Signaling networks in immunometabolism

Abstract

Adaptive immunity is essential for pathogen and tumor eradication, but may also trigger uncontrolled or pathological inflammation. T cell receptor, co-stimulatory and cytokine signals coordinately dictate specific signaling networks that trigger the activation and functional programming of T cells. In addition, cellular metabolism promotes T cell responses and is dynamically regulated through the interplay of serine/threonine kinases, immunological cues and nutrient signaling networks. In this review, we summarize the upstream regulators and signaling effectors of key serine/threonine kinase-mediated signaling networks, including PI3K-AGC kinases, mTOR and LKB1-AMPK pathways that regulate metabolism, especially in T cells. We also provide our perspectives about the pending questions and clinical applicability of immunometabolic signaling. Understanding the regulators and effectors of immunometabolic signaling networks may uncover therapeutic targets to modulate metabolic programming and T cell responses in human disease.

Fig. 1. PI3K–AGC signaling in T cell activation and metabolic reprogramming.

Activation of TCR, CD28 and IL-2R induces phosphorylation and activation of PI3K and also inactivation of PI3K-suppressing molecules, such as PTEN and PIK3IP1. PIP₂ is converted to PIP₃ via the activity of PI3K, and PIP₃ facilitates plasma membrane recruitment and activation of downstream signaling molecules including PDK1 and Akt. mTORC2 further activates Akt and promotes increased metabolism and T cell effector function.

Fig. 2. mTOR signaling in T cells.

The discrete mTOR complexes, mTORC1 (consists of mTOR, Raptor, PRAS1, DEPTOR and MLST8) and mTORC2 (consists of mTOR, Rictor, Protor1/2, mSIN1 and DEPTOR), are activated by immunological receptors (TCR, CD28 and IL-2R) and growth factors. mTORC1 activation is also sensitive to nutrients such as amino acids. Amino acids promote mTORC1 activation through the Rag complex, which also plays a permissive ‘licensing’ role to allow for TCR and CD28 co-stimulatory signals to induce mTORC1 activation. The Tsc complex, whose activity is suppressed by immune and growth factor signals, inhibits the activation of the small G protein Rheb, which promotes mTORC1 activation. mTORC1 induces cell growth and protein translation through S6K and eIF4E, as well as lipid synthesis through PPARγ and SREBP1. mTORC1 inhibits autophagy through ULK1 under nutrient-replete conditions. In contrast, mTORC2 is activated by growth factors and it mainly regulates survival and actin reorganization via Akt, SGK1 and PKC. mTORC2 also plays critical roles in context- or subset-specific metabolic reprogramming for cell growth, proliferation and survival.

Fig. 3. Metabolic programming in T cells through LKB1 and AMPK signaling.

The energy stress pathway kinases LKB1 and AMPK are activated by TCR and CD28 co-stimulatory signals, with AMPK activity being mediated, in part, by the Ca²⁺–CAMMK2 pathway. Energy stress, such as deprivation of glucose or glutamine or an imbalance of AMP/ADP-to-ATP ratio, can also promote LKB1–AMPK signaling. Upstream nutrient-sensing proteins, such as the Fnip–Flcn complex and Roquin, can restrain AMPK function, although the contribution of Fnip and Flcn to AMPK signaling in T cells is still unknown. The activation of LKB1 is associated with changes in mitochondrial metabolism and fitness, as well as increased mevalonate metabolism under certain contexts. By regulating the activity of several downstream targets, AMPK signaling can impede metabolic programming toward glycolysis, glutaminolysis and fatty acid synthesis, while promoting catabolic processes, such as mitophagy and autophagy. AMPK also supports mitochondrial fitness by driving mitochondrial biogenesis and mitochondrial dynamics by promoting mitochondrial fission.

Fig. 4. Cross-regulation of immunometabolic signaling pathways.

Under nutrient-deprived conditions, LKB1–AMPK signaling inhibits anabolism-associated programs, such as glycolysis and fatty acid synthesis, while promoting mitochondrial homeostasis and autophagy; however, these mechanisms require additional investigation in primary T cells. AMPK directly inhibits mTORC1 through phosphorylation of its obligate adapter protein Raptor (not depicted). During activation and/or replete nutrient conditions, PI3K–Akt and mTORC1 signaling promotes glycolysis, mitochondrial biogenesis and fatty acid synthesis, while inhibiting autophagy. Akt can reportedly phosphorylate LKB1 to suppress its functional localization, but this regulation is not yet reported to occur in T cells.