Competition for nutrients and its role in controlling immune responses

Nidhi Kedia-Mehta, David K Finlay, Nidhi Kedia-Mehta, David K Finlay

Abstract

Changes in cellular metabolism are associated with the activation of diverse immune subsets. These changes are fuelled by nutrients including glucose, amino acids and fatty acids, and are closely linked to immune cell fate and function. An emerging concept is that nutrients are not equally available to all immune cells, suggesting that the regulation of nutrient utility through competitive uptake and use is important for controlling immune responses. This review considers immune microenvironments where nutrients become limiting, the signalling alterations caused by insufficient nutrients, and the importance of nutrient availability in the regulation of immune responses.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Metabolism configured to support energy homoeostasis and biosynthesis. Cellular metabolism can be configured to efficiently generate energy in the form of ATP. Glucose is metabolised by aerobic glycolysis (red) and via glycolysis coupled to the tricarboxylic acid (TCA) cycle (purple) to drive oxidative phosphorylation (OXPHOS) (blue) and the generation of energy in the form of ATP. Additional fuels, including fatty acids and the amino acid glutamine, can be used to support OXPHOS. Various other amino acids can also feed into both glycolysis and the TCA cycle. In addition to fuelling energy production, glucose and amino acids can be metabolised and used to support biosynthetic processes (green). Intermediates of glycolysis and the TCA cycle can be diverted into metabolic pathways to generate biosynthetic precursors important for the synthesis of lipids, nucleotides and proteins. Fatty acids can also be directly used for biosynthesis
Fig. 2
Fig. 2
Illustrating the different metabolic configurations of immune cells. a T cells: Naive T cells (TN) have low metabolic rates fueled by glucose and glutamine. Effector T cell (TE) subsets tend to have elevated levels of both aerobic glycolysis (for metabolising glucose to lactate (Lac)) and OXPHOS (as fueled by glucose (Glc) and glutamine (Gln)). Memory T cells (TM) maintain intracellular fuel stores in the form of glycogen (Glg) and triacylglycerides (TG) fueled by glucose and fatty acid (FA) uptake, and primarily use OXPHOS rather than glycolysis. TM have metabolic plasticity as they can engage multiple opposing metabolic pathways including gluconeogenesis/glycolysis, glycogenesis/glycogenolysis and FA synthesis/FA oxidation. TG stores are generated using imported glycerol (Gl). This metabolic configuration supports two key features of TM cells; long term survival by providing dependable fuel sources within the cell (TG and Glg) and rapid metabolic responses to re-stimulation because the metabolic machinery is already present and in use. Regulatory T cells (TReg) import FA for use in biosynthesis and to generate energy through FA oxidation. b Other immune cells: Natural killer (NK) cells primarily use glucose as a fuel, which supports aerobic glycolysis and drives OXPHOS through the citrate-malate shuttle (CMS) but not the TCA cycle. In M1 macrophages (M1Mφ) the TCA cycle is broken, and glucose is metabolised to lactate and citrate (Cit) (used to make immunoregulatory molecules such as itaconate) while glutamine is metabolised to succinate (Suc) (used to generate mitochondrial ROS). By contrast, M2 macrophages (M2Mφ) maintain an intact TCA and favour oxidative metabolism that is fuelled by the uptake of fatty acids, glutamine and glucose. Neutrophils primarily use glycolysis fuelled by glucose uptake and internal glycogen stores, and have very low OXPHOS
Fig. 3
Fig. 3
Competition for nutrients between immune cells. Antigen-presenting dendritic cells (DC) can be found at the centre of cell clusters consisting of numerous different types of activated immune cells, including CD8 T cells, CD4 T cells, NK cells and plasmacytoid dendritic cells (pDC), with elevated nutrient uptake rates that will compete for nutrients (blue dots). Depending on the number of clustering cells surrounding an antigen-presenting DC, nutrients may be available (left panel) or depleted (right panel) in the immediate surrounding microenvironment due to competitive uptake. Nutrient starvation will have consequences for the DC including the inactivation of mTORC1 signalling, which has been linked to increased proinflammatory DC functions
Fig. 4
Fig. 4
Competition for nutrients and the impact on signal transduction. Decreased levels of various nutrients within immune microenvironments could occur due to competitive uptake by surrounding cells. Alternatively, the expression of enzymes that consume nutrients, such as arginase, inducible nitric oxide synthase (iNOS) and Indoleamine-pyrrole 2,3-dioxygenase (IDO), can lead to reduced levels of arginine (Arg) and tryptophan (Trp). Limiting levels of nutrients will affect various signalling pathways. Mammalian target of rapamycin complex 1 (mTORC1) signalling is sensitive to levels of arginine, leucine (Leu) and glutamine (Gln). Glucose deprivation will also activate AMP-activated protein kinase (AMPK) due to reduced levels of ATP or fructose-1,6-bisphosphate (FBP) leading to the inhibition of mTORC1 activity. The metabolite phosphoenolpyruvate (PEP), generated when glucose is metabolised by glycolysis, can affect the duration of NFAT signalling. Gln and glucose are required for the production of uridine diphosphate N-acetylglucosamine (GlcNAc) that is important in sustaining the expression of the transcription factor cMyc. Decreased levels of amino acids in general will lead to the activation of general control nonderepressible 2 (GCN2). The product of IDO-mediated Trp metabolism, kynurenine (Kyn), can promote signalling through the aryl hydrocarbon receptor (AhR). NFAT nuclear factor of activated T cells
Fig. 5
Fig. 5
Immunological consequences of changes in nutrient signalling. Activation of AMP-activated protein kinase (AMPK) or inhibition of mammalian Target of Rapamycin Complex 1 (mTORC1) signalling promotes the differentiation of regulatory T (TReg) cells over effector T cell subsets (TE), inhibits natural killer (NK) cell functions, and increases the proinflammatory outputs of dendritic cells (DC). Loss of cMyc expression inhibits the functions of TE subsets and NK cells. Activation of general control nonderepressible 2 (GCN2) signalling promotes TReg differentiation, inhibits Th17 differentiation, inhibits CD8 T cell function, and enhances the function of DC. Kynurenine (Kyn)-mediated aryl hydrocarbon receptor (AhR) signalling promotes the differentiation of TReg

References

    1. O’Neill LA, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 2016;16:553–565. doi: 10.1038/nri.2016.70.
    1. Murray PJ, Rathmell J, Pearce E. SnapShot: immunometabolism. Cell Metab. 2015;22:190–190 e1. doi: 10.1016/j.cmet.2015.06.014.
    1. Loftus RM, Finlay DK. Immunometabolism: cellular metabolism turns immune regulator. J. Biol. Chem. 2016;291:1–10. doi: 10.1074/jbc.R115.693903.
    1. Buck MD, O’Sullivan D, Pearce EL. T cell metabolism drives immunity. J. Exp. Med. 2015;212:1345–1360. doi: 10.1084/jem.20151159.
    1. Ma Ruihua, Ji Tiantian, Zhang Huafeng, Dong Wenqian, Chen Xinfeng, Xu Pingwei, Chen Degao, Liang Xiaoyu, Yin Xiaonan, Liu Yuying, Ma Jingwei, Tang Ke, Zhang Yi, Peng Yue’e, Lu Jinzhi, Zhang Yi, Qin Xiaofeng, Cao Xuetao, Wan Yonghong, Huang Bo. A Pck1-directed glycogen metabolic program regulates formation and maintenance of memory CD8+ T cells. Nature Cell Biology. 2017;20(1):21–27. doi: 10.1038/s41556-017-0002-2.
    1. Sinclair LV, et al. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat. Immunol. 2013;14:500–508. doi: 10.1038/ni.2556.
    1. Ma EH, et al. Serine is an essential metabolite for effector T cell expansion. Cell Metab. 2017;25:345–357. doi: 10.1016/j.cmet.2016.12.011.
    1. Geiger R, et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell. 2016;167:829–842 e13. doi: 10.1016/j.cell.2016.09.031.
    1. Swamy M, et al. Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy. Nat. Immunol. 2016;17:712–720. doi: 10.1038/ni.3439.
    1. Finlay DK, et al. PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J. Exp. Med. 2012;209:2441–2453. doi: 10.1084/jem.20112607.
    1. Wang R, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011;35:871–882. doi: 10.1016/j.immuni.2011.09.021.
    1. Zeng H, Chi H. Metabolic control of regulatory T cell development and function. Trends Immunol. 2015;36:3–12. doi: 10.1016/j.it.2014.08.003.
    1. Gerriets VA, et al. Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nat. Immunol. 2016;17:1459–1466. doi: 10.1038/ni.3577.
    1. Zeng H, et al. mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature. 2013;499:485–490. doi: 10.1038/nature12297.
    1. Doughty CA, et al. Antigen receptor-mediated changes in glucose metabolism in B lymphocytes: role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth. Blood. 2006;107:4458–4465. doi: 10.1182/blood-2005-12-4788.
    1. Dufort FJ, et al. Glucose-dependent de novo lipogenesis in B lymphocytes: a requirement for atp-citrate lyase in lipopolysaccharide-induced differentiation. J. Biol. Chem. 2014;289:7011–7024. doi: 10.1074/jbc.M114.551051.
    1. Le A, et al. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab. 2012;15:110–121. doi: 10.1016/j.cmet.2011.12.009.
    1. Assmann N, et al. Srebp-controlled glucose metabolism is essential for NK cell functional responses. Nat. Immunol. 2017;18:1197–1206. doi: 10.1038/ni.3838.
    1. Loftus RM, et al. Amino acid-dependent cMyc expression is essential for NK cell metabolic and functional responses in mice. Nat. Commun. 2018;9:2341. doi: 10.1038/s41467-018-04719-2.
    1. O’Neill LA, Pearce EJ. Immunometabolism governs dendritic cell and macrophage function. J. Exp. Med. 2016;213:15–23. doi: 10.1084/jem.20151570.
    1. Robinson JM, Karnovsky ML, Karnovsky MJ. Glycogen accumulation in polymorphonuclear leukocytes, and other intracellular alterations that occur during inflammation. J. Cell Biol. 1982;95:933–942. doi: 10.1083/jcb.95.3.933.
    1. Thwe PM, et al. Cell-intrinsic glycogen metabolism supports early glycolytic reprogramming required for dendritic cell immune responses. Cell Metab. 2017;26:558–567 e5. doi: 10.1016/j.cmet.2017.08.012.
    1. Everts B, et al. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKvarepsilon supports the anabolic demands of dendritic cell activation. Nat. Immunol. 2014;15:323–332. doi: 10.1038/ni.2833.
    1. Krawczyk CM, et al. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood. 2010;115:4742–4749. doi: 10.1182/blood-2009-10-249540.
    1. Lawless Simon J., Kedia-Mehta Nidhi, Walls Jessica F., McGarrigle Ryan, Convery Orla, Sinclair Linda V., Navarro Maria N., Murray James, Finlay David K. Glucose represses dendritic cell-induced T cell responses. Nature Communications. 2017;8:15620. doi: 10.1038/ncomms15620.
    1. Hirayama A, et al. Quantitative metabolome profiling of colon and stomach cancer microenvironment by capillary electrophoresis time-of-flight mass spectrometry. Cancer Res. 2009;69:4918–4925. doi: 10.1158/0008-5472.CAN-08-4806.
    1. Ho Ping-Chih, Bihuniak Jessica Dauz, Macintyre Andrew N., Staron Matthew, Liu Xiaojing, Amezquita Robert, Tsui Yao-Chen, Cui Guoliang, Micevic Goran, Perales Jose C., Kleinstein Steven H., Abel E. Dale, Insogna Karl L., Feske Stefan, Locasale Jason W., Bosenberg Marcus W., Rathmell Jeffrey C., Kaech Susan M. Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. Cell. 2015;162(6):1217–1228. doi: 10.1016/j.cell.2015.08.012.
    1. Chang Chih-Hao, Qiu Jing, O’Sullivan David, Buck Michael D., Noguchi Takuro, Curtis Jonathan D., Chen Qiongyu, Gindin Mariel, Gubin Matthew M., van der Windt Gerritje J.W., Tonc Elena, Schreiber Robert D., Pearce Edward J., Pearce Erika L. Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell. 2015;162(6):1229–1241. doi: 10.1016/j.cell.2015.08.016.
    1. Still ER, Yuneva MO. Hopefully devoted to Q: targeting glutamine addiction in cancer. Br. J. Cancer. 2017;116:1375–1381. doi: 10.1038/bjc.2017.113.
    1. Zhu L, et al. Metabolic imaging of glutamine in cancer. J. Nucl. Med. 2017;58:533–537. doi: 10.2967/jnumed.116.182345.
    1. Zhou R, et al. [(18)F](2S,4R)4-Fluoroglutamine PET detects glutamine pool size changes in triple-negative breast cancer in response to glutaminase inhibition. Cancer Res. 2017;77:1476–1484. doi: 10.1158/0008-5472.CAN-16-1945.
    1. Cascone T, et al. Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metab. 2018;27:977–987 e4. doi: 10.1016/j.cmet.2018.02.024.
    1. Thai M, et al. Adenovirus E4ORF1-induced MYC activation promotes host cell anabolic glucose metabolism and virus replication. Cell Metab. 2014;19:694–701. doi: 10.1016/j.cmet.2014.03.009.
    1. Piccoli C, et al. HCV infection induces mitochondrial bioenergetic unbalance: causes and effects. Biochim. Biophys. Acta. 2009;1787:539–46. doi: 10.1016/j.bbabio.2008.11.008.
    1. Ripoli M, et al. Hepatitis C virus-linked mitochondrial dysfunction promotes hypoxia-inducible factor 1 alpha-mediated glycolytic adaptation. J. Virol. 2010;84:647–60. doi: 10.1128/JVI.00769-09.
    1. Yu Y, Maguire TG, Alwine JC. Human cytomegalovirus activates glucose transporter 4 expression to increase glucose uptake during infection. J. Virol. 2011;85:1573–1580. doi: 10.1128/JVI.01967-10.
    1. Gualdoni GA, et al. Rhinovirus induces an anabolic reprogramming in host cell metabolism essential for viral replication. Proc. Natl Acad. Sci. USA. 2018;115:E7158–E7165. doi: 10.1073/pnas.1800525115.
    1. Palmer CS, et al. Increased glucose metabolic activity is associated with CD4+ T-cell activation and depletion during chronic HIV infection. AIDS. 2014;28:297–309. doi: 10.1097/QAD.0000000000000128.
    1. Smallwood HS, et al. Targeting metabolic reprogramming by influenza infection for therapeutic intervention. Cell Rep. 2017;19:1640–1653. doi: 10.1016/j.celrep.2017.04.039.
    1. Chi, P. I. et al. Avian reovirus sigmaA-modulated suppression of lactate dehydrogenase and upregulation of glutaminolysis and the mTOC1/eIF4E/HIF-1alpha pathway to enhance glycolysis and the TCA cycle for virus replication. Cell Microbiol.20, e12946 (2018).
    1. Thai M, et al. MYC-induced reprogramming of glutamine catabolism supports optimal virus replication. Nat. Commun. 2015;6:8873. doi: 10.1038/ncomms9873.
    1. Escoll P, Buchrieser C. Metabolic reprogramming of host cells upon bacterial infection: why shift to a Warburg-like metabolism? FEBS J. 2018;285:2146–2160. doi: 10.1111/febs.14446.
    1. Gleeson LE, et al. Cutting edge: Mycobacterium tuberculosis induces aerobic glycolysis in human alveolar macrophages that is required for control of intracellular bacillary replication. J. Immunol. 2016;196:2444–2449. doi: 10.4049/jimmunol.1501612.
    1. Shi L, et al. Infection with Mycobacterium tuberculosis induces the Warburg effect in mouse lungs. Sci. Rep. 2015;5:18176. doi: 10.1038/srep18176.
    1. Bowden SD, et al. Glucose and glycolysis are required for the successful infection of macrophages and mice by Salmonella enterica serovar typhimurium. Infect. Immun. 2009;77:3117–26. doi: 10.1128/IAI.00093-09.
    1. Vitko, N. P., Spahich, N. A. & Richardson, A. R. Glycolytic dependency of high-level nitric oxide resistance and virulence in Staphylococcus aureus. MBio6, 10.1128/mBio.00045-15 (2015).
    1. Tamune H, et al. Cerebrospinal fluid/blood glucose ratio as an indicator for bacterial meningitis. Am. J. Emerg. Med. 2014;32:263–266. doi: 10.1016/j.ajem.2013.11.030.
    1. Cheng H, et al. Nitric oxide in cancer metastasis. Cancer Lett. 2014;353:1–7. doi: 10.1016/j.canlet.2014.07.014.
    1. Kostourou V, et al. The role of tumour-derived iNOS in tumour progression and angiogenesis. Br. J. Cancer. 2011;104:83–90. doi: 10.1038/sj.bjc.6606034.
    1. Mondanelli G, et al. The immune regulation in cancer by the amino acid metabolizing enzymes ARG and IDO. Curr. Opin. Pharm. 2017;35:30–39. doi: 10.1016/j.coph.2017.05.002.
    1. Fletcher M, et al. l-Arginine depletion blunts antitumor T-cell responses by inducing myeloid-derived suppressor cells. Cancer Res. 2015;75:275–283. doi: 10.1158/0008-5472.CAN-14-1491.
    1. Lamas B, et al. Altered functions of natural killer cells in response to L-Arginine availability. Cell Immunol. 2012;280:182–190. doi: 10.1016/j.cellimm.2012.11.018.
    1. Goh CC, et al. Hepatitis C virus-induced myeloid-derived suppressor cells suppress NK cell IFN-gamma production by altering cellular metabolism via Arginase-1. J. Immunol. 2016;196:2283–2292. doi: 10.4049/jimmunol.1501881.
    1. Norian LA, et al. Tumor-infiltrating regulatory dendritic cells inhibit CD8+ T cell function via L-arginine metabolism. Cancer Res. 2009;69:3086–3094. doi: 10.1158/0008-5472.CAN-08-2826.
    1. Munn DH, Mellor AL. IDO in the tumor mcroenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol. 2016;37:193–207. doi: 10.1016/j.it.2016.01.002.
    1. Prendergast GC, et al. Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer. Cancer Immunol. Immunother. 2014;63:721–735. doi: 10.1007/s00262-014-1549-4.
    1. Taylor MW, Feng GS. Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J. 1991;5:2516–2522. doi: 10.1096/fasebj.5.11.1907934.
    1. Schmidt SV, Schultze JL. New insights into IDO biology in bacterial and viral infections. Front. Immunol. 2014;5:384. doi: 10.3389/fimmu.2014.00384.
    1. Daubener W, et al. Restriction of Toxoplasma gondii growth in human brain microvascular endothelial cells by activation of indoleamine 2,3-dioxygenase. Infect. Immun. 2001;69:6527–6531. doi: 10.1128/IAI.69.10.6527-6531.2001.
    1. Gobert AP, et al. Helicobacter pylori arginase inhibits nitric oxide production by eukaryotic cells: a strategy for bacterial survival. Proc. Natl Acad. Sci. USA. 2001;98:13844–13849. doi: 10.1073/pnas.241443798.
    1. Weinberg JB, et al. Arginine, nitric oxide, carbon monoxide, and endothelial function in severe malaria. Curr. Opin. Infect. Dis. 2008;21:468–475. doi: 10.1097/QCO.0b013e32830ef5cf.
    1. Gerard A, et al. Secondary T cell-T cell synaptic interactions drive the differentiation of protective CD8+ T cells. Nat. Immunol. 2013;14:356–363. doi: 10.1038/ni.2547.
    1. Bousso P, Robey E. Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes. Nat. Immunol. 2003;4:579–585. doi: 10.1038/ni928.
    1. Mempel TR, Henrickson SE, Andrian UHVon. T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature. 2004;427:154–159. doi: 10.1038/nature02238.
    1. Mingozzi F, et al. Prolonged contact with dendritic cells turns lymph node-resident NK cells into anti-tumor effectors. EMBO Mol. Med. 2016;8:1039–1051. doi: 10.15252/emmm.201506164.
    1. Hor JL, et al. Spatiotemporally distinct interactions with dendritic cell subsets facilitates CD4+ and CD8+ T cell activation to localized viral infection. Immunity. 2015;43:554–565. doi: 10.1016/j.immuni.2015.07.020.
    1. Castellino F, et al. Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction. Nature. 2006;440:890–895. doi: 10.1038/nature04651.
    1. Brewitz A, et al. CD8(+) T cells orchestrate pDC-XCR1(+) dendritic cell spatial and functional cooperativity to optimize priming. Immunity. 2017;46:205–219. doi: 10.1016/j.immuni.2017.01.003.
    1. Wensveen FM, van Gisbergen KP, Eldering E. The fourth dimension in immunological space: how the struggle for nutrients selects high-affinity lymphocytes. Immunol. Rev. 2012;249:84–103. doi: 10.1111/j.1600-065X.2012.01156.x.
    1. Man K, et al. The transcription factor IRF4 is essential for TCR affinity-mediated metabolic programming and clonal expansion of T cells. Nat. Immunol. 2013;14:1155–65. doi: 10.1038/ni.2710.
    1. Lin SC, Hardie DG. AMPK: sensing glucose as well as cellular energy status. Cell Metab. 2018;27:299–313. doi: 10.1016/j.cmet.2017.10.009.
    1. Rolf J, et al. AMPKalpha1: a glucose sensor that controls CD8 T-cell memory. Eur. J. Immunol. 2013;43:889–896. doi: 10.1002/eji.201243008.
    1. Blagih J, et al. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity. 2015;42:41–54. doi: 10.1016/j.immuni.2014.12.030.
    1. Powell Jonathan D., Pollizzi Kristen N., Heikamp Emily B., Horton Maureen R. Regulation of Immune Responses by mTOR. Annual Review of Immunology. 2012;30(1):39–68. doi: 10.1146/annurev-immunol-020711-075024.
    1. Golks A, et al. Requirement for O-linked N-acetylglucosaminyltransferase in lymphocytes activation. EMBO J. 2007;26:4368–4379. doi: 10.1038/sj.emboj.7601845.
    1. Ramakrishnan P, et al. Activation of the transcriptional function of the NF-kappaB protein c-Rel by O-GlcNAc glycosylation. Sci. Signal. 2013;6:ra75. doi: 10.1126/scisignal.2004097.
    1. Walls J, Sinclair L, Finlay D. Nutrient sensing, signal transduction and immune responses. Semin. Immunol. 2016;28:396–407. doi: 10.1016/j.smim.2016.09.001.
    1. Preston GC, et al. Single cell tuning of Myc expression by antigen receptor signal strength and interleukin-2 in T lymphocytes. EMBO J. 2015;34:2008–2024. doi: 10.15252/embj.201490252.
    1. Chou C, et al. c-Myc-induced transcription factor AP4 is required for host protection mediated by CD8+ T cells. Nat. Immunol. 2014;15:884–893. doi: 10.1038/ni.2943.
    1. Grallert B, Boye E. GCN2, an old dog with new tricks. Biochem. Soc. Trans. 2013;41:1687–1691. doi: 10.1042/BST20130210.
    1. Ravindran R, et al. Vaccine activation of the nutrient sensor GCN2 in dendritic cells enhances antigen presentation. Science. 2014;343:313–317. doi: 10.1126/science.1246829.
    1. Ravindran R, et al. The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation. Nature. 2016;531:523–527. doi: 10.1038/nature17186.
    1. Munn DH, et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity. 2005;22:633–642. doi: 10.1016/j.immuni.2005.03.013.
    1. Fallarino F, et al. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J. Immunol. 2006;176:6752–6761. doi: 10.4049/jimmunol.176.11.6752.

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