mTORC1 and mTORC2 as regulators of cell metabolism in immunity

Abstract

The mechanistic target of rapamycin (mTOR) pathway is an evolutionarily conserved signaling pathway that senses intra- and extracellular nutrients, growth factors, and pathogen-associated molecular patterns to regulate the function of innate and adaptive immune cell populations. In this review, we focus on the role of the mTOR complex 1 (mTORC1) and mTORC2 in the regulation of the cellular energy metabolism of these immune cells to regulate and support immune responses. In this regard, mTORC1 and mTORC2 generally promote an anabolic response by stimulating protein synthesis, glycolysis, mitochondrial functions, and lipid synthesis to influence proliferation and survival, effector and memory responses, innate training and tolerance as well as hematopoietic stem cell maintenance and differentiation. Deactivation of mTOR restores cell homeostasis after immune activation and optimizes antigen presentation and memory T-cell generation. These findings show that the mTOR pathway integrates spatiotemporal information of the environmental and cellular energy status by regulating cellular metabolic responses to guide immune cell activation. Elucidation of the metabolic control mechanisms of immune responses will help to generate a systemic understanding of the immune system.

Keywords: T-cell; dendritic cell; glycolysis; immune cell metabolism; lipid metabolism; mTORC1; mTORC2; macrophage; mitochondria.

Figure 1. The mTOR pathway

Cytokines, T-cell receptor (TCR) engagement and co-stimulation, growth factors but also pathogen associated molecular patterns (PAMPs) induce the activation of class I phosphatidylinositol 3-kinases (PI3Ks). PI3K generates phosphatidylinositol-3,4,5-trisphosphate (PIP3) to act as a second messenger that induces the phosphorylation of Akt on Thr308. PI3K signaling induces mechanistic target of rapamycin complex 2 (mTORC2) activation, which in turn phosphorylates its downstream targets serum- and glucocorticoid-regulated kinase 1 (SGK1), protein kinase C (PKC) and Akt on Ser473. Phosphatase and tensin homologue (PTEN) negatively regulates PI3K signaling, by dephosphorylating PIP3. Akt phosphorylates and thereby inhibits the heterodimer tuberous sclerosis complex 1 (TSC1)/TSC2, which inhibits activation of the small GTPase Ras homologue enriched in brain (Rheb), thus releasing mTORC1 activation. However, this activation is dependent on amino acid sufficiency that is sensed by mTORC1 via the RAS-related GTP-binding protein (RAG) GTPases. During starvation periods, AMP-activated protein kinase (AMPK) either directly inhibits mTORC1 activity or phosphorylates TSC2. In contrast to the Akt-mediated phosphorylation, AMPK supports the inhibitory function of this complex and therefore represses mTORC1 activation. The best described downstream effectors of mTORC1 are ribosomal S6 kinase1 (S6K1) and eIF4E- binding protein 1 (4E-BP1). The phosphorylation of these effectors promotes translation. Activating phosphorylations and GTP are marked in bright orange, while inhibitory phosphorylations are displayed in faded red. Abbreviations: Raptor – regulatory-associated protein of mTOR; Rictor – Rapamycin insensitive companion of mTOR; SIN1 – stress-activated MAP kinase interacting protein1; mLST8 – mammalian lethal with sec-13 protein 8.

Figure 2. Metabolic control by mTOR

In innate immune cells mechanistic target of rapamycin (mTOR)-mediated metabolism can either support the response of inflammatory dendritic cells (DCs) and M1 polarized macrophages (red highlighted lines), as it happens for example during bacterial infection, or it can prime the immunometabolism of resident and M2 polarized macrophages (green highlighted lines). Both mTOR complex 1 (mTORC1) and mTORC2 promote glucose uptake via the glucose transporter 1 (Glut1). mTORC1 fosters inflammatory polarization via activation of hypoxia-inducible factor 1α (HIF1α) and c-Myc mediated glycolytic gene expression. It also promotes the production of toxic nitric oxide (NO), which poisons the electron transport chain. This feeds back into increased lactate production and fatty acid synthesis (FAS). In other cases, mTORC1 promotes FAS via sterol regulatory element-binding proteins (SREBPs), although this has not been formally shown in macrophages. FAS-derived fatty acids are utilized to rapidly expand the Golgi apparatus and endoplasmic reticulum (ER). This enables the cells to produce huge amounts of inflammatory cytokines. In a homeostatic setting mTORC1 also promotes glucose uptake, mitochondrial biogenesis and thus oxidative phosphorylation (OXPHOS). IL-4 promotes mTORC1 mediated ACLY to achieve epigenetic rewiring using citrate-derived acetyl-CoA and fatty acid oxidation (FAO) via mTORC2.

Figure 3. mTOR mediated metabolism shapes T-cell fate.

Naïve T-cells mainly rely on oxidative phosphorylation (OXPHOS) to maintain their identity. However, upon activation T-cells induce an mTOR-dependent glycolytic metabolism and utilize fatty acid synthesis (FAS) to support clonal expansion and effector function. mTOR complex 1 (mTORC1) is required for T helper 1 (Th1), Th2, Th17, follicular T helper (Tfh) cell and in very low doses for Treg differentiation, while additionally mTORC2 is indispensable for Th2 and Tfh cell fate. Memory T-cells and Tregs upregulate AMP-activated protein kinase (AMPK)-dependent fatty acid oxidation (FAO) in addition to OXPHOS to meet their metabolic demand.