title: Characterization of the metabolic phenotype of rapamycin-treated CD8+ T cells with augmented ability to generate long-lasting memory cells.
abstract: BACKGROUND
  Cellular metabolism plays a critical role in regulating T cell responses and the development of memory T cells with long-term protections. However, the metabolic phenotype of antigen-activated T cells that are responsible for the generation of long-lived memory cells has not been characterized.
  
  
  METHODS
  Using lymphocytic choriomeningitis virus (LCMV) peptide gp33-specific CD8(+) T cells derived from T cell receptor transgenic mice, we characterized the metabolic phenotype of proliferating T cells that were activated and expanded in vitro in the presence or absence of rapamycin, and determined the capability of these rapamycin-treated T cells to generate long-lived memory cells in vivo.
  
  
  RESULTS
  Antigen-activated CD8(+) T cells treated with rapamycin gave rise to 5-fold more long-lived memory T cells in vivo than untreated control T cells. In contrast to that control T cells only increased glycolysis, rapamycin-treated T cells upregulated both glycolysis and oxidative phosphorylation (OXPHOS). These rapamycin-treated T cells had greater ability than control T cells to survive withdrawal of either glucose or growth factors. Inhibition of OXPHOS by oligomycin significantly reduced the ability of rapamycin-treated T cells to survive growth factor withdrawal. This effect of OXPHOS inhibition was accompanied with mitochondrial hyperpolarization and elevation of reactive oxygen species that are known to be toxic to cells.
  
  
  CONCLUSIONS
  Our findings indicate that these rapamycin-treated T cells may represent a unique cell model for identifying nutrients and signals critical to regulating metabolism in both effector and memory T cells, and for the development of new methods to improve the efficacy of adoptive T cell cancer therapy.
authors: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
authors: Shan
authors: S
authors: He
authors: Koji
authors: K
authors: Kato
authors: Jiu
authors: J
authors: Jiang
authors: Daniel R
authors: DR
authors: Wahl
authors: Shin
authors: S
authors: Mineishi
authors: Erin M
authors: EM
authors: Fisher
authors: Donna M
authors: DM
authors: Murasko
authors: Gary D
authors: GD
authors: Glick
authors: Yi
authors: Y
authors: Zhang
references: J Clin Invest. 2002 May;109(10):1335-44
references: 12021249
references: J Immunol. 2005 Nov 1;175(9):5732-43
references: 16237064
references: Immunity. 2007 Oct;27(4):670-84
references: 17950003
references: Biol Blood Marrow Transplant. 2006 Sep;12(9):905-18
references: 16920556
references: Metabolism. 2007 Nov;56(11):1500-7
references: 17950100
references: Immunol Cell Biol. 2008 May-Jun;86(4):325-32
references: 18362944
references: Nat Rev Immunol. 2009 Sep;9(9):662-8
references: 19680250
references: Science. 2009 Jan 23;323(5913):505-9
references: 19164749
references: Free Radic Biol Med. 2009 Oct 1;47(7):891-905
references: 19577640
references: J Clin Invest. 2005 Jun;115(6):1616-26
references: 15931392
references: Biochem Med Metab Biol. 1991 Feb;45(1):28-40
references: 1707637
references: Science. 1996 Apr 5;272(5258):54-60
references: 8600537
references: J Immunol. 2005 Mar 1;174(5):3051-8
references: 15728519
references: J Immunol. 2007 Jul 1;179(1):21-5
references: 17579015
references: Science. 2007 Mar 23;315(5819):1687-91
references: 17332376
references: Eur J Biochem. 1993 Feb 15;212(1):95-9
references: 8444168
references: J Biol Chem. 2006 Sep 15;281(37):27643-52
references: 16847060
references: Immunol Rev. 2006 Jun;211:67-80
references: 16824118
references: Nature. 2009 Jul 2;460(7251):108-12
references: 19543266
references: Arthritis Res Ther. 2004;6(6):265-78
references: 15535839
references: J Virol. 2004 Jun;78(11):5535-45
references: 15140950
references: Immunity. 2007 Sep;27(3):393-405
references: 17892848
references: Cell. 2002 Dec 13;111(6):837-51
references: 12526810
references: Eur J Immunol. 2003 Aug;33(8):2223-32
references: 12884297
references: Immunity. 2007 Aug;27(2):173-8
references: 17723208
references: Eur J Immunol. 2007 Nov;37 Suppl 1:S103-10
references: 17972353
references: Metabolism. 2006 Dec;55(12):1637-44
references: 17142137
references: Blood. 1998 Jul 1;92(1):118-28
references: 9639507
references: Exp Cell Res. 1973 Mar 15;77(1):127-35
references: 4690164
references: J Exp Med. 2008 Sep 29;205(10):2397-408
references: 18809716
references: Immunity. 2007 Aug;27(2):281-95
references: 17723218
references: Adv Cancer Res. 2009;102:197-227
references: 19595310
references: Cell. 2005 Feb 25;120(4):497-512
references: 15734682
references: Trends Immunol. 2004 Jul;25(7):360-7
references: 15207503
references: J Mol Cell Cardiol. 1999 Oct;31(10):1863-72
references: 10525424
references: J Exp Med. 2005 Jan 17;201(2):259-66
references: 15642745
references: Lupus. 2010 Nov;19(13):1492-501
references: 20647250
references: J Immunol. 2001 Mar 1;166(5):3201-9
references: 11207273
references: Mol Cell Biol. 2002 Aug;22(15):5575-84
references: 12101249
references: Int J Radiat Oncol Biol Phys. 1989 Nov;17(5):1033-40
references: 2808036
references: Cancer Res. 1983 Oct;43(10):4662-4
references: 6883323
references: Nat Rev Immunol. 2006 May;6(5):383-93
references: 16622476
references: J Biol Chem. 2004 Jan 9;279(2):910-9
references: 14573608
references: Immunol Rev. 2006 Jun;211:146-53
references: 16824124
references: Nat Immunol. 2002 Jun;3(6):515-21
references: 12032565
references: Nat Rev Immunol. 2004 Aug;4(8):595-602
references: 15286726
references: Immunity. 2010 Jan 29;32(1):67-78
references: 20060330
references: J Immunol. 2008 Jan 1;180(1):89-105
references: 18097008
references: Nat Rev Immunol. 2003 Dec;3(12):939-51
references: 14647476
references: J Clin Invest. 2007 May;117(5):1204-12
references: 17476350
references: Cell Div. 2006 Aug 31;1:19
references: 16945145
references: J Immunol. 2006 Jun 15;176(12):7301-7
references: 16751373
references: Nat Rev Immunol. 2006 Aug;6(8):618-23
references: 16868553
references: Nature. 2009 Jul 2;460(7251):103-7
references: 19494812
references: Cancer Res. 2007 Jul 15;67(14):6745-52
references: 17638885
references: Methods Enzymol. 2008;442:439-57
references: 18662583
references: J Immunol. 2008 Feb 1;180(3):1309-15
references: 18209024
references: Nature. 2007 Nov 29;450(7170):736-40
references: 18046414
references: Microbes Infect. 2003 Mar;5(3):227-31
references: 12681412
references: Ann Rheum Dis. 2003 Feb;62(2):133-9
references: 12525382
references: Nat Rev Immunol. 2005 Nov;5(11):844-52
references: 16239903
references: Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16689-94
references: 18946035
references: World J Surg. 2009 Apr;33(4):661-6
references: 19034564
references: Indian J Biochem Biophys. 1991 Jun;28(3):203-9
references: 1786971
references: Nat Immunol. 2003 Mar;4(3):225-34
references: 12563257
references: Biochim Biophys Acta. 1989 Mar 6;1010(3):342-5
references: 2920182
references: Blood. 2004 May 15;103(10):3970-8
references: 14764532
references: Nat Rev Immunol. 2002 Aug;2(8):547-56
references: 12154374
references: Cell. 2006 Feb 10;124(3):471-84
references: 16469695