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 T H 1 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. C ell metabolism refers to the intracellular chemical reactions that convert nutrients and endogenous molecules into energy and biomass (proteins, nucleic acids, and lipids). Emerging evidence highlights an intimate interaction between metabolism and immunity (1-3). For example, activated T cells are highly glycolytic and rely on glycolysis to generate ATP (even in the presence of high levels of oxygen), a phenomenon known as Warburg metabolism, which is unique to cancer cells and activated lymphocytes. Blocking glycolysis impairs activation and differentiation of T cells and the outcome of adaptive immune responses, thereby indicating a prerequisite role of metabolism in T-cell fate determination (4-6). Other modes of metabolism, such as lipid metabolism and fatty acid oxidation, are also important regulators of T-cell responses (7-10). Although most studies of metabolic controls of cell fate are focused on T cellmediated adaptive immunity, we are beginning to appreciate that activation of innate immune cells is also metabolically demanding. Engagement of toll-like receptors (TLRs) expressed by dendritic cells (DCs), the specialized antigen-presenting cells for bridging innate and adaptive immunity, triggers a profound metabolic transition to aerobic glycolysis, similar to Warburg metabolism. Glucose restriction inhibits the activation and life span of TLR-stimulated

Immunometabolism governs dendritic cell and macrophage function

“…Consistent with a role for mTORC1 in DCs, rapamycin, an inhibitor of mTOR, has been shown to selectively inhibit aspects of TLR-driven DC activation in GM-DCs and human monocyte-derived DCs, including the expression of IL-6 and IL-10 and possibly TNF (Cao et al, 2008;Boor et al, 2013;Hussaarts et al, 2013), and diminish their immunogenicity (Haidinger et al, 2010). Moreover, deletion of Tsc1, a negative regulator of mTORC1, allows increased basal expression of activation markers (Wang et al, 2013). Nevertheless, in some circumstances, rapamycin may also promote DC immunogenicity by extending cell longevity .…”

Dendritic cell SIRT1–HIF1α axis programs the differentiation of CD4 + T cells through IL-12 and TGF-β1

“…Recent studies indicated that a Tolllike receptor signaling-mediated metabolic reprogramming is required for DC maturation and antigen presentation (57)(58)(59). Moreover, the dysregulated mTORC1 or the adenosine monophosphate (AMP)-activated protein kinase (AMPK) activity results in an impaired DC development and maturation, indicating a metabolic checkpoint sensing amino acids and intracellular ATP during DC development and maturation (58,60). Our current study further implicated a metabolic checkpoint in DCs requiring the interplay of SIRT1 and HIF1α, two metabolic sensors of redox and oxygen states, respectively (61)(62)(63).…”

β-Catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8+T cells through regulation of IL-10

“…Taken together, our data indicate that activation of β-catenin in DCs either genetically or induced by tumors inhibits cross-priming by up-regulating IL-10. mTOR, a serine/threonine kinase that exerts its effects through two complexes, mTOR complex 1 (mTORC1) and mTORC2, plays a critical role in DC development and function (36)(37)(38). Rapamycin-sensitive mTORC1 has emerged as a key regulator of IL-10 in DCs (18,19,36).…”