Metabolic programming is emerging as a critical mechanism to alter immune cell activation, differentiation and function. Targeting metabolism does not completely suppress or activate the immune system but selectively regulates immune responses. The different metabolic requirements of the diverse cells that constitute an immune response provide a unique opportunity to separate effector functions from regulatory functions. Likewise, cells can be metabolically reprogrammed to promote either their short-term effector functions or long-term memory capacity. Studies in the growing field of immunometabolism support a paradigm of ‘cellular selectivity based on demand’, in which generic inhibitors of ubiquitous metabolic processes selectively affect cells with the greatest metabolic demand and have few effects on other cells of the body. Targeting metabolism, rather than particular cell types or cytokines, in metabolically demanding processes such as autoimmunity, graft rejection, cancer and uncontrolled inflammation could lead to successful strategies in controlling the pathogenesis of these complex disorders.
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Buck, M. D., Sowell, R. T., Kaech, S. M. & Pearce, E. L. Metabolic instruction of immunity. Cell 169, 570–586 (2017).
Frauwirth, K. A. et al. The CD28 signaling pathway regulates glucose metabolism. Immunity 16, 769–777 (2002). This seminal article was one of the first to demonstrate a critical role for co-stimulation in the form of CD28 signalling to regulate metabolic reprogramming on T cell activation.
Zheng, Y. et al. A role for mammalian target of rapamycin in regulating T cell activation versus anergy. J. Immunol. 178, 2163–2170 (2007).
Zheng, Y., Delgoffe, G. M., Meyer, C. F., Chan, W. & Powell, J. D. Anergic T cells are metabolically anergic. J. Immunol. 183, 6095–6101 (2009). This report demonstrated that on rechallenge, anergic T cells fail to upregulate metabolic programmes necessary for activation, suggesting that metabolism may in part be responsible for maintaining the anergic state.
Wang, R. et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35, 871–882 (2011). Initial T cell activation and proliferation leads to a dramatic demand for energy and biosynthetic precursors that is facilitated by increased glycolysis, glutamine oxidation and nucleotide synthesis. This report demonstrates that these metabolic processes are coordinated by the upregulation of MYC.
Finlay, D. K. et al. PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J. Exp. Med. 209, 2441–2453 (2012).
Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).
Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).
Menk, A. V. et al. Early TCR signaling induces rapid aerobic glycolysis enabling distinct acute T cell effector functions. Cell Rep. 22, 1509–1521 (2018).
Caro-Maldonado, A. et al. Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells. J. Immunol. 192, 3626–3636 (2014).
Macintyre, A. N. et al. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 20, 61–72 (2014).
Michalek, R. D. et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 186, 3299–3303 (2011). This was one of the first reports to demonstrate that effector and regulatory CD4 + T cells use different metabolic programmes.
Angelin, A. et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 25, 1282–1293 (2017).
Sun, I. H. et al. mTOR complex 1 signaling regulates the generation and function of central and effector Foxp3(+) regulatory T cells. J. Immunol. 201, 481–492 (2018).
Swamy, M. et al. Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy. Nat. Immunol. 17, 712–720 (2016).
Araujo, L., Khim, P., Mkhikian, H., Mortales, C. L. & Demetriou, M. Glycolysis and glutaminolysis cooperatively control T cell function by limiting metabolite supply to N-glycosylation. eLife 6, e21330 (2017).
Shi, L. Z. et al. HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 208, 1367–1376 (2011).
Dang, E. V. et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 146, 772–784 (2011).
Franchi, L. et al. Inhibiting oxidative phosphorylation in vivo restrains Th17 effector responses and ameliorates murine colitis. J. Immunol. 198, 2735–2746 (2017).
Sukumar, M. et al. Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J. Clin. Invest. 123, 4479–4488 (2013). This work demonstrates that inhibiting the glycolytic pathway with 2-DG during in vitro T cell activation results in superior and persistent antitumour memory-like CD8 + T cells.
Pollizzi, K. N. et al. mTORC1 and mTORC2 selectively regulate CD8+ T cell differentiation. J. Clin. Invest. 125, 2090–2108 (2015).
van der Windt, G. J. et al. CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability. Proc. Natl Acad. Sci. USA 110, 14336–14341 (2013).
van der Windt, G. et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36, 68–78 (2011). This report elucidates a central link between mitochondrial spare respiratory capacity and FAO-dependent oxidative metabolism for the development and stability of CD8 + T cell memory.
Phan, A. T. et al. Constitutive glycolytic metabolism supports CD8(+) T cell effector memory differentiation during viral infection. Immunity 45, 1024–1037 (2016).
Cham, C. M., Driessens, G., O’Keefe, J. P. & Gajewski, T. F. Glucose deprivation inhibits multiple key gene expression events and effector functions in CD8+ T cells. Eur. J. Immunol. 38, 2438–2450 (2008).
Cham, C. M. & Gajewski, T. F. Glucose availability regulates IFN-gamma production and p70S6 kinase activation in CD8+ effector T cells. J. Immunol. 174, 4670–4677 (2005).
Chang, C.-H. et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153, 1239–1251 (2013). This report demonstrates that one mechanism by which glycolysis regulates T cell effector function is through the ability of GAPDH to bind to the 3ʹ untranslated region of IFNγ mRNA.
Millet, P., Vachharajani, V., McPhail, L., Yoza, B. & McCall, C. E. GAPDH binding to TNF-alpha mRNA contributes to posttranscriptional repression in monocytes: a novel mechanism of communication between inflammation and metabolism. J. Immunol. 196, 2541–2551 (2016).
Peng, M. et al. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354, 481–484 (2016). This report demonstrates that the glycolytic enzyme LDHA regulates IFNγ production by modulating the availability of acetyl-CoA and consequently epigenetic changes at the IFNγ gene promoter.
Gubser, P. M. et al. Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch. Nat. Immunol. 14, 1064–1072 (2013).
Balmer, M. L. et al. Memory CD8(+) T cells require increased concentrations of acetate induced by stress for optimal function. Immunity 44, 1312–1324 (2016).
Ho, P.-C. C. et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162, 1217–1228 (2015).
Gerriets, V. A. et al. Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J. Clin. Invest. 125, 194–207 (2015).
Dunbar, E. M. et al. Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors. Invest. New Drugs 32, 452–464 (2014).
Ma, R. et al. A Pck1-directed glycogen metabolic program regulates formation and maintenance of memory CD8+ T cells. Nat. Cell Biol. 20, 21–27 (2018).
Thwe, P. M. et al. Cell-intrinsic glycogen metabolism supports early glycolytic reprogramming required for dendritic cell immune responses. Cell Metab. 26, 558–567 (2017).
Hall, C. J. et al. Immunoresponsive gene 1 augments bactericidal activity of macrophage-lineage cells by regulating beta-oxidation-dependent mitochondrial ROS production. Cell Metab. 18, 265–278 (2013).
Mills, E. L. et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167, 457–470 (2016).
Franchina, D. G., Dostert, C. & Brenner, D. Reactive oxygen species: involvement in T cell signaling and metabolism. Trends Immunol. 39, 489–502 (2018).
Sena, L. A. et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38, 225–236 (2013). This study demonstrates a link between mitochondrial function and T cell activation through the ability of ROS to regulate NFAT.
Previte, D. M. et al. Reactive oxygen species are required for driving efficient and sustained aerobic glycolysis during CD4+ T cell activation. PLOS ONE 12, e0175549 (2017).
Siska, P. J. et al. Fluorescence-based measurement of cystine uptake through xCT shows requirement for ROS detoxification in activated lymphocytes. J. Immunol. Methods 438, 51–58 (2016).
Mak, T. W. et al. Glutathione primes T cell metabolism for inflammation. Immunity 46, 675–689 (2017).
Hosios, A. M. et al. Amino acids rather than glucose account for the majority of cell mass in proliferating mammalian cells. Dev. Cell 36, 540–549 (2016).
Altman, B. J., Stine, Z. E. & Dang, C. V. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat. Rev. Cancer 16, 619–634 (2016).
Sinclair, L. V. et al. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat. Immunol. 14, 500–508 (2013). This report demonstrates a critical link between T cell activation and the upregulation of the amino acid transporter SLC7A5, which in turn promotes leucine influx and mTORC1 activation.
Ananieva, E. A., Patel, C. H., Drake, C. H., Powell, J. D. & Hutson, S. M. Cytosolic branched chain aminotransferase (BCATc) regulates mTORC1 signaling and glycolytic metabolism in CD4+ T cells. J. Biol. Chem. 289, 18793–18804 (2014).
Kolev, M. et al. Complement regulates nutrient influx and metabolic reprogramming during Th1 cell responses. Immunity 42, 1033–1047 (2015).
Rodriguez, P. C., Quiceno, D. G. & Ochoa, A. C. L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood 109, 1568–1573 (2007).
Geiger, R. et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167, 829–842 (2016).
El-Gayar, S., Thuring-Nahler, H., Pfeilschifter, J., Rollinghoff, M. & Bogdan, C. Translational control of inducible nitric oxide synthase by IL-13 and arginine availability in inflammatory macrophages. J. Immunol. 171, 4561–4568 (2003).
Albina, J. E. et al. Arginine metabolism in wounds. Am. J. Physiol. 254, E459–E467 (1988).
Rodriguez, P. C. et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T cell receptor expression and antigen-specific T cell responses. Cancer Res. 64, 5839–5849 (2004).
Munn, D. H. et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281, 1191–1193 (1998). This report demonstrated the ability of IDO to suppress immune responses through the depletion of tryptophan.
Munn, D. H. et al. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J. Exp. Med. 189, 1363–1372 (1999).
Routy, J. P., Routy, B., Graziani, G. M. & Mehraj, V. The kynurenine pathway is a double-edged sword in immune-privileged sites and in cancer: implications for immunotherapy. Int. J. Tryptophan Res. 9, 67–77 (2016).
Srivastava, M. K., Sinha, P., Clements, V. K., Rodriguez, P. & Ostrand-Rosenberg, S. Myeloid-derived suppressor cells inhibit T cell activation by depleting cystine and cysteine. Cancer Res. 70, 68–77 (2010).
Carr, E. L. et al. Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J. Immunol. 185, 1037–1044 (2010).
Nakaya, M. et al. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 40, 692–705 (2014).
Klysz, D. et al. Glutamine-dependent alpha-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Sci. Signal. 8, ra97 (2015).
Xu, T. et al. Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism. Nature 548, 228–233 (2017).
Johnson, M. O. et al. Distinct regulation of Th17 and Th1 cell differentiation by glutaminase-dependent metabolism. Cell 175, 1780–1795 (2018).
Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 496, 238–242 (2013). This report demonstrates that on macrophage stimulation, the TCA cycle intermediate succinate plays a critical role in promoting a proinflammatory response by mediating HIF1α transcriptional activity of IL-1β.
Jha, A. K. et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42, 419–430 (2015). This work combined expression profiling and metabolic profiling to elucidate distinct differences in M1 and M2 macrophage metabolism.
Arts, R. J. et al. Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab. 24, 807–819 (2016).
Kidani, Y. et al. Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat. Immunol. 14, 489–499 (2013). This report incisively connected fatty acid metabolism and T cell activation and function.
Yang, W. et al. Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism. Nature 531, 651–655 (2016).
Lee, J. et al. Regulator of fatty acid metabolism, acetyl coenzyme a carboxylase 1, controls T cell immunity. J. Immunol. 192, 3190–3199 (2014).
Berod, L. et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat. Med. 20, 1327–1333 (2014).
Wang, C. et al. CD5L/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity. Cell 163, 1413–1427 (2015).
Pearce, E. L. et al. Enhancing CD8 T cell memory by modulating fatty acid metabolism. Nature 460, 103–107 (2009).
Raud, B. et al. Etomoxir actions on regulatory and memory T cells are independent of Cpt1a-mediated fatty acid oxidation. Cell Metab. 28, 504–515 (2018).
O’Sullivan, D. et al. Memory CD8+ T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 41, 75–88 (2014).
Cui, G. et al. IL-7-induced glycerol transport and TAG synthesis promotes memory CD8+ T cell longevity. Cell 161, 750–761 (2015).
Pan, Y. et al. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 543, 252–256 (2017).
Buck, M. D. et al. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166, 63–76 (2016).
Jang, K. J. et al. Mitochondrial function provides instructive signals for activation-induced B cell fates. Nat. Commun. 6, 6750 (2015).
DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G. & Thompson, C. B. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 7, 11–20 (2008).
Tyrakis, P. A. et al. S-2-hydroxyglutarate regulates CD8(+) T-lymphocyte fate. Nature 540, 236–241 (2016).
Lampropoulou, V. et al. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab. 24, 158–166 (2016).
Mills, E. L. et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556, 113–117 (2018).
Shutt, D. C., O’Dorisio, M. S., Aykin-Burns, N. & Spitz, D. R. 2-Deoxy-D-glucose induces oxidative stress and cell killing in human neuroblastoma cells. Cancer Biol. Ther. 9, 853–861 (2010).
Raez, L. E. et al. A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 71, 523–530 (2013).
Lee, C.-F. F. et al. Preventing allograft rejection by targeting immune metabolism. Cell Rep. 13, 760–770 (2015). This report demonstrates the ability of targeting metabolism to inhibit solid organ graft rejection.
Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).
Wang, H., Franco, F. & Ho, P. C. Metabolic regulation of Tregs in cancer: opportunities for immunotherapy. Trends Cancer 3, 583–592 (2017).
O’Neill, L. A. & Pearce, E. J. Immunometabolism governs dendritic cell and macrophage function. J. Exp. Med. 213, 15–23 (2016).
Liu, P. S. et al. alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat. Immunol. 18, 985–994 (2017).
Sukumar, M. et al. Mitochondrial membrane potential identifies cells with enhanced stemness for cellular therapy. Cell Metab. 23, 63–76 (2016).
Scharping, N. E. et al. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 45, 374–388 (2016).
Menk, A. V. et al. 4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses. J. Exp. Med. 215, 1091–1100 (2018).
Teijeira, A. et al. Mitochondrial morphological and functional reprogramming following CD137 (4-1BB) costimulation. Cancer Immunol. Res. 6, 798–811 (2018).
Kawalekar, O. U. et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity 44, 380–390 (2016).
Zhao, Z. et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell 28, 415–428 (2015).
Crompton, J. G. et al. Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics. Cancer Res. 75, 296–305 (2015).
Ohshiro, T. & Tomoda, H. Isoform-specific inhibitors of ACATs: recent advances and promising developments. Future Med. Chem. 3, 2039–2061 (2011).
Fan, J. et al. Tetrameric acetyl-CoA acetyltransferase 1 is important for tumor growth. Mol. Cell 64, 859–874 (2016).
Yoshinaka, Y. et al. A selective ACAT-1 inhibitor, K-604, stimulates collagen production in cultured smooth muscle cells and alters plaque phenotype in apolipoprotein E-knockout mice. Atherosclerosis 213, 85–91 (2010).
Lopez-Farre, A. J., Sacristan, D., Zamorano-Leon, J. J., San-Martin, N. & Macaya, C. Inhibition of acyl-CoA cholesterol acyltransferase by F12511 (Eflucimibe): could it be a new antiatherosclerotic therapeutic? Cardiovasc. Ther. 26, 65–74 (2008).
Shibuya, Y., Chang, C. C., Huang, L. H., Bryleva, E. Y. & Chang, T. Y. Inhibiting ACAT1/SOAT1 in microglia stimulates autophagy-mediated lysosomal proteolysis and increases Abeta1-42 clearance. J. Neurosci. 34, 14484–14501 (2014).
Chamoto, K. et al. Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity. Proc. Natl Acad. Sci. USA 114, E761–E770 (2017).
Weinlich, G., Murr, C., Richardsen, L., Winkler, C. & Fuchs, D. Decreased serum tryptophan concentration predicts poor prognosis in malignant melanoma patients. Dermatology 214, 8–14 (2007).
Holmgaard, R. B., Zamarin, D., Munn, D. H., Wolchok, J. D. & Allison, J. P. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J. Exp. Med. 210, 1389–1402 (2013).
Munn, D. H. et al. Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J. Clin. Invest. 114, 280–290 (2004).
Polak, M. E. et al. Mechanisms of local immunosuppression in cutaneous melanoma. Br. J. Cancer 96, 1879–1887 (2007).
Egilmez, T. G., Rachael, B. R.-T., Mehmet, O. K. & Nejat, K. Central role of IFNγ–indoleamine 2,3-dioxygenase axis in regulation of interleukin-12–mediated antitumor immunity. Cancer Res. 70, 129–138 (2010).
Friberg, M. et al. Indoleamine 2,3-dioxygenase contributes to tumor cell evasion of T cell-mediated rejection. Int. J. Cancer 101, 151–155 (2002).
Labadie, B. W., Bao, R. & Luke, J. J. Reimagining IDO pathway inhibition in cancer immunotherapy via downstream focus on the tryptophan-kynurenine-aryl hydrocarbon axis. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-18-2882 (2018).
Cascone, T. et al. Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metab. 27, 977–987 (2018).
Scharping, N. E., Menk, A. V., Whetstone, R. D., Zeng, X. & Delgoffe, G. M. Efficacy of PD-1 blockade is potentiated by metformin-induced reduction of tumor hypoxia. Cancer Immunol. Res. 5, 9–16 (2017).
Jones, S. F. & Infante, J. R. Molecular pathways: fatty acid synthase. Clin. Cancer Res. 21, 5434–5438 (2015).
Rai, G. et al. Discovery and optimization of potent, cell-active pyrazole-based inhibitors of lactate dehydrogenase (LDH). J. Med. Chem. 60, 9184–9204 (2017).
Lacroix, R., Rozeman, E. A., Kreutz, M., Renner, K. & Blank, C. U. Targeting tumor-associated acidity in cancer immunotherapy. Cancer Immunol. Immunother. 67, 1331–1348 (2018).
Falchook, G. et al. First in human study of the first-in-class fatty acid synthase (FASN) inhibitor TVB-2640. Cancer Res. 77 (Suppl.), CT153 (2017).
Arkenau, H. T. et al. 27LBA Evidence of activity of a new mechanism of action (MoA): a first-in-human study of the first-in-class fatty acid synthase (FASN) inhibitor, TVB-2640, as monotherapy or in combination. Eur. J. Cancer 51, S724 (2015).
Brand, A. et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 24, 657–671 (2016).
Pilon-Thomas, S. et al. Neutralization of tumor acidity improves antitumor responses to immunotherapy. Cancer Res. 76, 1381–1390 (2016).
Farabegoli, F. et al. Galloflavin, a new lactate dehydrogenase inhibitor, induces the death of human breast cancer cells with different glycolytic attitude by affecting distinct signaling pathways. Eur. J. Pharm. Sci. 47, 729–738 (2012).
Martinez-Outschoorn, U. E., Peiris-Pages, M., Pestell, R. G., Sotgia, F. & Lisanti, M. P. Cancer metabolism: a therapeutic perspective. Nat. Rev. Clin. Oncol. 14, 11–31 (2017).
O’Sullivan, D., Sanin, D. E., Pearce, E. J. & Pearce, E. L. Metabolic interventions in the immune response to cancer. Nat. Rev. Immunol. 19, 324–335 (2019).
Araki, K. et al. mTOR regulates memory CD8 T cell differentiation. Nature 460, 108–112 (2009). This report linked the inhibition of mTORC1 activity and the enhancement of T cell memory generation.
Turner, A. P. et al. Sirolimus enhances the magnitude and quality of viral-specific CD8+ T cell responses to vaccinia virus vaccination in rhesus macaques. Am. J. Transplant. 11, 613–618 (2011).
Mannick, J. B. et al. mTOR inhibition improves immune function in the elderly. Sci. Transl Med. 6, 268ra179 (2014).
Keating, R. et al. The kinase mTOR modulates the antibody response to provide cross-protective immunity to lethal infection with influenza virus. Nat. Immunol. 14, 1266–1276 (2013).
Amiel, E. et al. Inhibition of mechanistic target of rapamycin promotes dendritic cell activation and enhances therapeutic autologous vaccination in mice. J. Immunol. 189, 2151–2158 (2012).
Li, Q. et al. Regulating mTOR to tune vaccination induced CD8+ T cell responses for tumor immunity1. J. Immunol. 188, 3080–3087 (2012).
Tsokos, G. C., Lo, M. S., Costa Reis, P. & Sullivan, K. E. New insights into the immunopathogenesis of systemic lupus erythematosus. Nat. Rev. Rheumatol. 12, 716–730 (2016).
Yin, Y. et al. Normalization of CD4+ T cell metabolism reverses lupus. Sci. Transl Med. 7, 274ra18 (2015). This report demonstrates the ability of targeting glycolysis with 2-DG and mitochondrial metabolism with metformin to treat a mouse model of SLE.
Zhang, Z. et al. Differential glucose requirement in skin homeostasis and injury identifies a therapeutic target for psoriasis. Nat. Med. 24, 617–627 (2018).
Suwannaroj, S., Lagoo, A., Keisler, D. & Lupus, M.-R. W. Antioxidants suppress mortality in the female NZB×NZW F1 mouse model of systemic lupus erythematosus (SLE). Lupus 10, 258–265 (2001).
Lai, Z. W. et al. N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 64, 2937–2946 (2012).
Fernandez, D., Bonilla, E., Mirza, N., Niland, B. & Perl, A. Rapamycin reduces disease activity and normalizes T cell activation-induced calcium fluxing in patients with systemic lupus erythematosus. Arthritis Rheum. 54, 2983–2988 (2006).
Warner, L. M., Adams, L. M. & Sehgal, S. N. Rapamycin prolongs survival and arrests pathophysiologic changes in murine systemic lupus erythematosus. Arthritis Rheum. 37, 289–297 (1994).
Lai, Z. W., Kelly, R., Winans, T., Marchena, I. & Lancet, S.-A. Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial. Lancet 391, 1186–1196 (2018).
Torigoe, M. et al. Metabolic reprogramming commits differentiation of human CD27+IgD+ B cells to plasmablasts or CD27−IgD− cells. J. Immunol. 199, 425–434 (2017).
Johnson, K. M. et al. Identification and validation of the mitochondrial F1F0-ATPase as the molecular target of the immunomodulatory benzodiazepine Bz-423. Chem. Biol. 12, 485–496 (2005).
Blatt, N. B. et al. Benzodiazepine-induced superoxide signals B cell apoptosis: mechanistic insight and potential therapeutic utility. J. Clin. Invest. 110, 1123–1132 (2002).
Imboden, J. B. The immunopathogenesis of rheumatoid arthritis. Annu. Rev. Pathol. 4, 417–434 (2009).
Son, H.-J. J. et al. Metformin attenuates experimental autoimmune arthritis through reciprocal regulation of Th17/Treg balance and osteoclastogenesis. Mediators Inflamm. 2014, 973986 (2014).
Yang, Z. et al. Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Sci. Transl Med. 8, 331ra38 (2016).
Okano, T. et al. 3-bromopyruvate ameliorate autoimmune arthritis by modulating Th17/Treg cell differentiation and suppressing dendritic cell activation. Sci. Rep. 7, 42412 (2017).
Abboud, G. et al. Inhibition of glycolysis reduces disease severity in an autoimmune model of rheumatoid arthritis. Front. Immunol. 9, 1973 (2018).
Bian, L. et al. Dichloroacetate alleviates development of collagen II-induced arthritis in female DBA/1 mice. Arthritis Res. Ther. 11, R132 (2009).
Kornberg, M. D. et al. Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity. Science 360, 449–453 (2018).
Liberti, M. V. et al. A predictive model for selective targeting of the Warburg effect through GAPDH inhibition with a natural product. Cell Metab. 26, 648–659 (2017).
Shriver, L. P. & Manchester, M. Inhibition of fatty acid metabolism ameliorates disease activity in an animal model of multiple sclerosis. Sci. Rep. 1, 79 (2011).
Sundrud, M. S. et al. Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Science 324, 1334–1338 (2009).
Schulte, M. L. et al. Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat. Med. 24, 194–202 (2018).
Sayegh, M. H. & Carpenter, C. B. Transplantation 50 years later—progress, challenges, and promises. N. Engl. J. Med. 351, 2761–2766 (2004).
Calne, R. Y. et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet 2, 1033–1036 (1979).
Kalluri, H. V. & Hardinger, K. L. Current state of renal transplant immunosuppression: present and future. World J. Transplant. 2, 51–68 (2012).
Saunders, R. N., Metcalfe, M. S. & Nicholson, M. L. Rapamycin in transplantation: a review of the evidence. Kidney Int. 59, 3–16 (2001).
Nguyen, L. S. et al. Sirolimus and mTOR inhibitors: a review of side effects and specific management in solid organ transplantation. Drug Saf. 42, 813–825 (2019).
Delgoffe, G. M. et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30, 832–844 (2009).
Powell, J. D. & Delgoffe, G. M. The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity 33, 301–311 (2010).
Delgoffe, G. M. et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat. Immunol. 12, 295–303 (2011).
Nguyen, H. D. et al. Metabolic reprogramming of alloantigen-activated T cells after hematopoietic cell transplantation. J. Clin. Invest. 126, 1337–1352 (2016).
Park, M.-J. J. et al. Metformin attenuates graft-versus-host disease via restricting mammalian target of rapamycin/signal transducer and activator of transcription 3 and promoting adenosine monophosphate-activated protein kinase-autophagy for the balance between T helper 17 and Tregs. Transl Res. 173, 115–130 (2016).
Herrero-Sánchez, M. et al. Targeting of PI3K/AKT/mTOR pathway to inhibit T cell activation and prevent graft-versus-host disease development. J. Hematol. Oncol. 9, 113 (2016).
Glick, G. D. et al. Anaplerotic metabolism of alloreactive T cells provides a metabolic approach to treat graft-versus-host disease. J. Pharmacol. Exp. Ther. 351, 298–307 (2014).
Gatza, E. et al. Manipulating the bioenergetics of alloreactive T cells causes their selective apoptosis and arrests graft-versus-host disease. Sci. Transl Med. 3, 67ra8 (2011).
Byersdorfer, C. A. et al. Effector T cells require fatty acid metabolism during murine graft-versus-host disease. Blood 122, 3230–3237 (2013).
Davidson, S. M. et al. Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer. Cell Metab. 23, 517–528 (2016).
Gross, M. I. et al. Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol. Cancer Ther. 13, 890–901 (2014).
Chen, Z. et al. Novel 1,3,4-selenadiazole containing kidney-type glutaminase inhibitors showed improved cellular uptake and antitumor activity. J. Med. Chem. 62, 589–603 (2019).
Rajeshkumar, N. V. et al. Treatment of pancreatic cancer patient-derived xenograft panel with metabolic inhibitors reveals efficacy of phenformin. Clin. Cancer Res. 23, 5639–5647 (2017).
Ostroukhova, M. et al. The role of low-level lactate production in airway inflammation in asthma. Am. J. Physiol. Lung Cell. Mol. Physiol. 302, L300–L307 (2012).
Chitnis, T. & Weiner, H. L. CNS inflammation and neurodegeneration. J. Clin. Invest. 127, 3577–3587 (2017).
Gordon, E. B. et al. Targeting glutamine metabolism rescues mice from late-stage cerebral malaria. Proc. Natl Acad. Sci. USA 112, 13075–13080 (2015). This report dramatically demonstrates the ability of targeting glutamine metabolism to inhibit and reverse disease in a mouse model of cerebral malaria.
Manivannan, S., Baxter, V. K., Schultz, K. L., Slusher, B. S. & Griffin, D. E. Protective effects of glutamine antagonist 6-diazo-5-oxo-l-norleucine in mice with alphavirus encephalomyelitis. J. Virol. 90, 9251–9262 (2016).
Rais, R. et al. Discovery of 6-diazo-5-oxo-l-norleucine (DON) prodrugs with enhanced CSF delivery in monkeys: a potential treatment for glioblastoma. J. Med. Chem. 59, 8621–8633 (2016).
Blair, D., Dufort, F. J. & Chiles, T. C. Protein kinase Cbeta is critical for the metabolic switch to glycolysis following B cell antigen receptor engagement. Biochem. J. 448, 165–169 (2012).
Boothby, M. & Rickert, R. C. Metabolic regulation of the immune humoral response. Immunity 46, 743–755 (2017).
Cho, S. et al. Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system. Nature 537, 234 (2016).
Freemerman, A. J. et al. Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype. J. Biol. Chem. 289, 7884–7896 (2014).
Huang, S. C. et al. Metabolic reprogramming mediated by the mTORC2-IRF4 signaling axis is essential for macrophage alternative activation. Immunity 45, 817–830 (2016).
Cheng, S. C. et al. mTOR- and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345, 1250684 (2014).
Arts, R. J. W. et al. Immunometabolic pathways in BCG-induced trained immunity. Cell Rep. 17, 2562–2571 (2016).
Everts, B. et al. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKvarepsilon supports the anabolic demands of dendritic cell activation. Nat. Immunol. 15, 323–332 (2014).
Araki, Y. et al. Genome-wide analysis of histone methylation reveals chromatin state-based complex regulation of differential gene transcription and function of CD8 memory T cells. Immunity 30, 912–925 (2009).
Russ, B. E. et al. Mapping histone methylation dynamics during virus-specific CD8+ T cell differentiation in response to infection. Immunity 41, 853–865 (2014).
Shih, H. Y. et al. Transcriptional and epigenetic networks of helper T and innate lymphoid cells. Immunol. Rev. 261, 23–49 (2014).
Wu, H. et al. Epigenetic regulation in B cell maturation and its dysregulation in autoimmunity. Cell. Mol. Immunol. 15, 676–684 (2018).
Chisolm, D. A. & Weinmann, A. S. Connections between metabolism and epigenetics in programming cellular differentiation. Annu. Rev. Immunol. 36, 221–246 (2018).
Schvartzman, J. M., Thompson, C. B. & Finley, L. W. S. Metabolic regulation of chromatin modifications and gene expression. J. Cell Biol. 217, 2247–2259 (2018).
Pietrocola, F., Galluzzi, L., Bravo-San Pedro, J. M., Madeo, F. & Kroemer, G. Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab. 21, 805–821 (2015).
Li, X., Egervari, G., Wang, Y., Berger, S. L. & Lu, Z. Regulation of chromatin and gene expression by metabolic enzymes and metabolites. Nat. Rev. Mol. Cell Biol. 19, 563–578 (2018).
Pechkovsky, D. V. et al. Alternatively activated alveolar macrophages in pulmonary fibrosis-mediator production and intracellular signal transduction. Clin. Immunol. 137, 89–101 (2010).
Madala, S. K. et al. Bone marrow-derived stromal cells are invasive and hyperproliferative and alter transforming growth factor-alpha-induced pulmonary fibrosis. Am. J. Respir. Cell. Mol. Biol. 50, 777–786 (2014).
Chen, Y. et al. Neutralization of interleukin-17A delays progression of silica-induced lung inflammation and fibrosis in C57BL/6 mice. Toxicol. Appl. Pharmacol. 275, 62–72 (2014).
Mi, S. et al. Blocking IL-17A promotes the resolution of pulmonary inflammation and fibrosis via TGF-beta1-dependent and -independent mechanisms. J. Immunol. 187, 3003–3014 (2011).
Braun, R. K. et al. IL-17 producing gammadelta T cells are required for a controlled inflammatory response after bleomycin-induced lung injury. Inflammation 31, 167–179 (2008).
Vigeland, C. L. et al. Deletion of mTORC1 activity in CD4+ T cells is associated with lung fibrosis and increased gammadelta T cells. PLOS ONE 11, e0163288 (2016).
Ask, K. et al. Progressive pulmonary fibrosis is mediated by TGF-beta isoform 1 but not TGF-beta3. Int. J. Biochem. Cell Biol. 40, 484–495 (2008).
Kolb, M., Margetts, P. J., Anthony, D. C., Pitossi, F. & Gauldie, J. Transient expression of IL-1beta induces acute lung injury and chronic repair leading to pulmonary fibrosis. J. Clin. Invest. 107, 1529–1536 (2001).
Henry, M. T. et al. Matrix metalloproteinases and tissue inhibitor of metalloproteinase-1 in sarcoidosis and IPF. Eur. Respir. J. 20, 1220–1227 (2002).
Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N. Engl. J. Med. 366, 1968–1977 (2012).
Zhao, X. et al. Metabolic regulation of dermal fibroblasts contributes to skin extracellular matrix homeostasis and fibrosis. Nat. Metab. 1, 147–157 (2019).
The authors thank members of the Powell laboratory for critical review of the manuscript. The authors are supported in part by National Institutes of Health (grants T32AI007247 and T32HL007227 to C.H.P. grant R01HL141490 to M.R.H. and grants R01AI077610, R01CA226765 and R01CA229451 to J.D.P.) and the Bloomberg~Kimmel Institute of Cancer Immunotherapy (J.D.P.).
J.D.P. has equity in Dracen, Sitryx (<5%) and Corvus (<5%); has consulted for Dracen, as well as for Sitryx, Corvus, Aeonian, Sigma and Quadriga; has received sponsored research money from Abbvie, Quadriga, Dracen, Bluebird and Bristol-Myers Squibb in the last year; and has patents licensed by Dracen. The other authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Signal 1
T cell receptor engagement of peptide–major histocompatibility complex.
A ligand–receptor signal provided by activated antigen-presenting cells (for example, B7-1 on antigen-presenting cells engaging CD28 on T cells) that leads to full T cell activation.
- Tolerant T cells
T cells that receive signal 1 (T cell receptor engagement) in the absence of co-stimulation are deleted or become anergic (tolerant) such that they fail to become fully activated on subsequent rechallenge.
- Regulatory T cells
(Treg cells). FOXP3+CD4+ T cells that negatively regulate immune responses and thus play an important role in preventing overexuberant inflammation and autoimmunity.
- Effector Treg cells
While circulating regulatory T cells (Treg cells) are relatively metabolically quiescent, on activation such cells become FOXP3+CD44hiCD62lomTORC1hi effector Treg cells (mTORC1 is mechanistic target of rapamycin complex 1) that are responsible for actively suppressing inflammatory/immune responses.
- IL-17-producing T helper cells
(TH17 cells). Characterized by the production of the proinflammatory cytokine IL-17, TH17 cells contribute to pathogen clearance at mucosal surfaces, but have also been implicated in autoimmune and inflammatory disorders.
- M1 macrophages
Known as ‘classically activated macrophages’, these cells protect against bacteria and viruses by producing proinflammatory cytokines and by phagocytizing and killing microorganisms by generating nitric oxide or reactive oxygen species.
- M2 macrophages
Known as ‘alternatively activated macrophages’, these cells are associated with wound healing and tissue repair by inducing proliferation or collagen deposition.
- Myeloid-derived suppressor cells
A myeloid-derived heterogeneous group of immature macrophages and granulocytes that actively suppress antitumour T cell responses.
- Trained immunity
The ability of the innate immune system to mount an enhanced memory response on reinfection.
- Induced Treg cells
FOXP3+CD4+ regulatory T cells (Treg cells) that are generated when naive CD4+ T cells are stimulated under suppressive conditions (such as in the presence of transforming growth factor-β).
- B6.Sle1.Sle2.Sle3 (TC) lupus-prone mouse model
A spontaneous mouse model of systemic lupus erythematosus that mimics human disease due to increased levels of autoantibodies and activated CD4+ T cells.
Antibody-secreting B cells in lymph nodes that demonstrate some features of a plasma cell but are typically short-lived compared with differentiated plasma cells.
- KBN mouse model
A spontaneous model of arthritis caused by the activation of T cell receptor transgenic CD4+ T cells from the KRN strain and glucose 6-phosphate isomerase peptides presented by the H-2g7 allele.
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Patel, C.H., Leone, R.D., Horton, M.R. et al. Targeting metabolism to regulate immune responses in autoimmunity and cancer. Nat Rev Drug Discov 18, 669–688 (2019). https://doi.org/10.1038/s41573-019-0032-5
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