title: Mitochondria-centric activation induced cell death of cytolytic T lymphocytes and its implications for cancer immunotherapy.
abstract: Premature death of the adoptively transferred cytolytic T lymphocytes (CTL) by means of activation induced cell death (AICD) represents one of the major constraints in devising an effective anti-cancer immune intervention strategy. Understanding the mechanism of AICD is, therefore, critical for developing methods to interfere with this death process. Although the existing paradigm on AICD centers around the initiation of the cascade of events originating from the engagement of death receptors leading to the activation of effector caspases and eventually resulting in cell death, recent findings have questioned the universal role of caspases as the cell death executioners. We here review our current understanding of the contribution of caspase-dependent and caspase-independent death executioners in AICD of T cells. We will also discuss the involvement of mitochondria-centric death pathway in AICD of human tumor associated antigen-specific primary CTL and its implications in cancer immunotherapy.
authors.affiliation: Department of Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA. arvindac@yahoo.com
authors.forename: Arvind
authors.initials: A
authors.lastname: Chhabra
mesh_terms: D019264:Adoptive Transfer; D017209:Apoptosis / Q000276:immunology*; D020169:Caspases / Q000276:immunology* / Q000378:metabolism; D002463:Cell Membrane Permeability; D006801:Humans; D007167:Immunotherapy; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D008928:Mitochondria / Q000276:immunology*; D051336:Mitochondrial Membranes / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases
references.citation: Biochem Biophys Res Commun. 2003 May 9;304(3):487-97
references.pmid: 12729583
references.citation: Science. 1986 Sep 19;233(4770):1318-21
references.pmid: 3489291
references.citation: Mol Cell. 2001 Sep;8(3):613-21
references.pmid: 11583623
references.citation: Cell Death Differ. 1999 Nov;6(11):1043-53
references.pmid: 10578172
references.citation: EMBO J. 1995 Dec 15;14(24):6136-47
references.pmid: 8557033
references.citation: Immunity. 1998 Oct;9(4):575-85
references.pmid: 9806643
references.citation: Mol Cell Biol. 2002 Jul;22(13):4929-42
references.pmid: 12052897
references.citation: Cell Death Differ. 2001 Aug;8(8):829-40
references.pmid: 11526436
references.citation: Science. 1998 Aug 28;281(5381):1322-6
references.pmid: 9735050
references.citation: J Leukoc Biol. 2002 Jun;71(6):907-20
references.pmid: 12050175
references.citation: J Clin Oncol. 2005 Apr 1;23(10):2346-57
references.pmid: 15800326
references.citation: Blood. 2000 Aug 1;96(3):1030-8
references.pmid: 10910919
references.citation: Nat Cell Biol. 1999 Dec;1(8):E209-16
references.pmid: 10587660
references.citation: J Biol Chem. 1990 Oct 5;265(28):17355-63
references.pmid: 2170374
references.citation: Nature. 1995 Feb 2;373(6513):438-41
references.pmid: 7530335
references.citation: Nat Med. 2004 Sep;10(9):909-15
references.pmid: 15340416
references.citation: J Exp Med. 1987 Jan 1;165(1):173-94
references.pmid: 3491868
references.citation: Cell. 2003 Oct 3;115(1):61-70
references.pmid: 14532003
references.citation: Neuron. 2003 Jun 19;38(6):899-914
references.pmid: 12818176
references.citation: Nat Immunol. 2003 May;4(5):416-23
references.pmid: 12719731
references.citation: J Exp Med. 1999 Dec 20;190(12):1891-6
references.pmid: 10601363
references.citation: Eur J Immunol. 2000 Mar;30(3):725-31
references.pmid: 10741386
references.citation: Nature. 1995 Feb 2;373(6513):441-4
references.pmid: 7530336
references.citation: Science. 2000 May 5;288(5467):870-4
references.pmid: 10797012
references.citation: Semin Cancer Biol. 2002 Feb;12(1):43-50
references.pmid: 11926411
references.citation: Immunol Lett. 2000 Sep 15;74(1):5-10
references.pmid: 10996622
references.citation: Cell. 1994 Mar 25;76(6):969-76
references.pmid: 7511063
references.citation: J Cell Biol. 2000 Dec 11;151(6):1247-56
references.pmid: 11121439
references.citation: J Biol Chem. 2002 Jan 4;277(1):439-44
references.pmid: 11602612
references.citation: Oncogene. 2002 Jul 25;21(32):4944-56
references.pmid: 12118373
references.citation: Proc Natl Acad Sci U S A. 1984 Jun;81(11):3511-5
references.pmid: 6610177
references.citation: Mol Cell Biol. 2000 Feb;20(3):929-35
references.pmid: 10629050
references.citation: Biochem J. 1999 Jul 15;341 ( Pt 2):233-49
references.pmid: 10393078
references.citation: Nature. 2000 Dec 21-28;408(6815):1004-8
references.pmid: 11140637
references.citation: Cell Death Differ. 2007 Jan;14(1):44-55
references.pmid: 17053807
references.citation: J Exp Med. 1992 Dec 1;176(6):1693-702
references.pmid: 1460426
references.citation: J Exp Med. 1999 Dec 20;190(12):1879-90
references.pmid: 10601362
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):8078-82
references.pmid: 7644541
references.citation: Cell. 2000 Jul 7;102(1):33-42
references.pmid: 10929711
references.citation: J Immunol. 2008 Jul 15;181(2):1063-70
references.pmid: 18606658
references.citation: J Immunol. 2004 Nov 15;173(10):6017-24
references.pmid: 15528336
references.citation: Nat Immunol. 2000 Dec;1(6):489-95
references.pmid: 11101870
references.citation: J Exp Med. 1996 Sep 1;184(3):1075-82
references.pmid: 9064324
references.citation: Cell Immunol. 1996 Mar 15;168(2):220-8
references.pmid: 8640868
references.citation: Nat Med. 2005 Jul;11(7):725-30
references.pmid: 16015365
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16168-73
references.pmid: 12427970
references.citation: J Immunol. 1984 Jan;132(1):510-9
references.pmid: 6197458
references.citation: Cancer J. 2009 Nov-Dec;15(6):451-5
references.pmid: 20010162
references.citation: J Exp Med. 2001 Feb 5;193(3):317-28
references.pmid: 11157052
references.citation: FASEB J. 2000 Apr;14(5):729-39
references.pmid: 10744629
references.citation: Nat Cell Biol. 2003 Feb;5(2):97-9
references.pmid: 12563272
references.citation: J Clin Invest. 2003 Mar;111(5):575-81
references.pmid: 12618509
references.citation: J Clin Invest. 2007 May;117(5):1195-203
references.pmid: 17476349
references.citation: Science. 1991 Dec 13;254(5038):1643-7
references.pmid: 1840703
references.citation: Nature. 1999 Feb 4;397(6718):441-6
references.pmid: 9989411
references.citation: Endocr Metab Immune Disord Drug Targets. 2009 Dec;9(4):344-52
references.pmid: 19807670
references.citation: Science. 2001 Apr 27;292(5517):624-6
references.pmid: 11330312
references.citation: Vaccine. 2007 Sep 27;25 Suppl 2:B4-16
references.pmid: 17646038
references.citation: J Biol Chem. 2001 May 11;276(19):16391-8
references.pmid: 11278689
references.citation: Immunol Cell Biol. 2002 Apr;80(2):131-7
references.pmid: 11940113
references.citation: J Biol Chem. 2003 Aug 15;278(33):31401-11
references.pmid: 12782632
references.citation: Nature. 2001 Jul 5;412(6842):95-9
references.pmid: 11452314
references.citation: Annu Rev Immunol. 2004;22:765-87
references.pmid: 15032596
references.citation: Immunity. 1999 Jun;10(6):735-44
references.pmid: 10403648
references.citation: Nature. 1989 Jun 22;339(6226):625-6
references.pmid: 2786609
references.citation: Cytokine. 1997 Nov;9(11):801-8
references.pmid: 9367540
references.citation: Biochim Biophys Acta. 2008 Jan;1784(1):76-93
references.pmid: 17964301
references.citation: J Exp Med. 1998 Nov 16;188(10):1817-30
references.pmid: 9815259
references.citation: J Exp Med. 1983 Jul 1;158(1):240-5
references.pmid: 6602860
references.citation: J Exp Med. 1994 Apr 1;179(4):1109-18
references.pmid: 8145033
references.citation: J Exp Med. 1998 Apr 20;187(8):1261-71
references.pmid: 9547337
references.citation: J Biol Chem. 2002 Jan 4;277(1):445-54
references.pmid: 11604410
references.citation: Cell. 1997 Apr 18;89(2):175-84
references.pmid: 9108473
references.citation: J Biol Chem. 1996 Dec 13;271(50):31929-36
references.pmid: 8943238
references.citation: J Exp Med. 1998 Sep 7;188(5):919-30
references.pmid: 9730893
references.citation: Nat Rev Drug Discov. 2003 Jul;2(7):554-65
references.pmid: 12815381
references.citation: Science. 1998 Aug 28;281(5381):1309-12
references.pmid: 9721092
references.citation: Nature. 1998 Jan 1;391(6662):96-9
references.pmid: 9422513
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14681-6
references.pmid: 9843949
references.citation: J Clin Immunol. 2003 Sep;23(5):355-61
references.pmid: 14601643
references.citation: Annu Rev Immunol. 2003;21:71-105
references.pmid: 12414721
references.citation: Annu Rev Immunol. 2002;20:55-72
references.pmid: 11861597
references.citation: Science. 2004 Feb 13;303(5660):1010-4
references.pmid: 14963330
references.citation: Nature. 1992 Mar 26;356(6367):314-7
references.pmid: 1372394
references.citation: J Cell Physiol. 2002 Aug;192(2):131-7
references.pmid: 12115719
references.citation: Cancer Res. 1995 Feb 15;55(4):748-52
references.pmid: 7531614
references.citation: Pharm Acta Helv. 2000 Mar;74(2-3):281-6
references.pmid: 10812970
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2432-7
references.pmid: 12591950
references.citation: Curr Opin Oncol. 1995 Mar;7(2):175-84
references.pmid: 7756383
references.citation: Cell. 2000 Oct 13;103(2):239-52
references.pmid: 11057897
references.citation: Pharmacol Ther. 2000 Dec;88(3):333-47
references.pmid: 11337030
references.citation: J Immunol. 2002 Dec 1;169(11):6218-30
references.pmid: 12444127
references.citation: Eur J Immunol. 2006 Dec;36(12):3167-74
references.pmid: 17109472
references.citation: Mol Cell. 2001 Sep;8(3):705-11
references.pmid: 11583631
references.citation: Nat Med. 1996 Jan;2(1):52-8
references.pmid: 8564842
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3011-6
references.pmid: 14970329