title: Mcl-1 antagonizes Bax/Bak to promote effector CD4(+) and CD8(+) T-cell responses.
abstract: Members of the Bcl-2 family have critical roles in regulating tissue homeostasis by modulating apoptosis. Anti-apoptotic molecules physically interact and restrain pro-apoptotic family members preventing the induction of cell death. However, the specificity of the functional interactions between pro- and anti-apoptotic Bcl-2 family members remains unclear. The pro-apoptotic Bcl-2 family member Bcl-2 interacting mediator of death (Bim) has a critical role in promoting the death of activated, effector T cells following viral infections. Although Bcl-2 is an important Bim antagonist in effector T cells, and Bcl-xL is not required for effector T-cell survival, the roles of other anti-apoptotic Bcl-2 family members remain unclear. Here, we investigated the role of myeloid cell leukemia sequence 1 (Mcl-1) in regulating effector T-cell responses in vivo. We found, at the peak of the response to lymphocytic choriomeningitis virus (LCMV) infection, that Mcl-1 expression was increased in activated CD4(+) and CD8(+) T cells. Retroviral overexpression of Mcl-1-protected activated T cells from death, whereas deletion of Mcl-1 during the course of infection led to a massive loss of LCMV-specific CD4(+) and CD8(+) T cells. Interestingly, the co-deletion of Bim failed to prevent the loss of Mcl-1-deficient T cells. Furthermore, lck-driven overexpression of a Bcl-xL transgene only partially rescued Mcl-1-deficient effector T cells suggesting a lack of redundancy between the family members. In contrast, additional loss of Bax and Bak completely rescued Mcl-1-deficient effector T-cell number and function, without enhancing T-cell proliferation. These data suggest that Mcl-1 is critical for promoting effector T-cell responses, but does so by combating pro-apoptotic molecules beyond Bim.
authors.affiliation: Division of Cellular and Molecular Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: P
authors.initials: P
authors.lastname: Tripathi
authors.forename: B
authors.initials: B
authors.lastname: Koss
authors.forename: J T
authors.initials: JT
authors.lastname: Opferman
authors.forename: D A
authors.initials: DA
authors.lastname: Hildeman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000502:physiology; D000072224:Bcl-2-Like Protein 11; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology* / Q000821:virology; D002470:Cell Survival / Q000502:physiology; D004195:Disease Models, Animal; D008216:Lymphocytic Choriomeningitis / Q000473:pathology / Q000503:physiopathology; D008217:Lymphocytic choriomeningitis virus / Q000502:physiology; D008565:Membrane Proteins / Q000172:deficiency / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000172:deficiency / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000502:physiology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000037:antagonists & inhibitors* / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; C494773:Bak1 protein, mouse; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C579094:Mcl1 protein, mouse; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
references.citation: Mol Cell. 2005 Feb 4;17(3):393-403
references.pmid: 15694340
references.citation: Nature. 2005 Jun 2;435(7042):677-81
references.pmid: 15902208
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11272-7
references.pmid: 16055554
references.citation: Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9781-6
references.pmid: 10449771
references.citation: Immunity. 1998 Jun;8(6):675-82
references.pmid: 9655481
references.citation: Science. 1999 Nov 26;286(5445):1735-8
references.pmid: 10576740
references.citation: Eur J Immunol. 2006 Jul;36(7):1694-706
references.pmid: 16761315
references.citation: Mol Cell Biol. 2010 Jun;30(12):3099-110
references.pmid: 20385764
references.citation: Nat Immunol. 2001 May;2(5):397-402
references.pmid: 11323692
references.citation: Science. 1993 Sep 17;261(5128):1584-8
references.pmid: 8372353
references.citation: Nat Immunol. 2003 Dec;4(12):1191-8
references.pmid: 14625547
references.citation: Cell. 2005 Jul 1;121(7):1085-95
references.pmid: 15989957
references.citation: J Virol. 2006 Sep;80(17):8627-38
references.pmid: 16912311
references.citation: J Immunol. 2010 Aug 15;185(4):2116-24
references.pmid: 20644163
references.citation: J Immunol. 2007 May 15;178(10):6083-91
references.pmid: 17475833
references.citation: Cancer Cell. 2006 Nov;10(5):389-99
references.pmid: 17097561
references.citation: J Immunol. 2009 Jun 15;182(12):7482-9
references.pmid: 19494271
references.citation: J Immunol. 2011 May 15;186(10):5729-37
references.pmid: 21451108
references.citation: Genes Dev. 2005 Jun 1;19(11):1294-305
references.pmid: 15901672
references.citation: Infect Immun. 2008 Mar;76(3):1179-85
references.pmid: 18086806
references.citation: J Immunol. 1999 Apr 15;162(8):4527-35
references.pmid: 10201991
references.citation: J Exp Med. 2007 Jul 9;204(7):1665-75
references.pmid: 17591857
references.citation: Cell. 1993 Oct 22;75(2):229-40
references.pmid: 8402909
references.citation: J Immunol. 2008 Jul 1;181(1):521-8
references.pmid: 18566418
references.citation: Immunity. 1995 Jul;3(1):87-98
references.pmid: 7621080
references.citation: Semin Immunol. 2009 Apr;21(2):92-8
references.pmid: 19269192
references.citation: J Immunol. 2011 Jul 1;187(1):7-9
references.pmid: 21690331
references.citation: Immunity. 2002 Jun;16(6):759-67
references.pmid: 12121658
references.citation: Science. 1988 Aug 26;241(4869):1089-92
references.pmid: 2970670
references.citation: Genes Dev. 2000 Aug 15;14(16):2060-71
references.pmid: 10950869
references.citation: Nat Immunol. 2002 Oct;3(10):932-9
references.pmid: 12244308
references.citation: Cancer Cell. 2006 Nov;10(5):375-88
references.pmid: 17097560
references.citation: J Immunol. 2011 Jan 1;186(1):156-63
references.pmid: 21098226
references.citation: Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10967-71
references.pmid: 20534453
references.citation: Biochem Cell Biol. 2010 Oct;88(5):809-18
references.pmid: 20921992
references.citation: Curr Opin Immunol. 2007 Oct;19(5):516-21
references.pmid: 17644328
references.citation: J Immunol. 2003 Jan 1;170(1):477-86
references.pmid: 12496434
references.citation: Nature. 2003 Dec 11;426(6967):671-6
references.pmid: 14668867
references.citation: Immunol Rev. 2010 Jul;236:54-67
references.pmid: 20636808
references.citation: Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16689-94
references.pmid: 18946035
references.citation: Nat Cell Biol. 2012 Apr 29;14(6):575-83
references.pmid: 22544066
references.citation: J Biol Chem. 2004 May 21;279(21):22020-9
references.pmid: 15014070
references.citation: Cell Death Dis. 2011 Oct 06;2:e214
references.pmid: 21975296
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15035-40
references.pmid: 14657380
references.citation: J Virol. 1997 Dec;71(12):9672-8
references.pmid: 9371632
references.citation: Genes Dev. 2000 Jan 1;14(1):23-7
references.pmid: 10640272
references.citation: J Immunol. 2005 Jun 1;174(11):6967-73
references.pmid: 15905539
references.citation: Science. 2005 Feb 18;307(5712):1101-4
references.pmid: 15718471