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T cell metabolism: new insights in systemic lupus erythematosus pathogenesis and therapy

Nature Reviews Rheumatology volume 16, pages 100–112 (2020)Cite this article

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Abstract

T cell subsets are critically involved in the development of systemic autoimmunity and organ inflammation in systemic lupus erythematosus (SLE). Each T cell subset function (such as effector, helper, memory or regulatory function) is dictated by distinct metabolic pathways requiring the availability of specific nutrients and intracellular enzymes. The activity of these enzymes or nutrient transporters influences the differentiation and function of T cells in autoimmune responses. Data are increasingly emerging on how metabolic processes control the function of various T cell subsets and how these metabolic processes are altered in SLE. Specifically, aberrant glycolysis, glutaminolysis, fatty acid and glycosphingolipid metabolism, mitochondrial hyperpolarization, oxidative stress and mTOR signalling underwrite the known function of T cell subsets in patients with SLE. A number of medications that are used in the care of patients with SLE affect cell metabolism, and the development of novel therapeutic approaches to control the activity of metabolic enzymes in T cell subsets represents a promising endeavour in the search for effective treatment of systemic autoimmune diseases.

Key points

  • The fate of T cell differentiation can be determined by the activity of various metabolic pathways in the cell, reflecting the central role of metabolism in controlling T cell plasticity.

  • In systemic lupus erythematosus (SLE), T cells are chronically active as a result of T cell receptor rewiring, hypomethylation of genes related to cell activation, an increase in lipid raft formation and multifactorial mTORC1 activation.

  • Manipulating metabolic pathways in T cells is a promising strategy in SLE and could enable the inhibition of pathogenic effector T cell activation and differentiation and the promotion of regulatory T cells.

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Fig. 1: Metabolic pathways in immune cells.
Fig. 2: Metabolic requirements of T cells.
Fig. 3: Effect of metabolism on TH1 cell versus TH17 cell differentiation.
Fig. 4: Metabolic pathways in Treg cells.
Fig. 5: T cell metabolism in SLE.

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References

  1. Kasper, I. R., Apostolidis, S. A., Sharabi, A. & Tsokos, G. C. Empowering regulatory T cells in autoimmunity. Trends Mol. Med. 22, 784–797 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Katsuyama, T., Tsokos, G. C. & Moulton, V. R. Aberrant T cell signaling and subsets in systemic lupus erythematosus. Front. Immunol. 9, 1088 (2018).

    PubMed  PubMed Central  Google Scholar 

  3. Suárez-Fueyo, A., Bradley, S. J., Klatzmann, D. & Tsokos, G. C. T cells and autoimmune kidney disease. Nat. Rev. Nephrol. 16, 329–343 (2017).

    Google Scholar 

  4. Perl, A. Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases. Nat. Rev. Rheumatol. 12, 169–182 (2016).

    CAS  PubMed  Google Scholar 

  5. Morel, L. Immunometabolism in systemic lupus erythematosus. Nat. Rev. Rheumatol. 13, 280–290 (2017).

    CAS  PubMed  Google Scholar 

  6. Buck, M. D., Sowell, R. T., Kaech, S. M. & Pearce, E. L. Metabolic instruction of immunity. Cell 169, 570–586 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Chi, H. Regulation and function of mTOR signalling in T cell fate decisions. Nat. Rev. Immunol. 12, 325–338 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Finlay, D. & Cantrell, D. A. Metabolism, migration and memory in cytotoxic T cells. Nat. Rev. Immunol. 11, 109–117 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang, R. et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35, 871–882 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Frauwirth, K. A. et al. The CD28 signaling pathway regulates glucose metabolism. Immunity 16, 769–777 (2002).

    CAS  PubMed  Google Scholar 

  12. MacIver, N. J., Michalek, R. D. & Rathmell, J. C. Metabolic regulation of T lymphocytes. Annu. Rev. Immunol. 31, 259–283 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Verbist, K. C. et al. Metabolic maintenance of cell asymmetry following division in activated T lymphocytes. Nature 532, 389–393 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. D’Souza, A. D., Parikh, N., Kaech, S. M. & Shadel, G. S. Convergence of multiple signaling pathways is required to coordinately up-regulate mtDNA and mitochondrial biogenesis during T cell activation. Mitochondrion 7, 374–385 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Sena, L. A. et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38, 225–236 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Taniuchi, I. CD4 Helper and CD8 Cytotoxic T Cell Differentiation. Annu. Rev. Immunol. 36, 579–601 (2018).

    CAS  PubMed  Google Scholar 

  17. Guma, M., Tiziani, S. & Firestein, G. S. Metabolomics in rheumatic diseases: desperately seeking biomarkers. Nat. Rev. Rheumatol. 12, 269–281 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Zeng, H. et al. mTORC1 and mTORC2 kinase signaling and glucose metabolism drive follicular helper T cell differentiation. Immunity 45, 540–554 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Oestreich, K. J. et al. Bcl-6 directly represses the gene program of the glycolysis pathway. Nat. Immunol. 15, 957–964 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Man, K. et al. The transcription factor IRF4 is essential for TCR affinity-mediated metabolic programming and clonal expansion of T cells. Nat. Immunol. 14, 1155–1165 (2013).

    CAS  PubMed  Google Scholar 

  21. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Shehade, H., Acolty, V., Moser, M. & Oldenhove, G. Cutting edge: hypoxia-inducible factor 1 negatively regulates Th1 function. J. Immunol. 195, 1372–1376 (2015).

    CAS  PubMed  Google Scholar 

  23. Jacobs, S. R. et al. Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and indepndent pathways. J. Immunol. 180, 4476–4486 (2008).

    CAS  PubMed  Google Scholar 

  24. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Yang, J. Q. et al. RhoA orchestrates glycolysis for TH2 cell differentiation and allergic airway inflammation. J. Allergy Clin. Immunol. 137, 231–245 (2016).

    CAS  PubMed  Google Scholar 

  26. Kono, M. et al. Pyruvate dehydrogenase phosphatase catalytic subunit 2 limits Th17 differentiation. Proc. Natl Acad. Sci. USA 115, 9288–9293 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Yoshida, N. et al. ICER is requisite for Th17 differentiation. Nat. Commun. 7, 12993 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Gerriets, V. A. et al. Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J. Clin. Invest. 125, 194–207 (2015).

    PubMed  Google Scholar 

  29. Yin, Y. et al. Normalization of CD4+ T cell metabolism reverses lupus. Sci. Transl. Med. 7, 274ra18 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Yin, Y. et al. Glucose oxidation is critical for CD4+T cell activation in a mouse model of systemic lupus erythematosus. J. Immunol. 196, 80–90 (2016).

    CAS  PubMed  Google Scholar 

  31. Hasegawa, H. et al. Pioglitazone, a peroxisome proliferator-activated receptor γ activator, ameliorates experimental autoimmune myocarditis by modulating Th1/Th2 balance. J. Mol. Cell. Cardiol. 38, 257–265 (2005).

    CAS  PubMed  Google Scholar 

  32. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Wolfson, R. L. et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science 351, 43–48 (2016).

    CAS  PubMed  Google Scholar 

  34. Nakajima, H. & Kunimoto, H. TET2 as an epigenetic master regulator for normal and malignant hematopoiesis. Cancer Sci. 105, 1093–1099 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Xu, T. et al. Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism. Nature 548, 228–233 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–384 (2011).

    PubMed  PubMed Central  Google Scholar 

  37. Sundrud, M. S. et al. Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Science 324, 1334–1338 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Nakaya, M. et al. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 40, 692olde5 (2014).

    Google Scholar 

  39. Kono, M., Yoshida, N., Maeda, K. & Tsokos, G. C. Transcriptional factor ICER promotes glutaminolysis and the generation of Th17 cells. Proc. Natl Acad. Sci. USA 115, 2478–2483 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Johnson, M. O. et al. Distinct regulation of Th17 and Th1 cell differentiation by glutaminase-dependent metabolism. Cell 175, 1780–1795 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Raposo, B., Vaartjes, D., Ahlqvist, E., Nandakumar, K. S. & Holmdahl, R. System A amino acid transporters regulate glutamine uptake and attenuate antibody-mediated arthritis. Immunology 146, 607–617 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Klysz, D. et al. Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Sci. Signal. 8, ra97 (2015).

    PubMed  Google Scholar 

  43. Ma, E. H. et al. Serine is an essential metabolite for effector T cell expansion. Cell Metab. 25, 345–357 (2017).

    CAS  PubMed  Google Scholar 

  44. Huennekens, F. M. The methotrexate story: a paradigm for development of cancer chemotherapeutic agents. Adv. Enzyme Regul. 34, 397–419 (1994).

    CAS  PubMed  Google Scholar 

  45. Hardie, D. G. AMP-activated protein kinase: a cellular energy sensor with a key role in metabolic disorders and in cancer. Biochem. Soc. Trans. 39, 1–13 (2011).

    CAS  PubMed  Google Scholar 

  46. 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).

    CAS  PubMed  Google Scholar 

  47. Haghikia, A. et al. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. Immunity 43, 817–829 (2015).

    CAS  PubMed  Google Scholar 

  48. Mangalam, A. et al. Profile of circulatory metabolites in a relapsing-remitting animal model of multiple sclerosis using global metabolomics. J. Clin. Cell Immunol. https://doi.org/10.4172/2155-9899.1000150 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Zhang, X., Tao, Y., Troiani, L. & Markovic-Plese, S. Simvastatin inhibits IFN regulatory factor 4 expression and Th17 cell differentiation in CD4+ T cells derived from patients with multiple sclerosis. J. Immunol. 187, 3431–3437 (2011).

    CAS  PubMed  Google Scholar 

  50. Youssef, S. et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420, 78–84 (2002).

    CAS  PubMed  Google Scholar 

  51. Mueller, S. N. & Mackay, L. K. Tissue-resident memory T cells: local specialists in immune defence. Nat. Rev. Immunol. 16, 79–89 (2016).

    CAS  PubMed  Google Scholar 

  52. Bantug, G. R., Galluzzi, L., Kroemer, G. & Hess, C. The spectrum of T cell metabolism in health and disease. Nat. Rev. Immunol. 18, 4 (2018).

    Google Scholar 

  53. Wherry, E. J. et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat. Immunol. 4, 225–234 (2003).

    CAS  PubMed  Google Scholar 

  54. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Pan, Y. et al. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 543, 252–256 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Pearce, E. L., Poffenberger, M. C., Chang, C. H. & Jones, R. G. Fueling immunity: insights into metabolism and lymphocyte function. Science 342, 1242425 (2013).

    Google Scholar 

  57. van der Windt, G. J. et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36, 68–78 (2012).

    PubMed  Google Scholar 

  58. 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).

    CAS  PubMed  Google Scholar 

  59. Phan., A. T. et al. Constitutive glycolytic metabolism supports CD8+ T cell effector memory differentiation during viral infection. Immunity 45, 1024–1037 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 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).

    CAS  PubMed  Google Scholar 

  61. 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).

    CAS  PubMed  Google Scholar 

  62. Boothby, M. Signaling in T cells—is anything the m(a)TOR with the picture(s)? F1000Res. https://doi.org/10.12688/f1000research.7027.1 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Zeng, H. & Chi, H. Metabolic control of regulatory T cell development and function. Trends Immunol. 36, 3–12 (2015).

    CAS  PubMed  Google Scholar 

  64. De Rosa, V. et al. Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants. Nat. Immunol. 16, 1174–1184 (2015).

    PubMed  PubMed Central  Google Scholar 

  65. Gerriets, V. A. et al. Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nat. Immunol. 17, 1459–1466 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Angelin, A. et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 25, 1282–1293 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Pacella, I. et al. Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth. Proc. Natl Acad. Sci. USA 115, E6546–E6555 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Burzyn, D., Benoist, C. & Mathis, D. Regulatory T cells in nonlymphoid tissues. Nat. Immunol. 14, 1007–1013 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Procaccini, C., Galgani, M., De Rosa, V. & Matarese, G. Intracellular metabolic pathways control immune tolerance. Trends Immunol. 33, 1–7 (2012).

    CAS  PubMed  Google Scholar 

  70. Feuerer, M. et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15, 930–939 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).

    CAS  PubMed  Google Scholar 

  72. Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).

    CAS  PubMed  Google Scholar 

  73. Sharabi, A. et al. Regulatory T cells in the treatment of disease. Nat. Rev. Drug Discov. 17, 823–844 (2018).

    CAS  PubMed  Google Scholar 

  74. Mezrich, J. D. et al. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J. Immunol. 185, 3190–3198 (2010).

    CAS  PubMed  Google Scholar 

  75. Buck, M. D., O’Sullivan, D. & Pearce, E. L. T cell metabolism drives immunity. J. Exp. Med. 212, 1345–1360 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Cobbold, S. P. et al. Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc. Natl Acad. Sci. USA 106, 12055–12060 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Apostolidis, S. A. et al. Phosphatase PP2A is requisite for the function of regulatory T cells. Nat. Immunol. 17, 556–564 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Zeng, H. et al. mTORC1 couples immune signals and metabolic programming to establish Treg-cell function. Nature 499, 485–490 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Wu, D. et al. Lkb1 maintains Treg cell lineage identity. Nat. Commun. 8, 15876 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Yang, K. et al. Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling. Nature 548, 602–606 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. He, N. et al. Metabolic control of regulatory T cell (Treg) survival and function by Lkb1. Proc. Natl Acad. Sci. USA 114, 12542–12547 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Wahl, D. R. et al. Characterization of the metabolic phenotype of chronically activated lymphocytes. Lupus 19, 1492–1501 (2010).

    CAS  PubMed  Google Scholar 

  83. Gergely, P. Jr. et al. Mitochondrial hyperpolarization and ATP depletion in patients with systemic lupus erythematosus. Arthritis Rheum. 46, 175–190 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Perl, A. et al. Comprehensive metabolome analyses reveal N-acetylcysteine-responsive accumulation of kynurenine in systemic lupus erythematosus: implications for activation of the mechanistic target of rapamycin. Metabolomics 11, 1157–1174 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Juang, Y. T. et al. PP2A dephosphorylates Elf-1 and determines the expression of CD3ζ and FcRγ in human systemic lupus erythematosus T cells. J. Immunol. 181, 3658–3664 (2008).

    CAS  PubMed  Google Scholar 

  86. Krishnan, S., Farber, D. L. & Tsokos, G. C. T cell rewiring in differentiation and disease. J. Immunol. 171, 3325–3331 (2003).

    CAS  PubMed  Google Scholar 

  87. Tsokos, G. C. Systemic lupus erythematosus. N. Engl. J. Med. 365, 2110–2121 (2011).

    CAS  PubMed  Google Scholar 

  88. Ichinose, K. et al. Lupus nephritis IgG induction of calcium/calmodulin-dependent protein kinase IV expression in podocytes and alteration of their function. Arthritis Rheumatol. 68, 944–952 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Li, Y., Gorelik, G., Strickland, F. M. & Richardson, B. C. Oxidative stress, T cell DNA methylation, and lupus. Arthritis Rheumatol. 66, 1574–1582 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Sunahori, K. et al. The catalytic subunit of protein phosphatase 2A (PP2Ac) promotes DNA hypomethylation by suppressing the phosphorylated mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/phosphorylated ERK/DNMT1 protein pathway in T-cells from controls and systemic lupus erythematosus patients. J. Biol. Chem. 288, 21936–21944 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Li, H. et al. Precision DNA demethylation ameliorates disease in lupus-prone mice. JCI Insight https://doi.org/10.1172/jci.insight.120880 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Perry, D. J. et al. Murine lupus susceptibility locus Sle1c2 mediates CD4+ T cell activation and maps to estrogen-related receptor γ. J. Immunol. 189, 793–803 (2012).

    CAS  PubMed  Google Scholar 

  93. Morel, L., Blenman, K. R., Croker, B. P. & Wakeland, E. K. The major murine systemic lupus erythematosus susceptibility locus, Sle1, is a cluster of functionally related genes. Proc. Natl Acad. Sci. USA 98, 1787–1792 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Vyshkina, T. et al. Association of common mitochondrial DNA variants with multiple sclerosis and systemic lupus erythematosus. Clin. Immunol. 129, 31–35 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. McDonald, G. et al. Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients. J. Clin. Invest. 124, 712–724 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Krishnan, S. et al. Alterations in lipid raft composition and dynamics contribute to abnormal T cell responses in systemic lupus erythematosus. J. Immunol. 172, 7821–7831 (2004).

    CAS  PubMed  Google Scholar 

  97. Waddington, K. E., Jury, E. C. & Pineda-Torra, I. Liver X receptors in immune cell function in humans. Biochem. Soc. Trans. 43, 752–757 (2015).

    CAS  PubMed  Google Scholar 

  98. Anderson, M. K., Hernandez-Hoyos, G., Diamond, R. A. & Rothenberg, E. V. Precise developmental regulation of Ets family transcription factors during specification and commitment to the T cell lineage. Development 126, 3131–3148 (1999).

    CAS  PubMed  Google Scholar 

  99. Zhang, L. et al. An immunological renal disease in transgenic mice that overexpress Fli-1, a member of the ets family of transcription factor genes. Mol. Cell. Biol. 15, 6961–6970 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Zhang, X. K. et al. Decreased expression of the Ets family transcription factor Fli-1 markedly prolongs survival and significantly reduces renal disease in MRL/lpr mice. J. Immunol. 173, 6481–6489 (2004).

    CAS  PubMed  Google Scholar 

  101. Mathenia, J. et al. Impact of Fli-1 transcription factor on autoantibody and lupus nephritis in NZM2410 mice. Clin. Exp. Immunol. 162, 362–371 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Richard, E. M. et al. Reducing FLI1 levels in the MRL/lpr lupus mouse model impacts T cell function by modulating glycosphingolipid metabolism. PLOS ONE 8, e75175 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Sundararaj, K. P. et al. FLI1 levels impact CXCR3 expression and renal infiltration of T cells and renal glycosphingolipid metabolism in the MRL/lpr lupus mouse strain. J. Immunol. 195, 5551–5560 (2015).

    CAS  PubMed  Google Scholar 

  104. Morris, E. E. et al. A GA microsatellite in the Fli1 promoter modulates gene expression and is associated with systemic lupus erythematosus patients without nephritis. Arthritis Res. Ther. 12, R212 (2010).

    PubMed  PubMed Central  Google Scholar 

  105. Nowling, T. K. et al. Renal glycosphingolipid metabolism is dysfunctional in lupus nephritis. J. Am. Soc. Nephrol. 26, 1402–1413 (2015).

    CAS  PubMed  Google Scholar 

  106. Perl, A. Oxidative stress in the pathology and treatment of systemic lupus erythematosus. Nat. Rev. Rheumatol. 9, 674–686 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Delgoffe, G. M. et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30, 832–844 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Lai, Z. W. et al. Mechanistic target of rapamycin activation triggers IL-4 production and necrotic death of double-negative T cells in patients with systemic lupus erythematosus. J. Immunol. 191, 2236–2246 (2013).

    CAS  PubMed  Google Scholar 

  110. Lee, S. Y. et al. Metformin suppresses systemic autoimmunity in Roquin san/san mice through inhibiting B cell differentiation into plasma cells via regulation of AMPK/mTOR/STAT3. J. Immunol. 198, 2661–2670 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Koga, T. et al. CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance. J. Clin. Invest. 124, 2234–2245 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Katsuyama, T., Li, H., Comte, D., Tsokos, G. C. & Moulton, V. R. Splicing factor SRSF1 controls T cell hyperactivity and systemic autoimmunity. J. Clin. Invest. https://doi.org/10.1172/JCI127949 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Psarelis, S. & Nikiphorou, E. Coexistence of SLE, tuberous sclerosis and aggressive natural killer-cell leukaemia: coincidence or correlated? Lupus 26, 107–108 (2017).

    CAS  PubMed  Google Scholar 

  114. Olde Bekkink, M., Ahmed-Ousenkova, Y. M., Netea, M. G., van der Velden, W. J. & Berden, J. H. Coexistence of systemic lupus erythematosus, tuberous sclerosis and aggressive natural killer-cell leukaemia: coincidence or correlated? Lupus 25, 766–771 (2016).

    CAS  PubMed  Google Scholar 

  115. Carrasco Cubero, C., Bejarano Moguel, V., Fernández Gil, M. Á. & Álvarez Vega, J. L. Coincidence of tuberous sclerosis and systemic lupus erythematosus—a case report. Reumatol. Clin. 12, 219–222 (2016).

    PubMed  Google Scholar 

  116. Singh, N., Birkenbach, M., Caza, T., Perl, A. & Cohen, P. L. Tuberous sclerosis and fulminant lupus in a young woman. J. Clin. Rheumatol. 19, 134–137 (2013).

    PubMed  PubMed Central  Google Scholar 

  117. Koga, T. et al. Promotion of calcium/calmodulin-dependent protein kinase 4 by GLUT1-dependent glycolysis in systemic lupus erythematosus. Arthritis Rheumatol. 71, 766–772 (2019).

    CAS  PubMed  Google Scholar 

  118. Kono, M. et al. Glutaminase 1 inhibition reduces glycolysis and ameliorates lupus-like disease in MRL/lpr mice and experimental autoimmune encephalomyelitis. Arthritis Rheumatol. 71, 1869–1878 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Huang, N. & Perl, A. Metabolism as a target for modulation in autoimmune diseases. Trends Immunol. 39, 562–576 (2018).

    CAS  PubMed  Google Scholar 

  120. Moreno-Aurioles, V. R. & Sobrino, F. Glucocorticoids inhibit fructose 2,6-bisphosphate synthesis in rat thymocytes. Opposite effect of cycloheximide. Biochim. Biophys. Acta 1091, 96–100 (1991).

    CAS  PubMed  Google Scholar 

  121. Domhan, S. et al. Molecular mechanisms of the antiangiogenic and antitumor effects of mycophenolic acid. Mol. Cancer Ther. 7, 1656–1668 (2008).

    CAS  PubMed  Google Scholar 

  122. He, X. et al. Mycophenolic acid-mediated suppression of human CD4+ T cells: more than mere guanine nucleotide deprivation. Am. J. Transplant. 11, 439–449 (2011).

    CAS  PubMed  Google Scholar 

  123. Shuvalov, O. et al. One-carbon metabolism and nucleotide biosynthesis as attractive targets for anticancer therapy. Oncotarget 8, 23955–23977 (2017).

    PubMed  PubMed Central  Google Scholar 

  124. Fernández-Ramos, A. A., Poindessous, V., Marchetti-Laurent, C., Pallet, N. & Loriot, M. A. The effect of immunosuppressive molecules on T-cell metabolic reprogramming. Biochimie 127, 23–36 (2016).

    PubMed  Google Scholar 

  125. Furst, D. E. The rational use of methotrexate in rheumatoid arthritis and other rheumatic diseases. Br. J. Rheumatol. 36, 1196–1204 (1997).

    CAS  PubMed  Google Scholar 

  126. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Lai, Z. W. et al. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Choi, S. C. et al. Inhibition of glucose metabolism selectively targets autoreactive follicular helper T cells. Nat. Commun. 9, 4369 (2018).

    PubMed  PubMed Central  Google Scholar 

  129. Wang, H., Li, T., Chen, S., Gu, Y. & Ye, S. Neutrophil extracellular trap mitochondrial DNA and its autoantibody in systemic lupus erythematosus and a proof-of-concept trial of metformin. Arthritis Rheumatol. 67, 3190–3200 (2015).

    CAS  PubMed  Google Scholar 

  130. Zhao, W. et al. The peroxisome-proliferator activated receptor-γ agonist pioglitazone modulates aberrant T cell responses in systemic lupus erythematosus. Clin. Immunol. 149, 119–132 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 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).

    CAS  PubMed  Google Scholar 

  132. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Bednarski, J. J. et al. Attenuation of autoimmune disease in Fas-deficient mice by treatment with a cytotoxic benzodiazepine. Arthritis Rheum. 48, 757–766 (2003).

    CAS  PubMed  Google Scholar 

  134. Bengtsson, A. A. et al. Metabolic profiling of systemic lupus erythematosus and comparison with primary Sjögren’s syndrome and systemic sclerosis. PLOS ONE 11, e0159384 (2016).

    PubMed  PubMed Central  Google Scholar 

  135. Actelion Press Release August. Zavesca approved —first oral treatment option for type 1 Gaucher disease. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021348s010lbl.pdf (2003).

  136. Oya, Y. et al. Lack of B and T lymphocyte attenuator exacerbates autoimmune disorders and induces Fas-independent liver injury in MRL-lpr/lpr mice. Int. Immunol. 23, 335–344 (2011).

    CAS  PubMed  Google Scholar 

  137. Kashiwakuma, D. et al. B and T lymphocyte attenuator suppresses IL-21 production from follicular Th cells and subsequent humoral immune responses. J. Immunol. 185, 2730–2736 (2010).

    CAS  PubMed  Google Scholar 

  138. Sawaf, M. et al. Defective BTLA functionality is rescued by restoring lipid metabolism in lupus CD4+ T cells. JCI Insight https://doi.org/10.1172/jci.insight.99711 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Hansen, A. L. et al. Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling. Proc. Natl Acad. Sci. USA 115, E7768–E7775 (2018).

    PubMed  PubMed Central  Google Scholar 

  140. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02460146 (2016).

  141. Israelsen, W. J. & Vander Heiden, M. G. Pyruvate kinase: function, regulation and role in cancer. Semin. Cell Dev. Biol. 43, 43–51 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Van Bruggen, M. C., Walgreen, B., Rijke, T. P. & Berden, J. H. Attenuation of murine lupus nephritis by mycophenolate mofetil. J. Am. Soc. Nephrol. 9, 1407–1415 (1998).

    PubMed  Google Scholar 

  143. Dörner, T. & Furie, R. Novel paradigms in systemic lupus erythematosus. Lancet 393, 2344–2358 (2019).

    PubMed  Google Scholar 

  144. Segal, R., Dayan, M., Zinger, H. & Mozes, E. Methotrexate treatment in murine experimental systemic lupus erythematosus (SLE); clinical benefits associated with cytokine manipulation. Clin. Exp. Immunol. 101, 66–72 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Lui, S. L. et al. Rapamycin attenuates the severity of established nephritis in lupus-prone NZB/W F1 mice. Nephrol. Dial. Transplant. 23, 2768–2776 (2008).

    CAS  PubMed  Google Scholar 

  146. Jones, D. D. et al. mTOR has distinct functions in generating versus sustaining humoral immunity. J. Clin. Invest. 126, 4250–4261 (2016).

    PubMed  PubMed Central  Google Scholar 

  147. Zhao, W. et al. The peroxisome proliferator-activated receptor γ agonist pioglitazone improves cardiometabolic risk and renal inflammation in murine lupus. J. Immunol. 183, 2729–2740 (2009).

    CAS  PubMed  Google Scholar 

  148. Suwannaroj, S., Lagoo, A., Keisler, D. & McMurray, R. W. Antioxidants suppress mortality in the female NZB × NZW F1 mouse model of systemic lupus erythematosus (SLE). Lupus 10, 258–265 (2001).

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Amir Sharabi & George C. Tsokos

  2. Clinical Microbiology & Immunology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

    Amir Sharabi

  3. Rheumatology Institute, Rabin Medical Center, Petach-Tikva, Israel

    Amir Sharabi

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  1. Amir Sharabi
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The authors contributed equally to all aspects of the article.

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Glossary

Nonessential amino acids

Six amino acids that can be synthesized in sufficient quantities in the body (alanine, aspartic acid, asparagine, glutamic acid, serine and selenocysteine), unlike essential amino acids that must be supplied in the diet.

Anabolic metabolism phenotype

A phenotype characterized by rapid biosynthesis of molecules through various metabolic pathways.

Mitochondrial biogenesis

The increase in mitochondrial mass within a cell as a result of cellular stress or prolonged activation. This process includes an increase in metabolic enzymes involved in glycolysis and oxidative phosphorylation and is regulated by AMPK and transcriptional modifications.

Malate-aspartate shuttle

A cytoplasmic–mitochondrial network in which reducing equivalents (such as NADH) in the cytoplasm are carried by malate across the inner membrane of the mitochondria to drive oxidative phosphorylation.

One-carbon metabolism

A cytoplasmic network of interlinking metabolic pathways, including the folate and the methionine cycles, that transfer carbon units (from amino acids) to metabolic pathways related to cell proliferation and growth.

Mevalonate pathway

Also known as the HMG-CoA reductase pathway, this pathway uses acetyl-CoA to generate two five-carbon structures called isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) that are used in macromolecules called isoprenoids, such as cholesterol, vitamin K and steroids.

Pentose phosphate pathway

One of three glucose metabolism pathways that branch from the glycolysis pathway. This pathway converts glucose-6-phosphate to ribose-5-phosphate to generate reducing equivalents, including NADPH, for the synthesis of nucleic acids and amino acids during cell activation.

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Sharabi, A., Tsokos, G.C. T cell metabolism: new insights in systemic lupus erythematosus pathogenesis and therapy. Nat Rev Rheumatol 16, 100–112 (2020). https://doi.org/10.1038/s41584-019-0356-x

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