Mesenchymal Stromal Cells Disrupt mTOR-Signaling and Aerobic Glycolysis during T-Cell Activation

Stem Cells

Volumn 34, Issue 2, 2016, Pages 516-521

  Böttcher, Martin ^a   D Hofmann, Andreas ^a   Bruns, Heiko ^a   Haibach, Martina ^a   Loschinski, Romy ^a   Saul, Domenica ^a   Mackensen, Andreas ^a   Le Blanc, Katarina ^b   Jitschin, Regina ^a   Mougiakakos, Dimitrios ^a  

^a UNIVERSITY OF ERLANGEN NUREMBERG   (Germany)

^b KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

Author keywords

IDO; Immunometabolism; Mesenchymal stromal cells; mTOR Signaling; T cell suppression

Indexed keywords

INDOLEAMINE 2,3 DIOXYGENASE; MAMMALIAN TARGET OF RAPAMYCIN; TRYPTOPHAN; MTOR PROTEIN, HUMAN; TARGET OF RAPAMYCIN KINASE;

ARTICLE; AUTOPHAGY; CATABOLISM; CELL METABOLISM; CELL STIMULATION; CONTROLLED STUDY; GLUCOSE TRANSPORT; GLYCOLYSIS; HUMAN; HUMAN CELL; MEMORY CELL; MESENCHYMAL STROMA CELL; OXIDATIVE STRESS; PHENOTYPE; PROTEIN EXPRESSION; SIGNAL TRANSDUCTION; T LYMPHOCYTE ACTIVATION; UPREGULATION; CELLULAR IMMUNITY; CYTOLOGY; FEMALE; IMMUNOLOGY; LYMPHOCYTE ACTIVATION; MALE; T LYMPHOCYTE;

FEMALE; GLYCOLYSIS; HUMANS; IMMUNITY, CELLULAR; LYMPHOCYTE ACTIVATION; MALE; MESENCHYMAL STROMAL CELLS; SIGNAL TRANSDUCTION; T-LYMPHOCYTES; TOR SERINE-THREONINE KINASES;

EID: 84958160380     PISSN: 10665099     EISSN: 15494918     Source Type: Journal    
DOI: 10.1002/stem.2234     Document Type: Article

References (25)

1. Wolf D, von Lilienfeld-Toal M, Wolf AM, et al., Novel treatment concepts for graft-versus-host disease. Blood 2012; 119: 16-25.
2. Le Blanc K, Mougiakakos D,. Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol 2012; 12: 383-396.
3. Krampera M, Galipeau J, Shi Y, et al., Immunological characterization of multipotent mesenchymal stromal cells-The International Society for Cellular Therapy (ISCT) working proposal. Cytotherapy 2013; 15: 1054-1061.
4. Meisel R, Zibert A, Laryea M, et al., Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 2004; 103: 4619-4621.
5. Jitschin R, Mougiakakos D, Von Bahr L, et al., Alterations in the cellular immune compartment of patients treated with third-party mesenchymal stromal cells following allogeneic hematopoietic stem cell transplantation. Stem Cells 2013; 31: 1715-1725.
6. Mougiakakos D, Jitschin R, Johansson CC, et al., The impact of inflammatory licensing on heme oxygenase-1-mediated induction of regulatory T cells by human mesenchymal stem cells. Blood 2011; 117: 4826-4835.
7. Le Blanc K, Frassoni F, Ball L, et al., Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: A phase II study. Lancet 2008; 371: 1579-1586.
8. Han DM, Wang ZD, Zheng XL, et al., Co-infusion of mesenchymal stromal cells has no effect on relapse and infection in leukemia patients undergoing haploidentical hematopietic stem cell transplantation. Leuk Lymphoma 2015: 1-14.
9. Pollizzi KN, Powell JD,. Integrating canonical and metabolic signalling programmes in the regulation of T cell responses. Nat Rev Immunol 2014; 14: 435-446.
10. He S, Kato K, Jiang J, et al., Characterization of the metabolic phenotype of rapamycin-treated CD8 + T cells with augmented ability to generate long-lasting memory cells. Plos One 2011; 6: e20107.
11. Sukumar M, Liu J, Ji Y, et al., Inhibiting glycolytic metabolism enhances CD8 + T cell memory and antitumor function. J Clin Invest 2013; 123: 4479-4488.
12. Kesarwani P, Al-Khami AA, Scurti G, et al., Promoting thiol expression increases the durability of antitumor T-cell functions. Cancer Res 2014; 74: 6036-6047.
13. Crompton JG, Sukumar M, Roychoudhuri R, et al., Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics. Cancer Res 2015; 75: 296-305.
14. Jitschin R, Hofmann AD, Bruns H, et al., Mitochondrial metabolism contributes to oxidative stress and reveals therapeutic targets in chronic lymphocytic leukemia. Blood 2014; 123: 2663-2672.
15. Finlay DK, Rosenzweig E, Sinclair LV, et al., PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8 + T cells. J Exp Med 2012; 209: 2441-2453.
16. Kastenmuller W, Gasteiger G, Subramanian N, et al., Regulatory T cells selectively control CD8 + T cell effector pool size via IL-2 restriction. J Immunol 2011; 187: 3186-3197.
17. Shin HJ, Baker J, Leveson-Gower DB, et al., Rapamycin and IL-2 reduce lethal acute graft-versus-host disease associated with increased expansion of donor type CD4+CD25+Foxp3 + regulatory T cells. Blood 2011; 118: 2342-2350.
18. van der Windt GJ, Everts B, Chang CH, et al., Mitochondrial respiratory capacity is a critical regulator of CD8 + T cell memory development. Immunity 2012; 36: 68-78.
19. Cuddapah S, Barski A, Zhao K,. Epigenomics of T cell activation, differentiation, and memory. Curr Opin Immunol 2010; 22: 341-347.
20. Peter C, Waldmann H, Cobbold SP,. mTOR signalling and metabolic regulation of T cell differentiation. Curr Opin Immunol 2010; 22: 655-661.
21. Cheng SC, Quintin J, Cramer RA, et al., mTOR- and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 2014; 345: 1250684.
22. Metz R, Rust S, Duhadaway JB, et al., IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: A novel IDO effector pathway targeted by D-1-methyl-tryptophan. Oncoimmunology 2012; 1: 1460-1468.
23. Xu X, Araki K, Li S, et al., Autophagy is essential for effector CD8(+) T cell survival and memory formation. Nat Immunol 2014; 15: 1152-1161.
24. Ramanathan A, Schreiber SL,. Direct control of mitochondrial function by mTOR. Proc Natl Acad Sci USA 2009; 106: 22229-22232.
25. Armand P, Gannamaneni S, Kim HT, et al., Improved survival in lymphoma patients receiving sirolimus for graft-versus-host disease prophylaxis after allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning. J Clin Oncol 2008; 26: 5767-5774.