Mus musculus musculus Transcriptome or Gene expression. Mus musculus musculus

Functionally distinct T cell subsets can switch metabolic programs in response to environmental cues, such as inflammation and cancer. Quiescent T cells mainly require oxidative phosphorylation (OXPHOS) for energy production, while effector T cells predominantly rely on growth-promoting pathways, such as glycolysis, for proliferation. Regulatory T cells (Tregs) are thought to possess a unique, yet poorly understood metabolic feature distinct to that of conventional T cells. We find that the metabolic sensor Lkb1 is critical to maintain energy homeostasis in Tregs. Treg-specific deletion of Lkb1 in mice causes loss of Treg number and function, leading to a fatal, early onset autoimmune disorder. Tregs with Lkb1 deletion have defective mitochondria, compromised OXPHOS, altered lipid and nucleotide metabolism, and depleted cellular ATP. Consequently, Lkb1 deficient Tregs fail to fulfill the bioenergetic requirements for optimal survival and function in vivo and in vitro. We demonstrate that this regulation of Lkb1 in Tregs is largely independent of AMPK, instead involving the MAP/microtubule affinity-regulating kinases. Our results define a novel metabolic checkpoint in Tregs that couples metabolic regulation to immune homeostasis.