title: Tuberous sclerosis 1 (Tsc1)-dependent metabolic checkpoint controls development of dendritic cells.
abstract: Coordination of cell metabolism and immune signals is crucial for lymphocyte priming. Emerging evidence also highlights the importance of cell metabolism for the activation of innate immunity upon pathogen challenge, but there is little evidence of how this process contributes to immune cell development. Here we show that differentiation of dendritic cells (DCs) from bone marrow precursors is associated with dynamic regulation of mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) signaling and cell metabolism. Unexpectedly, enhancing mTORC1 activity via ablation of its negative regulator tuberous sclerosis 1 (Tsc1) impaired DC development in vivo and in vitro, associated with defective cell survival and proliferation. Moreover, Tsc1 deficiency caused DC spontaneous maturation but a propensity to differentiate into other lineages, and attenuated DC-mediated effector TH1 responses. Mechanistically, Tsc1-deficient DCs exhibited increased glycolysis, mitochondrial respiration, and lipid synthesis that were partly mediated by the transcription factor Myc, highlighting a key role of Tsc1 in modulating metabolic programming of DC differentiation. Further, Tsc1 signaled through Rheb to down-regulate mTORC1 for proper DC development, whereas its effect at modulating mTOR complex 2 (mTORC2) activity was largely dispensable. Our results demonstrate that the interplay between Tsc1-Rheb-mTORC1 signaling and Myc-dependent bioenergetic and biosynthetic activities constitutes a key metabolic checkpoint to orchestrate DC development.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Wang
authors.forename: Gonghua
authors.initials: G
authors.lastname: Huang
authors.forename: Hu
authors.initials: H
authors.lastname: Zeng
authors.forename: Kai
authors.initials: K
authors.lastname: Yang
authors.forename: Richard F
authors.initials: RF
authors.lastname: Lamb
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D004734:Energy Metabolism / Q000276:immunology; D005434:Flow Cytometry; D008213:Lymphocyte Activation / Q000276:immunology*; D053858:Metabolic Networks and Pathways / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000276:immunology / Q000378:metabolism*
chemical_list: C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins