Frontiers in immunology · 2026
Phospho-enol pyruvate carboxykinase inhibition limits effector function in inflammatory T cells.
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Brownlie Rebecca J, Carrasco Hope Helen, Wright David, Cook Graham P, Perales José C, Salmond Robert J
Аннотация
INTRODUCTION: Following antigenic stimulation, T cells switch from a catabolic metabolic state maintained by low levels of nutrient uptake to an anabolic metabolism that sustains the biosynthetic and energetic demands of clonal expansion, differentiation, and effector function. Much progress has been made in understanding the transcriptional and enzymatic regulation of activated T cell metabolism. However, less is understood of the role for regulators of anaplerosis and cataplerosis such as phospho-enol pyruvate carboxykinases (PEPCK) in T cells.
METHODS: Assessment of PEPCK expression in mouse T cells was performed. Pharmacological inhibitors were used to assess functional and metabolic roles for PEPCKs in T cell activation.
RESULTS: We show that mitochondrial PEPCK (PEPCK-M) is upregulated following T cell activation, while cytosolic PEPCK-C was not detected. The PEPCK inhibitors limited CD8+ T cell cytotoxic capacity and both CD4+ and CD8+ T cell inflammatory cytokine production. The suppression of T cell effector functions by PEPCK inhibitors was associated with decreased maximal mitochondrial respiration.
DISCUSSION: These data suggest that PEPCKs act to modulate mitochondrial metabolism, supporting effector function in T cells.
METHODS: Assessment of PEPCK expression in mouse T cells was performed. Pharmacological inhibitors were used to assess functional and metabolic roles for PEPCKs in T cell activation.
RESULTS: We show that mitochondrial PEPCK (PEPCK-M) is upregulated following T cell activation, while cytosolic PEPCK-C was not detected. The PEPCK inhibitors limited CD8+ T cell cytotoxic capacity and both CD4+ and CD8+ T cell inflammatory cytokine production. The suppression of T cell effector functions by PEPCK inhibitors was associated with decreased maximal mitochondrial respiration.
DISCUSSION: These data suggest that PEPCKs act to modulate mitochondrial metabolism, supporting effector function in T cells.