Abstract
Dendritic cells (DCs) play pivotal roles in T-cell homeostasis and activation, and metabolic programing has been recently linked to DC development and function. However, the metabolic underpinnings corresponding to distinct DC functions remain largely unresolved. Here, we demonstrate a special metabolic–epigenetic coupling mechanism orchestrated by tuberous sclerosis complex subunit 1 (TSC1)-mechanistic target of rapamycin (mTOR) for 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 cluster of differentiation (CD)8+ T cells, a defect fully rescued by concomitant ablation of mTor or regulatory associated protein of MTOR, complex 1 (Rptor) 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 the steady-state DCs tend to tune down de novo fatty acid synthesis and divert acetyl-coenzyme A (acetyl-CoA) for histone acetylation, a process critically controlled by TSC1-mTOR. Correspondingly, TSC1 deficiency elevated acetyl-CoA carboxylase 1 (ACC1) expression and fatty acid synthesis, leading to impaired epigenetic imprinting on selective genes such as major histocompatibility complex (MHC)-I and interleukin (IL)-7. Remarkably, tempering ACC1 activity was able to divert cytosolic acetyl-CoA for histone acetylation and restore the gene expression program compromised by TSC1 deficiency. Taken together, our results uncover a crucial role for TSC1-mTOR in metabolic programing of the homeostatic DCs for T-cell homeostasis and implicate metabolic-coupled epigenetic imprinting as a paradigm for DC specification.
Highlights
(CD11b+), natural killer cells (NKs) (NK1.1+), B cells (B220+), and CD8+ T cells isolated from TSC1DC-KO spleens (S1A and S1B Fig)
The percentages and numbers of CD8α+ dendritic cell (DC), CD11b+ or CD4+ DCs, and plasmacytoid DCs (pDCs) Ag-1 (PDCA1)+/B220+ pDCs were comparable in the thymuses and spleens of wild-type and TSC1DC-KO mice (Fig 1A and S1C Fig), indicating a dispensable role for tuberous sclerosis complex subunit 1 (TSC1) in DC lineage commitment and differentiation
We uncovered a central role for TSC1-mechanistic target of rapamycin (mTOR) in programing DC metabolism, a process integral to homeostatic DC–T cell interaction
Summary
2-DG, 2-deoxy-D-glucose; 2-NBDG, 2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl) amino]-D-glucose; Acaca, acetyl-coenzyme A carboxylase alpha; AntA, antimycin A; B2m, beta-2 microglobulin; BMDC, bone marrow–derived DC; BODIPY, boron-dipyrromethene; CD, cluster of differentiation; CFU, colony-forming unit; Ctrl, control; DC, dendritic cell; ECAR, extracellular acidification rate; Eto, etomoxir; Fasn, fatty acid synthase; FCCP, fluoro-carbonyl cyanide phenylhydrazone; H2-Aa, histocompatibility 2, class II antigen A, alpha; H2-Ab1, histocompatibility 2, class II antigen A, beta 1; H2-Db, histocompatibility 2, D region locus 1; H2-Kb, histocompatibility 2, K1, K region; Hk2, hexokinase 2; Hmgcr, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; Il, interleukin; Ldha, lactate dehydrogenase A; L.M., L. monocytogenes; MFI, mean fluorescence intensity; MHC, major histocompatibility complex; NCBI, National Center for Biotechnology Information; OCR, oxygen consumption rate; oligo, oligomycin; OVA, ovalbumin; RNA-seq, RNA sequencing; Rot, rotenone; Scap, sterol regulatory element binding transcription factor chaperone; Slc2a1, solute carrier family 2 member 1; SRC, spare respiratory capacity; Tsc1, tuberous sclerosis complex subunit 1; TSC1DC-KO, specific ablation of Tsc1 in the DC compartment; UI, uninfected; WT, wild-type.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.