Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARγ directs early activation of T cells

Nature Communications

Volumn 7, Issue , 2016, Pages

  Angela, Mulki ^a   Endo, Yusuke ^a   Asou, Hikari K ^a   Yamamoto, Takeshi ^a   Tumes, Damon J ^a,b   Tokuyama, Hirotake ^a   Yokote, Koutaro ^a   Nakayama, Toshinori ^a,c  

^a CHIBA UNIVERSITY   (Japan)

^b SOUTH AUSTRALIAN HEALTH AND MEDICAL RESEARCH INSTITUTE   (Australia)

^c JAPAN SCIENCE AND TECHNOLOGY AGENCY   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

CD4 ANTIGEN; FATTY ACID; MAMMALIAN TARGET OF RAPAMYCIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; SMALL INTERFERING RNA; TARGET OF RAPAMYCIN KINASE;

APOPTOSIS; BIOENERGETICS; CELLS AND CELL COMPONENTS; ENZYME ACTIVITY; FATTY ACID; METABOLISM; PHENOTYPE; PROTEIN; RODENT;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BIOENERGY; CD4+ T LYMPHOCYTE; CELL SIZE; CONTROLLED STUDY; FATTY ACID METABOLISM; FATTY ACID TRANSPORT; GENETIC ASSOCIATION; HUMAN; HUMAN CELL; LYMPHOCYTE PROLIFERATION; MOUSE; NONHUMAN; NUCLEAR REPROGRAMMING; T LYMPHOCYTE ACTIVATION; ANIMAL; ANTAGONISTS AND INHIBITORS; BAGG ALBINO MOUSE; C57BL MOUSE; CELL PROLIFERATION; CHROMATIN IMMUNOPRECIPITATION; GENE KNOCKDOWN; GENETICS; LYMPHOCYTE ACTIVATION; METABOLISM; NORMAL HUMAN; PHYSIOLOGY; SIGNAL TRANSDUCTION; TRANSGENIC MOUSE; UPREGULATION;

MUS;

ANIMALS; CD4-POSITIVE T-LYMPHOCYTES; CELL PROLIFERATION; CHROMATIN IMMUNOPRECIPITATION; FATTY ACIDS; GENE KNOCKDOWN TECHNIQUES; HEALTHY VOLUNTEERS; HUMANS; LYMPHOCYTE ACTIVATION; MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 1; MICE; MICE, INBRED BALB C; MICE, INBRED C57BL; MICE, TRANSGENIC; PPAR GAMMA; RNA, SMALL INTERFERING; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES; UP-REGULATION;

EID: 84999264542     PISSN: None     EISSN: 20411723     Source Type: Journal    
DOI: 10.1038/ncomms13683     Document Type: Article

References (49)

1. Smith-Garvin, J. E., Koretzky, G. A. & Jordan, M. S. T cell activation. Annu. Rev. Immunol. 27, 591-619 (2009).
2. Nakayama, T. & Yamashita, M. The TCR-mediated signaling pathways that control the direction of helper T cell differentiation. Semin. Immunol. 22, 303-309 (2010).
3. Colombetti, S., Basso, V., Mueller, D. L. & Mondino, A. Prolonged TCR/CD28 engagement drives IL-2-independent T cell clonal expansion through signaling mediated by the mammalian target of rapamycin. J. Immunol. 176, 2730-2738 (2006).
4. Mondino, A. & Mueller, D. L. mTOR at the crossroads of T cell proliferation and tolerance. Semin. Immunol. 19, 162-172 (2007).
5. Chi, H. Regulation and function of mTOR signalling in T cell fate decisions. Nat. Rev. Immunol. 12, 325-338 (2012).
6. Powell, J. D. & Delgoffe, G. M. The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity 33, 301-311 (2010).
7. Pearce, E. L. & Pearce, E. J. Metabolic pathways in immune cell activation and quiescence. Immunity 38, 633-643 (2013).
8. MacIver, N. J., Michalek, R. D. & Rathmell, J. C. Metabolic regulation of T lymphocytes. Annu. Rev. Immunol. 31, 259-283 (2013).
9. 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).
10. Frauwirth, K. A. et al. The CD28 signaling pathway regulates glucose metabolism. Immunity 16, 769-777 (2002).
11. 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).
12. 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).
13. Zheng, Y., Delgoffe, G. M., Meyer, C. F., Chan, W. & Powell, J. D. Anergic T cells are metabolically anergic. J. Immunol. 183, 6095-6101 (2009).
14. Man, K. & Kallies, A. Synchronizing transcriptional control of T cell metabolism and function. Nat. Rev. Immunol. 15, 574-584 (2015).
15. Wang, R. & Green, D. R. Metabolic checkpoints in activated T cells. Nat. Immunol. 13, 907-915 (2012).
16. 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).
17. Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029-1033 (2009).
18. Duvel, K. et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171-183 (2010).
19. Wang, R. et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35, 871-882 (2011).
20. Dang, E. V. et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 146, 772-784 (2011).
21. 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).
22. O'Sullivan, D. & Pearce, E. L. Targeting T cell metabolism for therapy. Trends Immunol. 36, 71-80 (2015).
23. Kidani, Y. et al. Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat. Immunol. 14, 489-499 (2013).
24. Ahmadian, M. et al. PPARgamma signaling and metabolism: the good, the bad and the future. Nat. Med. 19, 557-566 (2013).
25. Lodhi, I. J. & Semenkovich, C. F. Peroxisomes: a nexus for lipid metabolism and cellular signaling. Cell Metab. 19, 380-392 (2014).
26. Daynes, R. A. & Jones, D. C. Emerging roles of PPARs in inflammation and immunity. Nat. Rev. Immunol. 2, 748-759 (2002).
27. Klotz, L. et al. The nuclear receptor PPAR gamma selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity. J. Exp. Med. 206, 2079-2089 (2009).
28. Li, B., Reynolds, J. M., Stout, R. D., Bernlohr, D. A. & Suttles, J. Regulation of Th17 differentiation by epidermal fatty acid-binding protein. J. Immunol. 182, 7625-7633 (2009).
29. Cipolletta, D. et al. PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486, 549-553 (2012).
30. +T cell-mediated lymphopenia-associated autoimmunity. J. Immunol. 187, 4161-4169 (2011).
31. 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).
32. Everts, B. et al. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKvarepsilon supports the anabolic demands of dendritic cell activation. Nat. Immunol. 15, 323-332 (2014).
33. Huang, S. C. et al. Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat. Immunol. 15, 846-855 (2014).
34. Laplante, M. & Sabatini, D. M. An emerging role of mTOR in lipid biosynthesis. Curr. Biol. 19, R1046-R1052 (2009).
35. Northrup, D. L. & Zhao, K. Application of ChIP-Seq and related techniques to the study of immune function. Immunity 34, 830-842 (2011).
36. Farber, D. L., Yudanin, N. A. & Restifo, N. P. Human memory T cells: generation, compartmentalization and homeostasis. Nat. Rev. Immunol. 14, 24-35 (2014).
37. Endo, Y. et al. Eomesodermin controls interleukin-5 production in memory T helper 2 cells through inhibition of activity of the transcription factor GATA3. Immunity 35, 733-745 (2011).
38. Endo, Y. et al. The interleukin-33-p38 kinase axis confers memory T helper 2 cell pathogenicity in the airway. Immunity 42, 294-308 (2015).
39. Nakayama, T. & Yamashita, M. Critical role of the Polycomb and Trithorax complexes in the maintenance of CD4 T cell memory. Semin. Immunol. 21, 78-83 (2009).
40. Endo, Y. et al. Obesity drives Th17 cell differentiation by inducing the lipid metabolic kinase, ACC1. Cell Rep. 12, 1042-1055 (2015).
41. Byersdorfer, C. A. et al. Effector T cells require fatty acid metabolism during murine graft-versus-host disease. Blood 122, 3230-3237 (2013).
42. Chawla, A., Nguyen, K. D. & Goh, Y. P. Macrophage-mediated inflammation in metabolic disease. Nat. Rev. Immunol. 11, 738-749 (2011).
43. Osborn, O. & Olefsky, J. M. The cellular and signaling networks linking the immune system and metabolism in disease. Nat. Med. 18, 363-374 (2012).
44. Yang, K. et al. T cell exit from quiescence and differentiation into Th2 cells depend on Raptor-mTORC1-mediated metabolic reprogramming. Immunity 39, 1043-1056 (2013).
45. Lim, H. et al. Proatherogenic conditions promote autoimmune T helper 17 cell responses in vivo. Immunity 40, 153-165 (2014).
46. Currie, E., Schulze, A., Zechner, R., Walther, T. C. & Farese, Jr R. V. Cellular fatty acid metabolism and cancer. Cell Metab. 18, 153-161 (2013).
47. Rodriguez, A., Ezquerro, S., Mendez-Gimenez, L., Becerril, S. & Fruhbeck, G. Revisiting the adipocyte: a model for integration of cytokine signaling in the regulation of energy metabolism. Am. J. Physiol. Endocrinol. Metab. 309, E691-E714 (2015).
48. Liu, L. H. et al. Effects of a fatty acid synthase inhibitor on adipocyte differentiation of mouse 3T3-L1 cells. Acta Pharmacol. Sin. 25, 1052-1057 (2004).
49. Murphy, K. M., Heimberger, A. B. & Loh, D. Y. Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. Science 250, 1720-1723 (1990).