TSC1-mTOR-controlled metabolic-epigenetic crosstalk underlies DC control of CD8+ T cell homeostasis

Abstract

Abstract Dendritic cells (DCs) play pivotal roles in T cell homeostasis and activation, and metabolic programing has been linked to DC development and function recently. However, the metabolic underpinnings corresponding to distinct DC functions remain largely unresolved. Here we demonstrate a special metabolic-epigenetic coupling mechanism orchestrated by TSC1-mTOR for the homeostatic DC function. Specific ablation of TSC1 in the DC compartment (TSC1DC-KO) largely preserved DC development, but led to pronounced reduction in naïve and memory-phenotype CD8+ T cells, a defect fully rescued by the simultaneous deletion of mTOR or Raptor in DCs. Moreover, TSC1DC-KO mice were unable to launch efficient antigen-specific CD8+ T effector responses required for containing Listeria monocytogenes and B16 melanomas. Mechanistically, our data suggest that steady-state DCs tune down de novo fatty acid synthesis through TSC1 and divert acetyl-CoA for histone acetylation. Correspondingly, TSC1-deficiency elevated ACC1 expression and fatty acid synthesis in the steady-state DCs, leading to impaired epigenetic imprinting on selective genes such as MHC-I and IL-7. Remarkably, tempering ACC1 activity was able to avert cytosolic acetyl-CoA for histone acetylation and restoration of the gene expression program compromised by TSC1-deficiency. Taken together, our results uncover a crucial role for TSC1-mTOR in metabolic programing the homeostatic DCs for T cell homeostasis, and implicate metabolic-coupled epigenetic imprinting as a paradigm for DC specification.