Immune cells are highly dynamic in their response to the tissue environment. Most immune cells rapidly change their metabolic profile to obtain sufficient energy to engage in defensive or homeostatic processes. Such "immunometabolism" is governed through intermediate metabolites, and has a vital role in regulating immune-cell function. The underlying metabolic reactions are shaped by the abundance and accessibility of specific nutrients, as well as the overall metabolic status of the host. Here, we discuss how different immune-cell types gain a sufficient energy supply. We then explain how immune cells perform various functions under challenged conditions and expend energy to sustain homeostasis. Finally, we speculate on how the immune-cell metabolic profile might be modulated in health and disease, by manipulating nutrient availability. By such intervention, the recovery of patient with dysregulated immune system responses might be sped up and the fitness of an individual efficiently restored.

Department of Biology Faculty of Medicine Masaryk University Brno Czech Republic

Institute of Hematology and Blood Transfusion Prague Czech Republic

International Clinical Research Center St Anne's University Hospital Brno Czech Republic

See more in PubMed

Robinson, J. L., Kocabaş, P., Wang, H., Cholley, P. E., Cook, D., Nilsson, A., … Nielsen, J. (2020). An atlas of human metabolism. Sci Signal, 13. https://doi.org/10.1126/scisignal.aaz1482.

Schmid, D., Burmester, G. R., Tripmacher, R., Kuhnke, A., & Buttgereit, F. (2000). Bioenergetics of human peripheral blood mononuclear cell metabolism in quiescent, activated, and glucocorticoid-treated states. Biosci. Rep., 20, 289-302. https://doi.org/10.1023/a:1026445108136.

Straub, R. H., Cutolo, M., Buttgereit, F., & Pongratz, G. (2010). Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. J. Intern. Med., 267, 543-560. https://doi.org/10.1111/j.1365-2796.2010.02218.x.

O'Neill, L. A. J., Kishton, R. J., & Rathmell, J. (2016). A guide to immunometabolism for immunologists. Nat. Rev. Immunol., 16, 553-565. https://doi.org/10.1038/nri.2016.70.

Lee, M. K. S., Al-Sharea, A., Shihata, W. A., Bertuzzo Veiga, C., Cooney, O. D., Fleetwood, A. J., … Murphy, A. J. (2019). Glycolysis is required for LPS-induced activation and adhesion of human CD14+CD16− monocytes. Front Immunol, 10, 2054. https://doi.org/10.3389/fimmu.2019.02054.

Menk A, V., Scharping, N. E., Moreci, R. S., Zeng, X., Guy, C., Salvatore, S., … Delgoffe, G. M. (2018). Early TCR signaling induces rapid aerobic glycolysis enabling distinct acute T cell effector functions. Cell Rep., 22, 1509-1521. https://doi.org/10.1016/j.celrep.2018.01.040.

Yamada, K. J., Heim, C. E., Xi, X., Attri, K. S., Wang, D., Zhang, W., … Kielian, T. (2020). Monocyte metabolic reprogramming promotes pro-inflammatory activity and Staphylococcus aureus biofilm clearance. PLoS Pathog., 16 (3), e1008354. https://doi.org/10.1371/journal.ppat.1008354.

Wahl, D. R., Byersdorfer, C. A., Ferrara, J. L. M., Opipari, A. W., & Glick, G. D. (2012). Distinct metabolic programs in activated T cells: Opportunities for selective immunomodulation. Immunol Rev, 249, 104-115. https://doi.org/10.1111/j.1600-065X.2012.01148.x.

Venter, G., Oerlemans, F., Wijers, M., Willemse, M., Fransen, J. A. M., & Wieringa, B. (2014). Glucose controls morphodynamics of LPS-stimulated macrophages. PLoS One, 9, e96786. https://doi.org/10.1371/journal.pone.0096786.

Garcia, D., & Shaw, R. J. (2017). AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol. Cell, 66, 789-800. https://doi.org/10.1016/j.molcel.2017.05.032.

Howell, J. J., & Manning, B. D. (2011). MTOR couples cellular nutrient sensing to organismal metabolic homeostasis. Trends Endocrinol. Metab., 22, 94-102. https://doi.org/10.1016/j.tem.2010.12.003.

Mantovani, A., Biswas, S. K., Galdiero, M. R., Sica, A., & Locati, M. (2013). Macrophage plasticity and polarization in tissue repair and remodeling. J Pathol, 229, 176-185. https://doi.org/10.1002/path.4133.

Orecchioni, M., Ghosheh, Y., Pramod, A. B., & Ley, K. (2019). Macrophage polarization: different gene signatures in M1(Lps+) vs. classically and M2(LPS-) vs. Alternatively activated macrophages. Front Immunol, 10, 1084. https://doi.org/10.3389/fimmu.2019.01084.

Viola, A., Munari, F., Sánchez-Rodríguez, R., Scolaro, T., & Castegna, A. (2019). The metabolic signature of macrophage responses. Front Immunol, 10. https://doi.org/10.3389/fimmu.2019.01462.

Rath, M., Müller, I., Kropf, P., Closs, E. I., & Munder, M. (2014). Metabolism via arginase or nitric oxide synthase: two competing arginine pathways in macrophages. Front Immunol, 5. https://doi.org/10.3389/fimmu.2014.00532.

Tannahill, G. M., Curtis, A. M., Adamik, J., Palsson-Mcdermott, E. M., McGettrick, A. F., Goel, G., … O'Neill, L. A. J. (2013). Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature, 496, 238-242. https://doi.org/10.1038/nature11986.

Michelucci, A., Cordes, T., Ghelfi, J., Pailot, A., Reiling, N., Goldmann, O., … Hiller, K. (2013). Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. Proc Natl Acad Sci U S A, 110, 7820-7825. https://doi.org/10.1073/pnas.1218599110.

Coats, B. R., Schoenfelt, K. Q., Barbosa-Lorenzi, V. C., Peris, E., Cui, C., Hoffman, A., … Becker, L. (2017). Metabolically activated adipose tissue macrophages perform detrimental and beneficial functions during diet-induced obesity. Cell Rep., 20, 3149-3161. https://doi.org/10.1016/j.celrep.2017.08.096.

Kratz, M., Coats, B. R., Hisert, K. B., Hagman, D., Mutskov, V., Peris, E., … Becker, L. (2014). Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metab., 20, 614-625. https://doi.org/10.1016/j.cmet.2014.08.010.

Sheedy, F. J., Grebe, A., Rayner, K. J., Kalantari, P., Ramkhelawon, B., Carpenter, S. B., … Moore, K. J. (2013). CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat. Immunol., 14, 812-820. https://doi.org/10.1038/ni.2639.

Agoro, R., Taleb, M., Quesniaux, V. F. J., & Mura, C. (2018). Cell iron status influences macrophage polarization. PLoS One, 13, e0196921. https://doi.org/10.1371/journal.pone.0196921.

Gunasekar, P., Swier, V. J., Fleegel, J. P., Boosani, C. S., Radwan, M. M., & AgrawalI, D. K. (2018). Vitamin D and macrophage polarization in epicardial adipose tissue of atherosclerotic swine. PLoS One, 13. https://doi.org/10.1371/journal.pone.0199411.

Lawrence, S. M., Corriden, R., & Nizet, V. (2018). The Ontogeny of a neutrophil: mechanisms of granulopoiesis and homeostasis. Microbiol Mol Biol Rev, 82. https://doi.org/10.1128/mmbr.00057-17.

Kumar, S., & Dikshit, M. (2019). Metabolic insight of neutrophils in health and disease. Front Immunol, 10, 2099. https://doi.org/10.3389/fimmu.2019.02099.

Robinson, J. M., Karnovsky, M. L., & Karnovsky, M. I. (1982). Glycogen accumulation in polymorphonuclear leukocytes, and other intracellular alterations that occur during inflammation. J. Cell Biol., 95, 933-942. https://doi.org/10.1083/jcb.95.3.933.

Rodríguez-Espinosa, O., Rojas-Espinosa, O., Moreno-Altamirano, M. M. B., López-Villegas, E. O., & Sánchez-García, F. J. (2015). Metabolic requirements for neutrophil extracellular traps formation. Immunology, 145, 213-224. https://doi.org/10.1111/imm.12437.

Shi, L. Z., Wang, R., Huang, G., Vogel, P., Neale, G., Green, D. R., & Chi, H. (2011). HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med., 208, 1367-1376. https://doi.org/10.1084/jem.20110278.

Berod, L., Friedrich, C., Nandan, A., Freitag, J., Hagemann, S., Harmrolfs, K., … Sparwasser, T. (2014). De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat. Med., 20, 1327-1333. https://doi.org/10.1038/nm.3704.

Xu, T., Stewart, K. M., Wang, X., Liu, K., Xie, M., Kyu Ryu, J., … Ding, S. (2017). Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism. Nature, 548, 228-233. https://doi.org/10.1038/nature23475.

Nakaya, M., Xiao, Y., Zhou, X., Chang, J. H., Chang, M., Cheng, X., … Sun, S. C. (2014). Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity, 40, 692-705. https://doi.org/10.1016/j.immuni.2014.04.007.

Geiger, R., Rieckmann, J. C., Wolf, T., Basso, C., Feng, Y., Fuhrer, T., … Lanzavecchia, A. (2016). L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell, 167, 829-842.e13. https://doi.org/10.1016/j.cell.2016.09.031.

van der Windt, G. J. W., Everts, B., Chang, C. H., Curtis, J. D., Freitas, T. C., Amiel, E., … Pearce, E. L. (2012). Mitochondrial respiratory capacity is a critical regulator of CD8 + T cell memory development. Immunity, 36, 68-78. https://doi.org/10.1016/j.immuni.2011.12.007.

Michalek, R. D., Gerriets, V. A., Jacobs, S. R., Macintyre, A. N., MacIver, N. J., Mason, E. F., … Rathmell, J. C. (2011). Cutting edge: Distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4 + T cell subsets. . J. Immunol., 186, 3299-3303. https://doi.org/10.4049/jimmunol.1003613.

Buck, M. D., O'Sullivan, D., & Pearce, E. L. (2015). T cell metabolism drives immunity. J. Exp. Med., 212, 1345-1360. https://doi.org/10.1084/jem.20151159.

Ma, R., Ji, T., Zhang, H., Dong, W., Chen, X., Xu, P., … Huang, B. (2018). A Pck1-directed glycogen metabolic program regulates formation and maintenance of memory CD8 + T cells. Nat. Cell Biol., 20, 21-27. https://doi.org/10.1038/s41556-017-0002-2.

Sukumar, M., Liu, J., Ji, Y., Subramanian, M., Crompton, J. G., Yu, Z., … Gattinoni, L. (2013). Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J. Clin. Invest., 123, 4479-4488. https://doi.org/10.1172/JCI69589.

Pearce, E. L., Walsh, M. C., Cejas, P. J., Harms, G. M., Shen, H., Wang, L. S., … Choi, Y. (2009). Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature, 460, 103-107. https://doi.org/10.1038/nature08097.

Hortová-Kohoutková, M., Tidu, F., De Zuani, M., Šrámek, V., Helán, M., & Frič, J. (2020). Phagocytosis-inflammation crosstalk in sepsis. Shock Publish Ah, https://doi.org/10.1097/shk.0000000000001541.

Davies, L. C., Rice, C. M., McVicar, D. W., & Weiss, J. M. (2019). Diversity and environmental adaptation of phagocytic cell metabolism. J Leukoc Biol, 105, 37-48. https://doi.org/10.1002/JLB.4RI0518-195R.

Lachmandas, E., Boutens, L., Ratter, J. M., Hijmans, A., Hooiveld, G. J., Joosten, L. A. B., … Stienstra, R. (2017). Microbial stimulation of different toll-like receptor signalling pathways induces diverse metabolic programmes in human monocytes. Nat. Microbiol., 2, 16246. https://doi.org/10.1038/nmicrobiol.2016.246.

Zmijewski, J. W., Lorne, E., Banerjee, S., & Abraham, E. (2009). Participation of mitochondrial respiratory complex III in neutrophil activation and lung injury. Am J Physiol Cell Mol Physiol, 296, L624-L634. https://doi.org/10.1152/ajplung.90522.2008.

Galván-Peña, S., & O'Neill, L. A. J. (2014). Metabolic reprograming in macrophage polarization. Front Immunol, 5, 420. https://doi.org/10.3389/fimmu.2014.00420.

Canton, J., Khezri, R., Glogauer, M., & Grinstein, S. (2014). Contrasting phagosome pH regulation and maturation in human M1 and M2 macrophages. Mol. Biol. Cell, 25, 3330-3341. https://doi.org/10.1091/mbc.E14-05-0967.

Kumar, H., Kawai, T., & Akira, S. (2011). Pathogen recognition by the innate immune system. Int Rev Immunol, 30, 16-34. https://doi.org/10.3109/08830185.2010.529976.

Schroder, K., Zhou, R., & Tschopp, J. (2010). The NLRP3 inflammasome: a sensor for metabolic danger? Science (80-), 327, 296-300. https://doi.org/10.1126/science.1184003.

Yang, Y., Wang, H., Kouadir, M., Song, H., & Shi, F. (2019). Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors. Cell Death Dis., 10, 1-11. https://doi.org/10.1038/s41419-019-1413-8.

Próchnicki, T., & Latz, E. (2017). Inflammasomes on the crossroads of innate immune recognition and metabolic control. Cell Metab., 26, 71-93. https://doi.org/10.1016/j.cmet.2017.06.018.

Moon, J. S., Hisata, S., Park, M. A., DeNicola, G. M., Ryter, S. W., Nakahira, K., & Choi, A. M. K. (2015). MTORC1-induced HK1-dependent glycolysis regulates NLRP3 inflammasome activation. Cell Rep., 12, 102-115. https://doi.org/10.1016/j.celrep.2015.05.046.

O'Neill, L. A. J. (2015). A broken krebs cycle in macrophages. Immunity, 42, 393-394. https://doi.org/10.1016/j.immuni.2015.02.017.

Martínez-García, J. J., Martínez-Banaclocha, H., Angosto-Bazarra, D., de Torre-Minguela, C., Baroja-Mazo, A., Alarcón-Vila, C., … Pelegrin, P. (2019). P2 × 7 receptor induces mitochondrial failure in monocytes and compromises NLRP3 inflammasome activation during sepsis. Nat. Commun., 10, 2711. https://doi.org/10.1038/s41467-019-10626-x.

Esquerdo, K. F., Sharma, N. K., Brunialti, M. K. C., Baggio-Zappia, G. L., Assunção, M., Azevedo, L. C. P., … Salomao, R. (2017). Inflammasome gene profile is modulated in septic patients, with a greater magnitude in non-survivors. Clin. Exp. Immunol., 189, 232-240. https://doi.org/10.1111/cei.12971.

Papayannopoulos, V. (2018). Neutrophil extracellular traps in immunity and disease. Nat. Rev. Immunol., 18, 134-147. https://doi.org/10.1038/nri.2017.105.

Yousefi, S., Stojkov, D., Germic, N., Simon, D., Wang, X., Benarafa, C., & Simon, H. (2019). Untangling “NETosis” from NETs. Eur. J. Immunol., 49, 221-227. https://doi.org/10.1002/eji.201747053.

Cassetta, L., Baekkevold, E. S., Brandau, S., Bujko, A., Cassatella, M. A., Dorhoi, A., … Adema, G. J. (2019). Deciphering myeloid-derived suppressor cells: Isolation and markers in humans, mice and non-human primates. Cancer Immunol. Immunother., 68, 687-697. https://doi.org/10.1007/s00262-019-02302-2.

Hsu, B. E., Tabariès, S., Johnson, R. M., Andrzejewski, S., Senecal, J., Lehuédé, C., … Siegel, P. M. (2019). Immature low-density neutrophils exhibit metabolic flexibility that facilitates breast cancer liver metastasis. Cell Rep., 27, 3902-3915.e6. https://doi.org/10.1016/j.celrep.2019.05.091.

Borregaard, N., & Herlin, T. (1982). Energy metabolism of human neutrophils during phagocytosis. J. Clin. Invest., 70, 550-557. https://doi.org/10.1172/JCI110647.

Li, R. H. L., & Tablin, F. (2018). A comparative review of neutrophil extracellular traps in sepsis. Front Vet Sci, 5, 291. https://doi.org/10.3389/fvets.2018.00291.

Masopust, D., Sivula, C. P., & Jameson, S. C. (2017). Of mice, dirty mice, and men: using mice to understand human immunology. J. Immunol., 199, 383-388. https://doi.org/10.4049/jimmunol.1700453.

Tao, L., & Reese, T. A. (2017). Making mouse models that reflect human immune responses. Trends Immunol., 38, 181-193. https://doi.org/10.1016/j.it.2016.12.007.

Tucey, T. M., Verma, J., Harrison, P. F., Snelgrove, S. L., Lo, T. L., Scherer, A. K., … Traven, A. (2018). Glucose homeostasis is important for immune cell viability during candida challenge and host survival of systemic fungal infection. Cell Metab., 27, 988-1006.e7. https://doi.org/10.1016/j.cmet.2018.03.019.

Vitko, N. P., Spahich, N. A., & Richardson, A. R. (2015). Glycolytic dependency of high-level nitric oxide resistance and virulence in staphylococcus aureus. MBio, 6. https://doi.org/10.1128/mBio.00045-15.

Bowden, S. D., Rowley, G., Hinton, J. C. D., & Thompson, A. (2009). Glucose and glycolysis are required for the successful infection of macrophages and mice by salmonella enterica serovar typhimurium. Infect. Immun., 77, 3117-3126. https://doi.org/10.1128/IAI.00093-09.

Price, C. T. D., Al-Quadan, T., Santic, M., Rosenshine, I., & Abu Kwaik, Y. (2011). Host proteasomal degradation generates amino acids essential for intracellular bacterial growth. Science (80-), 334, 1553-1557. https://doi.org/10.1126/science.1212868.

Gobert, A. P., McGee, D. J., Akhtar, M., Mendz, G. L., Newton, J. C., Cheng, Y., … Wilson, K. T. (2001). Helicobacter pylori arginase inhibits nitric oxide production by eukaryotic cells: A strategy for bacterial survival. Proc Natl Acad Sci U S A, 98, 13844-13849. https://doi.org/10.1073/pnas.241443798.

Palmer, C. S., Ostrowski, M., Gouillou, M., Tsai, L., Yu, D., Zhou, J., … Crowe, S. M. (2014). Increased glucose metabolic activity is associated with CD4+ T-cell activation and depletion during chronic HIV infection. AIDS, 28, 297-309. https://doi.org/10.1097/QAD.0000000000000128.

Hollenbaugh, J. A., Munger, J., & Kim, B. (2011). Metabolite profiles of human immunodeficiency virus infected CD4+ T cells and macrophages using LC-MS/MS analysis. Virology, 415, 153-159. https://doi.org/10.1016/j.virol.2011.04.007.

Valle-Casuso, J. C., Angin, M., Volant, S., Passaes, C., Monceaux, V., Mikhailova, A., … Sáez-Cirión, A. (2019). Cellular metabolism is a major determinant of HIV-1 reservoir seeding in CD4 + T cells and offers an opportunity to tackle infection. Cell Metab., 29, 611-626.e5. https://doi.org/10.1016/j.cmet.2018.11.015.

Castellano, P., Prevedel, L., Valdebenito, S., & Eugenin, E. A. (2019). HIV infection and latency induce a unique metabolic signature in human macrophages. Sci. Rep., 9. https://doi.org/10.1038/s41598-019-39898-5.

Cheng, S. C., Scicluna, B. P., Arts, R. J. W., Gresnigt, M. S., Lachmandas, E., Giamarellos-Bourboulis, E. J., … Netea, M. G. (2016). Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nat. Immunol., 17, 406-413. https://doi.org/10.1038/ni.3398.

Su, L., Li, H., Xie, A., Liu, D., Rao, W., Lan, L., … Xie, L. (2015). Dynamic changes in amino acid concentration profiles in patients with sepsis. PLoS One, 10, 1-15. https://doi.org/10.1371/journal.pone.0121933.

Lee, I., & Hüttemann, M. (2014). Energy crisis: The role of oxidative phosphorylation in acute inflammation and sepsis. Biochim Biophys Acta - Mol Basis Dis, 1842, 1579-1586. https://doi.org/10.1016/j.bbadis.2014.05.031.

Hung, K. Y., Chen, Y. M., Wang, C. C., Wang, Y. H., Lin, C. Y., Chang, Y. T., … Fang, W. F. (2019). Insufficient nutrition and mortality risk in septic patients admitted to ICU with a focus on immune dysfunction. Nutrients, 11. https://doi.org/10.3390/nu11020367.

Wischmeyer, P. E. (2018). Nutrition therapy in sepsis. Crit Care Clin., 34, 107-125. https://doi.org/10.1016/j.ccc.2017.08.008.

Wang, A., Huen, S. C., Luan, H. H., Yu, S., Zhang, C., Gallezot, J. D., … Medzhitov, R. (2016). Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation. Cell, 166, 1512-1525.e12. https://doi.org/10.1016/j.cell.2016.07.026.

Alwarawrah, Y., Kiernan, K., & MacIver, N. J. (2018). Changes in nutritional status impact immune cell metabolism and function. Front Immunol, 9, 1055. https://doi.org/10.3389/fimmu.2018.01055.

Steiner, A. A., & Romanovsky, A. A. (2007). Leptin: At the crossroads of energy balance and systemic inflammation. Prog Lipid Res, 46, 89-107. https://doi.org/10.1016/j.plipres.2006.11.001.

Emamgholipour, S., Eshaghi, S. M., Hossein-nezhad, A., Mirzaei, K., Maghbooli, Z., & Sahraian, M. A. (2013). Adipocytokine profile, cytokine levels and foxp3 expression in multiple sclerosis: a possible link to susceptibility and clinical course of disease. PLoS One, 8, e76555. https://doi.org/10.1371/journal.pone.0076555.

Wang, X., Qiao, Y., Yang, L., Song, S., Han, Y., Tian, Y., … Liu, A. (2017). Leptin levels in patients with systemic lupus erythematosus inversely correlate with regulatory T cell frequency. Lupus, 26, 1401-1406. https://doi.org/10.1177/0961203317703497.

Wang, S., Baidoo, S. E., Liu, Y., Zhu, C., Tian, J., Ma, J., … Lu, L. (2013). T cell-derived leptin contributes to increased frequency of T helper type 17 cells in female patients with Hashimoto's thyroiditis. Clin. Exp. Immunol., 171, 63-68. https://doi.org/10.1111/j.1365-2249.2012.04670.x.

Lumeng, C. N., Bodzin, J. L., & Saltiel, A. R. (2007). Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest., 117, 175-184. https://doi.org/10.1172/JCI29881.

Gerriets, V. A., & MacIver, N. J. (2014). Role of T cells in malnutrition and obesity. Front Immunol, 5, 379. https://doi.org/10.3389/fimmu.2014.00379.

Osborn, O., & Olefsky, J. M. (2012). The cellular and signaling networks linking the immune system and metabolism in disease. Nat. Med., 18, 363-374. https://doi.org/10.1038/nm.2627.

Ouchi, N., Parker, J. L., Lugus, J. J., & Walsh, K. (2011). Adipokines in inflammation and metabolic disease. Nat. Rev. Immunol., 11, 85-97. https://doi.org/10.1038/nri2921.

Saucillo, D. C., Gerriets, V. A., Sheng, J., Rathmell, J. C., & MacIver, N. J. (2014). Leptin metabolically licenses T cells for activation to link nutrition and immunity. J. Immunol., 192, 136-144. https://doi.org/10.4049/jimmunol.1301158.

Nájera, O., González, C., Toledo, G., López, L., Cortés, E., Betancourt, M., & Ortiz, R. (2001). CD45RA and CD45RO isoforms in infected malnourished and infected well-nourished children. Clin. Exp. Immunol., 126, 461-465. https://doi.org/10.1046/j.1365-2249.2001.01694.x.

Nájera, O., González, C., Cortés, E., Toledo, G., & Ortiz, R. (2007). Effector T lymphocytes in well-nourished and malnourished infected children. Clin. Exp. Immunol., 148, 501-506. https://doi.org/10.1111/j.1365-2249.2007.03369.x.

Rytter, M. J. H., Kolte, L., Briend, A., Friis, H., & Christensen, V. B. (2014). The immune system in children with malnutrition - a systematic review. PLoS One, 9, e105017. https://doi.org/10.1371/journal.pone.0105017.

de Oliveira, D. C., Hastreiter, A. A., Mello, A. S., de Oliveira Beltran, J. S., Oliveira Santos, E. W. C., Borelli, P. and Fock, R. A. (2014). The effects of protein malnutrition on the TNF-RI and NF-κB expression via the TNF-α signaling pathway. Cytokine, 69, 218-225. https://doi.org/10.1016/j.cyto.2014.06.004.

González-Torres, C., González-Martínez, H., Miliar, A., Nájera, O., Graniel, J., Firo, V., … Rodríguez, L. (2013). Effect of malnutrition on the expression of cytokines involved in Th1 cell differentiation. Nutrients, 5, 579-593. https://doi.org/10.3390/nu5020579.

González-Martínez, H., Rodríguez, L., Nájera, O., Cruz, D., Miliar, A., Domínguez, A., … González-Torres, M. C. (2008). Expression of cytokine mRNA in lymphocytes of malnourished children. J Clin Immunol, 28, 593-599. https://doi.org/10.1007/s10875-008-9204-5.

Walker, J. A., & McKenzie, A. N. J. (2018). TH2 cell development and function. Nat. Rev. Immunol., 18, 121-133. https://doi.org/10.1038/nri.2017.118.

Corware, K., Yardley, V., Mack, C., Schuster, S., Al-Hassi, H., Herath, S., … Kropf, P. (2014). Protein energy malnutrition increases arginase activity in monocytes and macrophages. Nutr Metab, 11, 51. https://doi.org/10.1186/1743-7075-11-51.

Takele, Y., Adem, E., Getahun, M., Tajebe, F., Kiflie, A., Hailu, A., … Kropf, P. (2016). Malnutrition in healthy individuals results in increased mixed cytokine profiles, altered neutrophil subsets and function. PLoS One, 11, e0157919. https://doi.org/10.1371/journal.pone.0157919.

Rodríguez, L., González, C., Flores, L., Jiménez-Zamudio, L., Graniel, J., & Ortiz, R. (2005). Assessment by flow cytometry of cytokine production in malnourished children. Clin Diagn Lab Immunol, 12, 502-507. https://doi.org/10.1128/CDLI.12.4.502-507.2005.

Gerriets, V. A., Danzaki, K., Kishton, R. J., Eisner, W., Nichols, A. G., Saucillo, D. C., … MacIver, N. J. (2016). Leptin directly promotes T-cell glycolytic metabolism to drive effector T-cell differentiation in a mouse model of autoimmunity. Eur. J. Immunol., 46, 1970-1983. https://doi.org/10.1002/eji.201545861.

Ibrahim, M. K., Zambruni, M., Melby, C. L., & Melby, P. C. (2017). Impact of childhood malnutrition on host defense and infection. Clin. Microbiol. Rev., 30, 919-971. https://doi.org/10.1128/CMR.00119-16.

Lee, C., & Longo, V. (2016). Dietary restriction with and without caloric restriction for healthy aging. F1000Research, 5, 117. https://doi.org/10.12688/f1000research.7136.1.

Longo, V. D., & Mattson, M. P. (2014). Fasting: molecular mechanisms and clinical applications. Cell Metab., 19, 181-192. https://doi.org/10.1016/j.cmet.2013.12.008.

Longo, V. D. (2019). Programmed longevity, youthspan, and juventology. Aging Cell, 18, e12843. https://doi.org/10.1111/acel.12843.

Cheng, C. W., Adams, G. B., Perin, L., Wei, M., Zhou, X., Lam, B. S., … Longo, V. D. (2014). Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell- based regeneration and reverse immunosuppression. Cell Stem Cell, 14, 810-823. https://doi.org/10.1016/j.stem.2014.04.014.

Jordan, S., Tung, N., Casanova-Acebes, M., Chang, C., Cantoni, C., Zhang, D., … Merad, M. (2019). Dietary intake regulates the circulating inflammatory monocyte pool. Cell, 178, 1102-1114.e17. https://doi.org/10.1016/j.cell.2019.07.050.

Contreras, N. A., Fontana, L., Tosti, V., & Nikolich-Žugich, J. (2018). Calorie restriction induces reversible lymphopenia and lymphoid organ atrophy due to cell redistribution. GeroScience, 40, 279-291. https://doi.org/10.1007/s11357-018-0022-2.

Walrand, S., Moreau, K., Caldefie, F., Tridon, A., Chassagne, J., Portefaix, G., … Boirie, Y. (2001). Specific and nonspecific immune responses to fasting and refeeding differ in healthy young adult and elderly persons. Am. J. Clin. Nutr., 74, 670-678. https://doi.org/10.1093/ajcn/74.5.670.

Collins, N., Han, S. J., Enamorado, M., Link, V. M., Huang, B., Moseman, E. A., … Belkaid, Y. (2019). The bone marrow protects and optimizes immunological memory during dietary restriction. Cell, 178, 1088-1101.e15. https://doi.org/10.1016/j.cell.2019.07.049.

Lee, C., & Longo, V. D. (2011). Fasting versus dietary restriction in cellular protection and cancer treatment: From model organisms to patients. Oncogene, 30, 3305-3316. https://doi.org/10.1038/onc.2011.91.

Tang, D., Tao, S., Chen, Z., Koliesnik, I. O., Calmes, P. G., Hoerr, V., … Rudolph, K. L. (2016). Dietary restriction improves repopulation but impairs lymphoid differentiation capacity of hematopoietic stem cells in early aging. J. Exp. Med., 213, 535-553. https://doi.org/10.1084/JEM.20151100.

Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). MTOR is a key modulator of ageing and age-related disease. Nature, 493, 338-345. https://doi.org/10.1038/nature11861.

Goldberg, E. L., Romero-Aleshire, M. J., Renkema, K. R., Ventevogel, M. S., Chew, W. M., Uhrlaub, J. L., … Nikolich-Žugich, J. (2015). Lifespan-extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms. Aging Cell, 14, 130-138. https://doi.org/10.1111/acel.12280.

Gardner, E. M. (2005). Caloric restriction decreases survival of aged mice in response to primary influenza infection. J Gerontol A Biol Sci Med Sci, 60, 688-94. https://doi.org/10.1093/gerona/60.6.688.

Fali, T., Fabre-Mersseman, V., Yamamoto, T., Bayard, C., Papagno, L., Fastenackels, S., … Appay, V. (2018). Elderly human hematopoietic progenitor cells express cellular senescence markers and are more susceptible to pyroptosis. JCI insight, 3. https://doi.org/10.1172/jci.insight.95319.

Hansen, M., Rubinsztein, D. C., & Walker, D. W. (2018). Autophagy as a promoter of longevity: Insights from model organisms. Nat. Rev. Mol. Cell Biol., 19, 579-593. https://doi.org/10.1038/s41580-018-0033-y.

Pietrocola, F., Demont, Y., Castoldi, F., Enot, D., Durand, S., Semeraro, M., … Kroemer, G. (2017). Metabolic effects of fasting on human and mouse blood in vivo. Autophagy, 13, 567-578. https://doi.org/10.1080/15548627.2016.1271513.

Ron-Harel, N., Notarangelo, G., Ghergurovich, J. M., Paulo, J. A., Sage, P. T., Santos, D., … Haigis, M. C. (2018). Defective respiration and one-carbon metabolism contribute to impaired naïve T cell activation in aged mice. Proc Natl Acad Sci U S A, 115, 13347-13352. https://doi.org/10.1073/pnas.1804149115.

Pence, B. D., & Yarbro, J. R. (2018). Aging impairs mitochondrial respiratory capacity in classical monocytes. Exp. Gerontol., 108, 112-117. https://doi.org/10.1016/j.exger.2018.04.008.

Raulien, N., Friedrich, K., Strobel, S., Rubner, S., Baumann, S., von Bergen, M., … Wagner, U. (2017). fatty acid oxidation compensates for lipopolysaccharide-induced warburg effect in glucose-deprived monocytes. Front Immunol, 8, 609. https://doi.org/10.3389/fimmu.2017.00609.

Kim, J., Yang, G., Kim, Y., Kim, J., & Ha, J. (2016). AMPK activators: mechanisms of action and physiological activities. Exp. Mol. Med., 48, e224-e224. https://doi.org/10.1038/emm.2016.16.

Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., … Moller, D. E. (2001). Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest., 108, 1167-1174. https://doi.org/10.1172/JCI13505.

Hawley, S. A., Fullerton, M. D., Ross, F. A., Schertzer, J. D., Chevtzoff, C., Walker, K. J., … Hardie, D. G. (2012). The ancient drug salicylate directly activates AMP-activated protein kinase. Science (80-), 336, 918-922. https://doi.org/10.1126/science.1215327.

Tizazu, A. M., Nyunt, M. S. Z., Cexus, O., Suku, K., Mok, E., Xian, C. H., … Larbi, A. (2019). Metformin monotherapy downregulates diabetes-associated inflammatory status and impacts on mortality. Front Physiol, 10, 572. https://doi.org/10.3389/fphys.2019.00572.

Mor, A., Petersen, I., SØrensen, H. T., & Thomsen, R. W. (2016). Metformin and other glucose-lowering drug initiation and rates of community-based antibiotic use and hospital-treated infections in patients with type 2 diabetes: a Danish nationwide population-based cohort study. BMJ Open, 6, e011523. https://doi.org/10.1136/bmjopen-2016-011523.

Bai, A., Ma, A. G., Yong, M., Weiss, C. R., Ma, Y., Guan, Q., … Peng, Z. (2010). AMPK agonist downregulates innate and adaptive immune responses in TNBS-induced murine acute and relapsing colitis. Biochem. Pharmacol., 80, 1708-1717. https://doi.org/10.1016/j.bcp.2010.08.009.

Fan, K., Lin, L., Ai, Q., Wan, J., Dai, J., Liu, G., … Zhang, L. (2018). Lipopolysaccharide-induced dephosphorylation of AMPK-activated protein kinase potentiates inflammatory injury via repression of ULK1-dependent autophagy. Front Immunol, 9, 1464. https://doi.org/10.3389/fimmu.2018.01464.

Zheng, M., Zheng, M., Xie, L., Xie, L., Liang, Y., Wu, S., … Lu, K. (2015). Recognition of cytosolic DNA attenuates glucose metabolism and induces AMPK mediated energy stress response. Int J Biol Sci, 11, 587-594. https://doi.org/10.7150/ijbs.10945.

Vastag, L., Koyuncu, E., Grady, S. L., Shenk, T. E., & Rabinowitz, J. D. (2011). Divergent effects of human cytomegalovirus and herpes simplex virus-1 on cellular metabolism. PLoS Pathog., 7, e1002124. https://doi.org/10.1371/journal.ppat.1002124.

Silwal, P., Kim, J., Yuk, J. -. M., & Jo, E. -. K. (2018). AMP-Activated protein kinase and host defense against infection. Int. J. Mol. Sci., 19, 3495. https://doi.org/10.3390/ijms19113495.

Hossain, F., Al-Khami, A. A., Wyczechowska, D., Hernandez, C., Zheng, L., Reiss, K., … Ochoa, A. C. (2015). Inhibition of fatty acid oxidation modulates immunosuppressive functions of myeloid-derived suppressor cells and enhances cancer therapies. Cancer Immunol. Res., 3, 1236-1247. https://doi.org/10.1158/2326-6066.CIR-15-0036.

Jian, S. L., Chen, W. W., Su, Y. C., Su, Y. W., Chuang, T. H., Hsu, S. C., & Huang, L. R. (2017). Glycolysis regulates the expansion of myeloid-derived suppressor cells in tumor-bearing hosts through prevention of ROS-mediated apoptosis. Cell Death Dis., 8, e2779-e2779. https://doi.org/10.1038/cddis.2017.192.

Zhang, Y., Kurupati, R., Liu, L., Zhou, X. Y., Zhang, G., Hudaihed, A., … Ertl, H. C. J. (2017). Enhancing CD8+ T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell, 32, 377-391.e9. https://doi.org/10.1016/j.ccell.2017.08.004.

Bajgain, P., Tawinwung, S., D'Elia, L., Sukumaran, S., Watanabe, N., Hoyos, V., … Vera, J. F. (2018). CAR T cell therapy for breast cancer: Harnessing the tumor milieu to drive T cell activation. J Immunother Cancer, 6, 34. https://doi.org/10.1186/s40425-018-0347-5.

Yin, Z., Bai, L., Li, W., Zeng, T., Tian, H., & Cui, J. (2019). Targeting T cell metabolism in the tumor microenvironment: An anti-cancer therapeutic strategy. J Exp Clin Cancer Res, 38, 403. https://doi.org/10.1186/s13046-019-1409-3.

Pålsson-McDermott, E. M., & O'Neill, L. A. J. (2020). Targeting immunometabolism as an anti-inflammatory strategy. Cell Res., 1-15. https://doi.org/10.1038/s41422-020-0291-z.

Maiuri, M. C., & Kroemer, G. (2019). Therapeutic modulation of autophagy: Which disease comes first? Cell Death Differ., 26, 680-689. https://doi.org/10.1038/s41418-019-0290-0.

Chude, C. I., & Amaravadi, R. K. (2017). Targeting Autophagy in cancer: Update on clinical trials and novel inhibitors. Int. J. Mol. Sci., 18, 1279. https://doi.org/10.3390/ijms18061279.

Singh, J. A., Hossain, A., Kotb, A., & Wells, G. (2016). Risk of serious infections with immunosuppressive drugs and glucocorticoids for lupus nephritis: A systematic review and network meta-analysis. BMC Med., 14, 137. https://doi.org/10.1186/s12916-016-0673-8.

Rosenthal, M. D., & Moore, F. A. (2015). Persistent inflammatory, immunosuppressed, catabolic syndrome (PICS). A new phenotype of multiple organ failure. J Adv Nutr Hum Metab, 1. https://doi.org/10.14800/janhm.784.

Lactate from the tumor microenvironment - A key obstacle in NK cell-based immunotherapies

Immunosenescence in Childhood Cancer Survivors and in Elderly: A Comparison and Implication for Risk Stratification