Abstract :
[en] Th17 cells are a subset of effector CD4+ T cells essential for the protection against extracellular bacteria and fungi. At the same time, Th17 cells have been implicated in the progression of autoimmune diseases, including multiple sclerosis, rheumatoid arthritis and psoriasis. Effector T cells require energy and building blocks for their proliferation and effector function. To that end, these cells switch from oxidative and mitochondrial metabolism to fast and short pathways such as glycolysis and glutaminolysis. Pyruvate dehydrogenase (PDH) is the central enzyme connecting cytoplasmic glycolysis to the mitochondrial tricarboxylic acid (TCA) cycle. The specific role of PDH in inflammatory Th17 cells is unknown.
To unravel the role of this pivotal enzyme, a mutant mouse line where T cells do not express the catalytic subunit of the PDH complex was generated, using the Cre-Lox recombination system. In this study, PDH was shown to be essential for the generation of an exclusive glucose-derived citrate pool needed for the proliferation, survival, and effector functions of Th17 cells. In vivo, mice harboring a T cell-specific deletion of PDH were less susceptible to experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, showing lower disease burden and increased survival. In vitro, the absence of PDH in Th17 cells increased glutamine and glucose uptake, as well as glycolysis and glutaminolysis. Similarly, lipid uptake was increased through CD36 in a glutamine-mTOR axis-dependent manner. On the contrary, the TCA cycle was impaired, interfering with oxidative phosphorylation (OXPHOS) and causing levels of cellular citrate to remain critically low in mutant Th17 cells. Citrate is the substrate of ATP citrate synthase (ACLY), an enzyme responsible for the generation of acetyl-CoA, which is essential for lipid synthesis and histone acetylation, crucial for the transcription process. In line, PDH-deficient Th17 cells showed a reduced expression of Th17 signature genes. Notably, increasing cellular citrate by the addition of acetate in PDH-deficient Th17 cells restored their metabolism and function. PDH was identified as a pivotal enzyme for the maintenance of a metabolic feedback loop within central carbon metabolism that can be of relevance for therapeutically targeting Th17 cell-driven autoimmunity.
