PYRUVATE DEHYDROGENASE-DEPENDENT REGULATION OF TREG FUNCTION

Regulatory T cells (Tregs) are immunosuppressive cells, that maintain peripheral tolerance. Dysfunction in Treg suppression function often leads to autoimmunity. In the context of cancer, Tregs play a role in generating an immunosuppressive microenvironment, that suppresses cytotoxic function in effector cells. Thus, understanding Treg biology in detail is essential in order to develop novel therapeutic strategies to combat autoimmune disease and cancer.
Tregs mainly utilize oxidative metabolism, fatty acid oxidation and tricarboxylic acid (TCA) cycle, to maintain their function. Previous studies have linked glycolytic activity to the initial activation and proliferation of Tregs. Yet, Tregs with increased glycolytic activity display diminished suppressive function.
Pyruvate dehydrogenase (PDH) is an enzyme, which connects cytosolic glycolysis-derived pyruvate to the mitochondrial TCA cycle. Once pyruvate is transported to the mitochondrion, PDH catalyzes the conversion of pyruvate to acetyl-CoA, which is further metabolized in the TCA cycle. While previous studies have shown that PDH activity supports Treg function, the mechanisms behind that are not well understood.
We employed a conditionally targeted mouse model in which PDH is selectively deleted in Tregs upon Foxp3-Cre expression. Under homeostatic conditions and in implanted tumor models, PDH-deficient Tregs exhibited no notable defects in suppressive function. However, impairments became apparent in the T cell transfer colitis model, where mutant Tregs were less effective at controlling intestinal inflammation induced by naïve T cells in immunodeficient mice compared to wild-type Tregs. Metabolic tracing revealed that glucose-derived acetyl-CoA still contributes to the TCA cycle in the absence of PDH, indicating a degree of metabolic flexibility that supports Treg function under certain conditions. Nevertheless, this compensation is insufficient to maintain full suppressive capacity under inflammatory conditions. These data suggest that Tregs can preserve function without PDH by engaging alternative metabolic pathways that sustain TCA cycle activity, though the precise compensatory mechanisms remain to be identified. Additionally, PDH-deficient Tregs appear to increase extracellular fatty acid uptake, which may support their function but also potentially elevate ROS accumulation. In summary, our findings show that Tregs maintain function without PDH under homeostatic conditions by engaging compensatory metabolic pathways. However, this flexibility is insufficient under inflammatory stress, highlighting a context-dependent requirement for PDH in sustaining Treg suppression.