transfer, in PDK4-deficient CD4(+) T cells. Consistent with this, GM-10395, a novel inhibitor of PDK4, suppressed T-cell activation by reducing endoplasmic reticulum–mitochondria calcium transfer, thereby ameliorating murine colitis. CONCLUSIONS: PDK4 deletion from CD4(+) T cells mitigates colitis by metabolic and calcium signaling modulation, suggesting PDK4 as a potential therapeutic target for IBD.