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Emerging concepts of T cell metabolism as a target of immunotherapy

Abstract

T cells have a pivotal protective role in defense against infection and cancer but also are instrumental in the development of many autoimmune diseases. The regulation of nutrient uptake and utilization in T cells is critically important for the control of their differentiation, and manipulating metabolic pathways in these cells can alter their function and longevity. While the importance of T cell metabolic remodeling in different physiological settings is not fully understood, there is a growing realization that inappropriate metabolic remodeling underlies many aberrant immune responses and that manipulating cellular metabolism can beneficially enhance or temper immunity. Here we comment on the basic metabolic pathways in T cells, followed by a discussion on up-to-date findings about the relationship between metabolism and T cell function and longevity. Furthermore, we expand on potential approaches and applications in which T cells might be manipulated by the reprogramming of metabolic pathways for therapeutic purposes.

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Figure 1: Basic metabolic pathways in a T cell.

Kim Caesar/Nature Publishing Group

Figure 2: Metabolic interplay in the local microenvironment.

Kim Caesar/Nature Publishing Group

Figure 3: Targeting T cell metabolism for therapy.

Kim Caesar/Nature Publishing Group

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References

  1. 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 

  2. O'Sullivan, D. & Pearce, E.L. Targeting T cell metabolism for therapy. Trends Immunol. 36, 71–80 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Waickman, A.T. & Powell, J.D. mTOR, metabolism, and the regulation of T-cell differentiation and function. Immunol. Rev. 249, 43–58 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 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 

  5. 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).

    CAS  PubMed  Google Scholar 

  6. Cham, C.M. & Gajewski, T.F. Glucose availability regulates IFN-γ production and p70S6 kinase activation in CD8+ effector T cells. J. Immunol. 174, 4670–4677 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Doedens, A.L. et al. Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen. Nat. Immunol. 14, 1173–1182 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Shi, L.Z. et al. HIF1alpha-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 

  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. Villena, J.A. & Kralli, A. ERRa: a metabolic function for the oldest orphan. Trends Endocrinol. Metab. 19, 269–276 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Michalek, R.D. et al. Estrogen-related receptor-a is a metabolic regulator of effector T-cell activation and differentiation. Proc. Natl. Acad. Sci. USA 108, 18348–18353 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 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 

  14. Yao, S. et al. Interferon regulatory factor 4 sustains CD8+ T cell expansion and effector differentiation. Immunity 39, 833–845 (2013).

    CAS  PubMed  Google Scholar 

  15. MacIver, N.J. et al. The liver kinase B1 is a central regulator of T cell development, activation, and metabolism. J. Immunol. 187, 4187–4198 (2011).

    CAS  PubMed  Google Scholar 

  16. Chang, C.H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Blagih, J. et al. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity 42, 41–54 (2015).

    CAS  PubMed  Google Scholar 

  19. Mayer, A., Denanglaire, S., Viollet, B., Leo, O. & Andris, F. AMP-activated protein kinase regulates lymphocyte responses to metabolic stress but is largely dispensable for immune cell development and function. Eur. J. Immunol. 38, 948–956 (2008).

    CAS  PubMed  Google Scholar 

  20. 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 

  21. Ananieva, E.A., Patel, C.H., Drake, C.H., Powell, J.D. & Hutson, S.M. Cytosolic branched chain aminotransferase (BCATc) regulates mTORC1 signaling and glycolytic metabolism in CD4+ T cells. J. Biol. Chem. 289, 18793–18804 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Lee, J. et al. Regulator of fatty acid metabolism, acetyl coenzyme a carboxylase 1, controls T cell immunity. J. Immunol. 192, 3190–3199 (2014).

    CAS  PubMed  Google Scholar 

  23. Fischer, K. et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109, 3812–3819 (2007).

    CAS  PubMed  Google Scholar 

  24. Haas, R. et al. Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions. PLoS Biol. 13, e1002202 (2015).

    PubMed  PubMed Central  Google Scholar 

  25. Munn, D.H. et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22, 633–642 (2005).

    CAS  PubMed  Google Scholar 

  26. Opitz, C.A. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197–203 (2011).

    CAS  PubMed  Google Scholar 

  27. 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 

  28. Sharma, M.D. et al. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J. Clin. Invest. 117, 2570–2582 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Pearce, E.L. et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460, 103–107 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 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).

    CAS  PubMed  Google Scholar 

  32. Rolf, J. et al. AMPKa1: a glucose sensor that controls CD8 T-cell memory. Eur. J. Immunol. 43, 889–896 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. van der Windt, G.J. et al. CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability. Proc. Natl. Acad. Sci. USA 110, 14336–14341 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Fraser, K.A., Schenkel, J.M., Jameson, S.C., Vezys, V. & Masopust, D. Preexisting high frequencies of memory CD8+ T cells favor rapid memory differentiation and preservation of proliferative potential upon boosting. Immunity 39, 171–183 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 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 

  36. Cui, G. et al. IL-7-induced glycerol transport and TAG synthesis promotes memory CD8+ T Cell longevity. Cell 161, 750–761 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Maekawa, Y. et al. Notch controls the survival of memory CD4+ T cells by regulating glucose uptake. Nat. Med. 21, 55–61 (2015).

    CAS  PubMed  Google Scholar 

  38. Wang, Y., Wang, X.Y., Subjeck, J.R., Shrikant, P.A. & Kim, H.L. Temsirolimus, an mTOR inhibitor, enhances anti-tumour effects of heat shock protein cancer vaccines. Br. J. Cancer 104, 643–652 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Chaoul, N. et al. Rapamycin impairs antitumor CD8+ T-cell responses and vaccine-induced tumor eradication. Cancer Res. 75, 3279–3291 (2015).

    CAS  PubMed  Google Scholar 

  40. Gattinoni, L., Klebanoff, C.A. & Restifo, N.P. Pharmacologic induction of CD8+ T cell memory: better living through chemistry. Sci. Transl. Med. 1, 11ps12 (2009).

    PubMed  PubMed Central  Google Scholar 

  41. Patsoukis, N. et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat. Commun. 6, 6692 (2015).

    CAS  PubMed  Google Scholar 

  42. Calvaresi, E.C. et al. Dual targeting of the Warburg effect with a glucose-conjugated lactate dehydrogenase inhibitor. ChemBioChem 14, 2263–2267 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Lameris, R. et al. Bispecific antibody platforms for cancer immunotherapy. Crit. Rev. Oncol. Hematol. 92, 153–165 (2014).

    PubMed  Google Scholar 

  44. Mundra, V., Li, W. & Mahato, R.I. Nanoparticle-mediated drug delivery for treating melanoma. Nanomedicine (Lond.) 10, 2613–2633 (2015).

    CAS  Google Scholar 

  45. 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 

  46. 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 

  47. Maus, M.V. et al. Adoptive immunotherapy for cancer or viruses. Annu. Rev. Immunol. 32, 189–225 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Sukumar, M. et al. Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J. Clin. Invest. 123, 4479–4488 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Sukumar, M. et al. Mitochondrial membrane potential identifies cells with enhanced stemness for cellular therapy. Cell Metab. 23, 63–76 (2015).

    PubMed  PubMed Central  Google Scholar 

  50. Simpson, T.R. et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti CTLA-4 therapy against melanoma. J. Exp. Med. 210, 1695–1710 (2015).

    Google Scholar 

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Acknowledgements

Supported by the US National Institutes of Health (R01CA181125) and the Burroughs Wellcome Fund.

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Correspondence to Chih-Hao Chang or Erika L Pearce.

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Chang, CH., Pearce, E. Emerging concepts of T cell metabolism as a target of immunotherapy. Nat Immunol 17, 364–368 (2016). https://doi.org/10.1038/ni.3415

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