Signal 4 nutrients in directing T cell activation. (A) Overview of Signals 1 (TCR binding to antigen presented on MHC molecules), 2 (co-stimulation by CD28), 3 (cytokine signals), and 4 (nutrients) that drive T cell immunity. Signal 4 is mediated through a three-tiered process composed of nutrient transport, sensing, and signal transduction. Signals 1–3 can augment Signal 4 by promoting the expression of nutrient transporters, while Signal 4 also interplays with Signals 1–3, for example, by shaping signaling and metabolic events. Integration of Signals 1–4 results in metabolic reprogramming, associated with increased mTORC1 signaling, c-MYC activity, and activation of biosynthesis pathways and cellular bioenergetics, altogether driving T cell activation. (B) Glucose and amino acid uptake into T cells, mediated by membrane transporters, promotes mTORC1 activation and metabolic reprogramming. Sestrins, CASTOR1, and SAMTOR represent cytosolic sensors of amino acids. Leucine and arginine respectively bind to and sequester Sestrins and CASTOR1 from GATOR2, relieving their suppressive effects on GATOR2, thereby allowing GATOR2 to promote mTORC1 activation (via inhibiting GATOR1). SAMTOR senses the methionine metabolite S-adenosylmethionine (SAM). SAM binding to SAMTOR disrupts SAMTOR–GATOR1 complex formation, thereby inhibiting the ability of GATOR1 to negatively regulate mTORC1 activation. SLC38A9 senses arginine in the lysosome, and both SLC38A9 and v-ATPase signal the increase in intralysosomal amino acid concentrations to promote mTORC1 activation, which may involve controlling the efflux of amino acids from the lysosome. Arginine also promotes mTORC1 signaling by regulating TSC–RHEB signaling. Glutamine signals through ADP ribosylation factor 1 (ARF-1) to promote mTORC1. Asparagine is sensed by LCK to promote TCR-mediated PI3K–Akt signaling. The SWI/SNF complex (including SMARCB1) inhibits gene expression of Castor1 and thereby enhances mTORC1 activity. CCDC101-associated SAGA complex inhibits the expression of glucose and amino acid transporters genes (Slc2a1, Slc43a1, and Slc16a10) and maintains T cell quiescence. Positive regulators of mTORC1 are denoted in ovals and negative regulators of mTORC1 are denoted in rectangles. Blue arrows indicate nutrient sensing that remains to be validated in primary T cells. (C) Fatty acid (FA) and cholesterol sensing and signaling can promote T cell growth, proliferation, and differentiation. SCFAs signal through GPCRs, or intracellular SCFAs can act as HDAC inhibitors. LCFAs can be transported into cells by CD36 and sensed intracellularly by PPARs. Cholesterol and cholesterol sulfate regulate TCR nanoclustering to either promote or impair TCR signaling, respectively. Intracellular cholesterol and cholesterol derivatives are recognized and can signal through SCAP–SREBP to influence lipid synthesis and mevalonate metabolism. Cholesterol derivatives are recognized and can signal through LXR to regulate T cell differentiation. (D) Mechanisms to sense low intracellular nutrient and metabolite abundance are also present in T cells. Glucose or glutamine deprivation activates AMPK in T cells, and AMPK mediates increased glutaminolysis and reduced mTORC1 signaling during glucose deprivation. AMPK is activated when the levels of AMP or ADP are relatively higher than ATP, or by extracellular ATP indirectly (not depicted here). Low amino acid levels impair mTORC1 signaling and increase the number of uncharged tRNAs. General control nonderepressible 2 (GCN2) binds to uncharged tRNAs and inhibits eukaryotic translation initiator factor 2 α (EIF2α)–dependent protein translation. Low cholesterol levels activate SCAP–SREBP signaling, which promotes fatty acid synthesis and the mevalonate pathway by transcriptional induction of lipid biosynthetic enzyme expression.
Figure 1.

Signal 4 nutrients in directing T cell activation. (A) Overview of Signals 1 (TCR binding to antigen presented on MHC molecules), 2 (co-stimulation by CD28), 3 (cytokine signals), and 4 (nutrients) that drive T cell immunity. Signal 4 is mediated through a three-tiered process composed of nutrient transport, sensing, and signal transduction. Signals 1–3 can augment Signal 4 by promoting the expression of nutrient transporters, while Signal 4 also interplays with Signals 1–3, for example, by shaping signaling and metabolic events. Integration of Signals 1–4 results in metabolic reprogramming, associated with increased mTORC1 signaling, c-MYC activity, and activation of biosynthesis pathways and cellular bioenergetics, altogether driving T cell activation. (B) Glucose and amino acid uptake into T cells, mediated by membrane transporters, promotes mTORC1 activation and metabolic reprogramming. Sestrins, CASTOR1, and SAMTOR represent cytosolic sensors of amino acids. Leucine and arginine respectively bind to and sequester Sestrins and CASTOR1 from GATOR2, relieving their suppressive effects on GATOR2, thereby allowing GATOR2 to promote mTORC1 activation (via inhibiting GATOR1). SAMTOR senses the methionine metabolite S-adenosylmethionine (SAM). SAM binding to SAMTOR disrupts SAMTOR–GATOR1 complex formation, thereby inhibiting the ability of GATOR1 to negatively regulate mTORC1 activation. SLC38A9 senses arginine in the lysosome, and both SLC38A9 and v-ATPase signal the increase in intralysosomal amino acid concentrations to promote mTORC1 activation, which may involve controlling the efflux of amino acids from the lysosome. Arginine also promotes mTORC1 signaling by regulating TSC–RHEB signaling. Glutamine signals through ADP ribosylation factor 1 (ARF-1) to promote mTORC1. Asparagine is sensed by LCK to promote TCR-mediated PI3K–Akt signaling. The SWI/SNF complex (including SMARCB1) inhibits gene expression of Castor1 and thereby enhances mTORC1 activity. CCDC101-associated SAGA complex inhibits the expression of glucose and amino acid transporters genes (Slc2a1, Slc43a1, and Slc16a10) and maintains T cell quiescence. Positive regulators of mTORC1 are denoted in ovals and negative regulators of mTORC1 are denoted in rectangles. Blue arrows indicate nutrient sensing that remains to be validated in primary T cells. (C) Fatty acid (FA) and cholesterol sensing and signaling can promote T cell growth, proliferation, and differentiation. SCFAs signal through GPCRs, or intracellular SCFAs can act as HDAC inhibitors. LCFAs can be transported into cells by CD36 and sensed intracellularly by PPARs. Cholesterol and cholesterol sulfate regulate TCR nanoclustering to either promote or impair TCR signaling, respectively. Intracellular cholesterol and cholesterol derivatives are recognized and can signal through SCAP–SREBP to influence lipid synthesis and mevalonate metabolism. Cholesterol derivatives are recognized and can signal through LXR to regulate T cell differentiation. (D) Mechanisms to sense low intracellular nutrient and metabolite abundance are also present in T cells. Glucose or glutamine deprivation activates AMPK in T cells, and AMPK mediates increased glutaminolysis and reduced mTORC1 signaling during glucose deprivation. AMPK is activated when the levels of AMP or ADP are relatively higher than ATP, or by extracellular ATP indirectly (not depicted here). Low amino acid levels impair mTORC1 signaling and increase the number of uncharged tRNAs. General control nonderepressible 2 (GCN2) binds to uncharged tRNAs and inhibits eukaryotic translation initiator factor 2 α (EIF2α)–dependent protein translation. Low cholesterol levels activate SCAP–SREBP signaling, which promotes fatty acid synthesis and the mevalonate pathway by transcriptional induction of lipid biosynthetic enzyme expression.

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