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Metabolic waypoints during T cell differentiation

Nature Immunology volume 25, pages 206–217 (2024)Cite this article

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Abstract

This Review explores the interplay between T cell activation and cell metabolism and highlights how metabolites serve two pivotal functions in shaping the immune response. Traditionally, T cell activation has been characterized by T cell antigen receptor–major histocompatibility complex interaction (signal 1), co-stimulation (signal 2) and cytokine signaling (signal 3). However, recent research has unveiled the critical role of metabolites in this process. Firstly, metabolites act as signal propagators that aid in the transmission of core activation signals, such as specific lipid species that are crucial at the immune synapse. Secondly, metabolites also function as unique signals that influence immune differentiation pathways, such as amino acid-induced mTORC1 signaling. Metabolites also play a substantial role in epigenetic remodeling, by directly modifying histones, altering gene expression and influencing T cell behavior. This Review discusses how T cells integrate nutrient sensing with activating stimuli to shape their differentiation and sensitivity to metabolites. We underscore the integration of immunological and metabolic inputs in T cell function and suggest that metabolite availability is a fundamental determinant of adaptive immune responses.

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Fig. 1: Metabolites affect TCR signaling.
Fig. 2: Metabolic regulation of T cell epigenome.
Fig. 3: Metabolic sensitivity of T cells during an immune response.

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References

  1. Smith-Garvin, J. E., Koretzky, G. A. & Jordan, M. S. T cell activation. Annu. Rev. Immunol. 27, 591–619 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Pathan-Chhatbar, S. et al. Direct regulation of the T cell antigen receptor’s activity by cholesterol. Front. Cell Dev. Biol. 8, 615996 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Wu, W., Shi, X. & Xu, C. Regulation of T cell signalling by membrane lipids. Nat. Rev. Immunol. 16, 690–701 (2016).

    Article  CAS  PubMed  Google Scholar 

  4. He, H. T., Lellouch, A. & Marguet, D. Lipid rafts and the initiation of T cell receptor signaling. Semin. Immunol. 17, 23–33 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Jury, E. C., Flores-Borja, F. & Kabouridis, P. S. Lipid rafts in T cell signalling and disease. Semin. Cell Dev. Biol. 18, 608–615 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kabouridis, P. S. Lipid rafts in T cell receptor signalling. Mol. Membr. Biol. 23, 49–57 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chen, Y. et al. Cholesterol inhibits TCR signaling by directly restricting TCR-CD3 core tunnel motility. Mol. Cell 82, 1278–1287 (2022).

    Article  CAS  PubMed  Google Scholar 

  8. Bensinger, S. J. et al. LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell 134, 97–111 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wilfahrt, D. et al. Histone deacetylase 3 represses cholesterol efflux during CD4+ T-cell activation. Elife 10, e70978 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lu, W. et al. The phosphatidylinositol-transfer protein Nir3 promotes PI(4,5)P2 replenishment in response to TCR signaling during T cell development and survival. Nat. Immunol. 24, 136–147 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Edwards-Hicks, J. et al. Phosphoinositide acyl chain saturation drives CD8+ effector T cell signaling and function. Nat. Immunol. 24, 516–530 (2023).

    Article  CAS  PubMed  Google Scholar 

  12. Kremer, K. N. et al. LPA suppresses T cell function by altering the cytoskeleton and disrupting immune synapse formation. Proc. Natl Acad. Sci. USA 119, e2118816119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mathew, D. et al. LPA 5 is an inhibitory receptor that suppresses CD8 T-cell cytotoxic function via disruption of early TCR signaling. Front Immunol. 10, 1159 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhang, M. S. et al. Glycerol monolaurate (GML) induces filopodia formation by disrupting the association between LAT and SLP-76 microclusters. Sci. Signal 11, eaan9095 (2018).

    Article  Google Scholar 

  15. Castellano, F. & Molinier-Frenkel, V. Control of T-cell activation and signaling by amino-acid catabolizing enzymes. Front. Cell Dev. Biol. 8, 613416 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Wu, J. et al. Asparagine enhances LCK signalling to potentiate CD8+ T-cell activation and anti-tumour responses. Nat. Cell Biol. 23, 75–86 (2021).

    Article  CAS  PubMed  Google Scholar 

  17. Hope, H. C. et al. Coordination of asparagine uptake and asparagine synthetase expression modulates CD8+ T cell activation. JCI Insight 6, e137761 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Geiger, R. et al. L-Arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167, 829–842 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ginefra, P., Hope, H. C., Spagna, M., Zecchillo, A. & Vannini, N. Ionic regulation of T-cell function and anti-tumour immunity. Int. J. Mol. Sci. 22, 13668 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lötscher, J. et al. Magnesium sensing via LFA-1 regulates CD8+ T cell effector function. Cell 185, 585–602 (2022).

    Article  PubMed  Google Scholar 

  24. Luik, R. M., Wang, B., Prakriya, M., Wu, M. M. & Lewis, R. S. Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation. Nature 454, 538–542 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hogan, P. G. Calcium–NFAT transcriptional signalling in T cell activation and T cell exhaustion. Cell Calcium 63, 66–69 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Vaeth, M. et al. Store-operated Ca2+ entry controls clonal expansion of T cells through metabolic reprogramming. Immunity 47, 664–679 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang, Y. H., Tao, A. Y., Vaeth, M. & Feske, S. Calcium regulation of T cell metabolism. Curr. Opin. Physiol. 17, 207–223 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Balmer, M. L. et al. Memory CD8+ T cells balance pro- and anti-inflammatory activity by reprogramming cellular acetate handling at sites of infection. Cell Metab. 32, 457–467 (2020).

    Article  CAS  PubMed  Google Scholar 

  29. 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).

    Article  CAS  PubMed  Google Scholar 

  30. Desdín-Micó, G., Soto-Heredero, G. & Mittelbrunn, M. Mitochondrial activity in T cells. Mitochondrion 41, 51–57 (2018).

    Article  PubMed  Google Scholar 

  31. Lisci, M. & Griffiths, G. M. Arming a killer: mitochondrial regulation of CD8+ T cell cytotoxicity. Trends Cell Biol. 33, 138–147 (2023).

    Article  CAS  PubMed  Google Scholar 

  32. Quintana, A. et al. T cell activation requires mitochondrial translocation to the immunological synapse. Proc. Natl Acad. Sci. USA 104, 14418–14423 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yoast, R. E. et al. The mitochondrial Ca2+ uniporter is a central regulator of interorganellar Ca2+ transfer and NFAT activation. J. Biol. Chem. 297, 101174 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wu, H. et al. Genetic ablation of the mitochondrial calcium uniporter (MCU) does not impair T cell-mediated immunity in vivo. Front Pharmacol. 12, 734078 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Häusler, D. et al. High dose vitamin D exacerbates central nervous system autoimmunity by raising T-cell excitatory calcium. Brain 142, 2737–2755 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Liang, Y. et al. Retinoic acid modulates hyperactive T cell responses and protects vitamin A-deficient mice against persistent lymphocytic choriomeningitis virus infection. J. Immunol. 204, 2984–2994 (2020).

    Article  CAS  PubMed  Google Scholar 

  38. Ho, P. C. et al. Phosphoenolpyruvate Is a metabolic checkpoint of anti-tumor T cell responses. Cell 162, 1217–1228 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bunse, L. et al. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat. Med. 24, 1192–1203 (2018).

    Article  CAS  PubMed  Google Scholar 

  40. Boomer, J. S. & Green, J. M. An enigmatic tail of CD28 signaling. Cold Spring Harb. Perspect. Biol. 2, a002436 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Chapman, N. M., Boothby, M. R. & Chi, H. Metabolic coordination of T cell quiescence and activation. Nat. Rev. Immunol. 20, 55–70 (2020).

    Article  CAS  PubMed  Google Scholar 

  42. Benson, M. J., Pino-Lagos, K., Rosemblatt, M. & Noelle, R. J. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J. Exp. Med. 204, 1765–1774 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Basu, R. et al. IL-1 signaling modulates activation of STAT transcription factors to antagonize retinoic acid signaling and control the TH17 cell-iTreg cell balance. Nat. Immunol. 16, 286–295 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Friesen, L. R., Gu, B. & Kim, C. H. A ligand-independent fast function of RARα promotes exit from metabolic quiescence upon T cell activation and controls T cell differentiation. Mucosal Immunol. 14, 100–112 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Xu, K. et al. Glycolysis fuels phosphoinositide 3-kinase signaling to bolster T cell immunity. Science 371, 405–410 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Xu, K. et al. Glycolytic ATP fuels phosphoinositide 3-kinase signaling to support effector T helper 17 cell responses. Immunity 54, 976–987 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  48. Zhu, M., Foreman, D. P., O’Brien, S. A., Jin, Y. & Zhang, W. Phospholipase D in TCR-mediated signaling and T cell activation. J. Immunol. 200, 2165–2173 (2018).

    Article  CAS  PubMed  Google Scholar 

  49. Scheffel, M. J. et al. N-acetyl cysteine protects anti-melanoma cytotoxic T cells from exhaustion induced by rapid expansion via the downmodulation of Foxo1 in an Akt-dependent manner. Cancer Immunol. Immunother. 67, 691–702 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sengupta, S., Peterson, T. R. & Sabatini, D. M. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol. Cell 40, 310–322 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Szwed, A., Kim, E. & Jacinto, E. Regulation and metabolic functions of mTORC1 and mTORC2. Physiol. Rev. 101, 1371–1426 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Tan, H. et al. Integrative proteomics and phosphoproteomics profiling reveals dynamic signaling networks and bioenergetics pathways underlying T cell activation. Immunity 46, 488–503 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  58. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Eil, R. et al. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature 537, 539–543 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Yin, S., Liu, L. & Gan, W. The roles of post-translational modifications on mTOR signaling. Int. J. Mol. Sci. 22, 1784 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Su, W. et al. Protein prenylation drives discrete signaling programs for the differentiation and maintenance of effector Treg cells. Cell Metab. 32, 996–1011 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Yang, W. et al. Intestinal microbiota-derived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity. Nat. Commun. 11, 4457 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Fu, G. et al. Metabolic control of Tfh cells and humoral immunity by phosphatidylethanolamine. Nature 595, 724–729 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Dong, C. Cytokine regulation and function in T cells. Annu. Rev. Immunol. 39, 51–76 (2021).

    Article  CAS  PubMed  Google Scholar 

  66. Firestein, G. S. Evolving concepts of rheumatoid arthritis. Nature 423, 356–361 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Walker, L. S. K. & von Herrath, M. CD4 T cell differentiation in type 1 diabetes. Clin. Exp. Immunol. 183, 16–29 (2016).

    PubMed  Google Scholar 

  68. Ross, S. H. & Cantrell, D. A. Signaling and function of interleukin-2 in T lymphocytes. Annu. Rev. Immunol. 36, 411–433 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Chisolm, D. A. et al. CCCTC-binding factor translates interleukin 2- and α-ketoglutarate-sensitive metabolic changes in T cells into context-dependent gene programs. Immunity 47, 251–267 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Chang, C. H. et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153, 1239–1251 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Wang, Z. et al. Iron drives T helper cell pathogenicity by promoting RNA-binding protein PCBP1-mediated proinflammatory cytokine production. Immunity 49, 80–92 (2018).

    Article  CAS  PubMed  Google Scholar 

  72. Villarino, A. V et al. A central role for STAT5 in the transcriptional programing of T helper cell metabolism. Sci. Immunol. 7, eabl9467 (2022).

  73. Ray, J. P. et al. The interleukin-2–mTORc1 kinase axis defines the signaling, differentiation, and metabolism of T helper 1 and follicular B helper T cells. Immunity 43, 690–702 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Mo, F. et al. An engineered IL-2 partial agonist promotes CD8+ T cell stemness. Nature 597, 544–548 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. He, Y. et al. Gut microbial metabolites facilitate anticancer therapy efficacy by modulating cytotoxic CD8+ T cell immunity. Cell Metab. 33, 988–1000 (2021).

    Article  CAS  PubMed  Google Scholar 

  76. Wynn, T. A. Type 2 cytokines: mechanisms and therapeutic strategies. Nat. Rev. Immunol. 15, 271–282 (2015).

    Article  CAS  PubMed  Google Scholar 

  77. Morgan, R. et al. N-acetylglucosaminyltransferase V (Mgat5)-mediated N-glycosylation negatively regulates Th1 cytokine production by T cells. J. Immunol. 173, 7200–7208 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Jiang, H. et al. LZTFL1 upregulated by all-trans retinoic acid during CD4+ T cell activation enhances IL-5 production. J. Immunol. 196, 1081–1090 (2016).

    Article  CAS  PubMed  Google Scholar 

  79. Nalleweg, N. et al. IL-9 and its receptor are predominantly involved in the pathogenesis of UC. Gut 64, 743–755 (2015).

    Article  CAS  PubMed  Google Scholar 

  80. Wilhelm, C. et al. An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nat. Immunol. 12, 1071–1077 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Roy, S. et al. EGFR-HIF1α signaling positively regulates the differentiation of IL-9 producing T helper cells. Nat. Commun. 12, 3182 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Schwartz, D. M. et al. Retinoic acid receptor alpha represses a Th9 transcriptional and epigenomic program to reduce allergic pathology. Immunity 50, 106–120 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Asadzadeh, Z. et al. The paradox of Th17 cell functions in tumor immunity. Cell Immunol. 322, 15–25 (2017).

    Article  CAS  PubMed  Google Scholar 

  84. Tan, S. et al. The pro-inflammatory effect of triglyceride on human CD4+ T cells and experimental autoimmune uveitis. Clin. Immunol. 240, 109056 (2022).

    Article  CAS  PubMed  Google Scholar 

  85. Paik, D. et al. Human gut bacteria produce ΤΗ17-modulating bile acid metabolites. Nature 603, 907–912 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Duan, J. et al. Endoplasmic reticulum stress in the intestinal epithelium initiates purine metabolite synthesis and promotes Th17 cell differentiation in the gut. Immunity 56, 1115–1131 (2023).

  87. 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).

    Article  CAS  PubMed  Google Scholar 

  88. Wang, C. et al. CD5L/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity. Cell 163, 1413–1427 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Wagner, A. et al. Metabolic modeling of single Th17 cells reveals regulators of autoimmunity. Cell 184, 4168–4185 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lian, G. et al. Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation. Elife 7, e36158 (2018).

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

    Article  PubMed  Google Scholar 

  92. Zenewicz, L. A. et al. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 29, 947–957 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Ouyang, W. & O’Garra, A. IL-10 family cytokines IL-10 and IL-22: from basic science to clinical translation. Immunity 50, 871–891 (2019).

    Article  CAS  PubMed  Google Scholar 

  94. Ford, B. R. et al. Tumor microenvironmental signals reshape chromatin landscapes to limit the functional potential of exhausted T cells. Sci. Immunol. 7, eabj9123 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Quezada, L. K. et al. Early transcriptional and epigenetic divergence of CD8+ T cells responding to acute versus chronic infection. PLoS Biol. 21, e3001983 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Byvoet, P., Shepherd, G. R., Hardin, J. M. & Noland, B. J. The distribution and turnover of labeled methyl groups in histone fractions of cultured mammalian cells. Arch. Biochem. Biophys. 148, 558–567 (1972).

    Article  CAS  PubMed  Google Scholar 

  97. Murray, K. The occurrence of epsilon-N-methyl lysine in histones. Biochemistry 3, 10–15 (1964).

    Article  CAS  PubMed  Google Scholar 

  98. Fischle, W., Franz, H., Jacobs, S. A., Allis, C. D. & Khorasanizadeh, S. Specificity of the chromodomain Y chromosome family of chromodomains for lysine-methylated ARK(S/T) motifs. J. Biol. Chem. 283, 19626–19635 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Greer, E. L. & Shi, Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat. Rev. Genet. 13, 343–357 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Bernstein, B. E. et al. Methylation of histone H3 Lys 4 in coding regions of active genes. Proc. Natl Acad. Sci. USA 99, 8695–8700 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Correa, L. O., Jordan, M. S. & Carty, S. A. DNA methylation in T-cell development and differentiation. Crit. Rev. Immunol. 40, 135–156 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Lyko, F. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat. Rev. Genet. 19, 81–92 (2017).

    Article  PubMed  Google Scholar 

  104. Zhao, T. & Lum, J. J. Methionine cycle-dependent regulation of T cells in cancer immunity. Front Oncol. 12, 969563 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Roy, D. G. et al. Methionine metabolism shapes T helper cell responses through regulation of epigenetic reprogramming. Cell Metab. 31, 250–266 (2020).

    Article  CAS  PubMed  Google Scholar 

  106. Bian, Y. et al. Cancer SLC43A2 alters T cell methionine metabolism and histone methylation. Nature 585, 277–282 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. DeVorkin, L. et al. Autophagy regulation of metabolism is required for CD8+ T cell anti-tumor immunity. Cell Rep. 27, 502–513 (2019).

    Article  CAS  PubMed  Google Scholar 

  108. Scourzic, L., Mouly, E. & Bernard, O. A. TET proteins and the control of cytosine demethylation in cancer. Genome Med. 7, 9 (2015).

  109. 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).

    Article  PubMed  Google Scholar 

  110. Matias, M. I. et al. Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis. Cell Rep. 37, 109911 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Yang, M. & Pollard, P. J. Succinate: a new epigenetic hacker. Cancer Cell 23, 709–711 (2013).

    Article  CAS  PubMed  Google Scholar 

  112. Chen, X. et al. Succinate dehydrogenase/complex II is critical for metabolic and epigenetic regulation of T cell proliferation and inflammation. Sci. Immunol. 7, eabm8161 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Tyrakis, P. A. et al. The immunometabolite S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature 540, 236–241 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Marmorstein, R. & Zhou, M. M. Writers and readers of histone acetylation: structure, mechanism, and inhibition. Cold Spring Harb. Perspect. Biol. 6, a018762 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Bannister, A. J. & Kouzarides, T. Regulation of chromatin by histone modifications. Cell Res. 21, 381–395 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Yang, X. J. & Seto, E. HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention. Oncogene 26, 5310–5318 (2007).

    Article  CAS  PubMed  Google Scholar 

  117. Shahbazian, M. D. & Grunstein, M. Functions of site-specific histone acetylation and deacetylation. Annu. Rev. Biochem. 76, 75–100 (2007).

    Article  CAS  PubMed  Google Scholar 

  118. Lee, K. K. & Workman, J. L. Histone acetyltransferase complexes: one size doesn’t fit all. Nat. Rev. Mol. Cell Biol. 8, 284–295 (2007).

    Article  CAS  PubMed  Google Scholar 

  119. Schmitt, D. L. & An, S. Spatial organization of metabolic enzyme complexes in cells. Biochemistry 56, 3184–3196 (2017).

    Article  PubMed  Google Scholar 

  120. 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).

    Article  CAS  PubMed  Google Scholar 

  121. Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Peng, M. et al. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354, 481–484 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Bailis, W. et al. Distinct modes of mitochondrial metabolism uncouple T cell differentiation and function. Nature 571, 403–407 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Nakajima, T. et al. ACC1-expressing pathogenic T helper 2 cell populations facilitate lung and skin inflammation in mice. J. Exp. Med. 218, e20210639 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Puleston, D. J. et al. Polyamine metabolism is a central determinant of helper T cell lineage fidelity. Cell 184, 4186–4202 (2021).

    Article  Google Scholar 

  126. Hochrein, S. M. et al. The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming. Cell Metab. 34, 516–532 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Qiu, J. et al. Acetate promotes T cell effector function during glucose restriction. Cell Rep. 27, 2063–2074 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Chowdhury, S. et al. Intracellular Acetyl CoA potentiates the therapeutic efficacy of antitumor CD8+ T cells. Cancer Res. 82, 2640–2655 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Vodnala, S. K. et al. T cell stemness and dysfunction in tumors are triggered by a common mechanism. Science 363, eaau0135 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Drummond, D. C. et al. Clinical development of histone deacetylase inhibitors as anticancer agents. Annu. Rev. Pharmacol. Toxicol. 45, 495–528 (2005).

    Article  CAS  PubMed  Google Scholar 

  131. Feng, Q. et al. Lactate increases stemness of CD8+ T cells to augment anti-tumor immunity. Nat. Commun. 13, 4981 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Park, J. et al. Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR–S6K pathway. Mucosal Immunol. 8, 80–93 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Kibbie, J. J. et al. Butyrate directly decreases human gut lamina propria CD4 T cell function through histone deacetylase (HDAC) inhibition and GPR43 signaling. Immunobiology 226, 152126 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Zhang, D. et al. Metabolic regulation of gene expression by histone lactylation. Nature 574, 575–580 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Caslin, H. L., Abebayehu, D., Pinette, J. A. & Ryan, J. J. Lactate is a metabolic mediator that shapes immune cell fate and function. Front. Physiol. 12, 688485 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Jiang, G., Li, C., Lu, M., Lu, K. & Li, H. Protein lysine crotonylation: past, present, perspective. Cell Death Dis. 12, 703 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Kebede, A. F. et al. Histone propionylation is a mark of active chromatin. Nat. Struct. Mol. Biol. 24, 1048–1056 (2017).

    Article  CAS  PubMed  Google Scholar 

  138. Chen, Y. et al. Lysine propionylation and butyrylation are novel post-translational modifications in histones. Mol. Cell Proteomics 6, 812–819 (2007).

    Article  CAS  PubMed  Google Scholar 

  139. Karthik Varanasi, S., Vijaya Kumar, S. & Rouse, B. T. Determinants of tissue-specific metabolic adaptation of T cells. Cell Metab. 32, 908–919 (2020).

    Article  Google Scholar 

  140. Liu, X., Hoft, D. F. & Peng, G. Tumor microenvironment metabolites directing T cell differentiation and function. Trends Immunol. 43, 132–147 (2022).

    Article  CAS  PubMed  Google Scholar 

  141. Carrer, A. & Wellen, K. E. Metabolism and epigenetics: a link cancer cells exploit. Curr. Opin. Biotechnol. 34, 23–29 (2015).

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA

    Drew Wilfahrt & Greg M. Delgoffe

  2. Tumor Microenvironment Center and Department of Immunology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Greg M. Delgoffe

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  1. Drew Wilfahrt
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  2. Greg M. Delgoffe
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D.W. wrote the initial draft of the manuscript and designed the figures. G.M.D. supervised the writing of and edited the manuscript.

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Correspondence to Greg M. Delgoffe.

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Competing interests

D.W. declares no competing interests. G.M.D. has filed/awarded patents and founded companies around modulation of immune metabolism for disease treatment.

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Nature Immunology thanks Ping-Chih Ho and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Ioana Staicu, in collaboration with the Nature Immunology team.

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Wilfahrt, D., Delgoffe, G.M. Metabolic waypoints during T cell differentiation. Nat Immunol 25, 206–217 (2024). https://doi.org/10.1038/s41590-023-01733-5

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