title: Requirement for T-bet in the aberrant differentiation of unhelped memory CD8+ T cells.
abstract: Immunity to intracellular pathogens requires dynamic balance between terminal differentiation of short-lived, cytotoxic effector CD8+ T cells and self-renewal of central-memory CD8+ T cells. We now show that T-bet represses transcription of IL-7Ralpha and drives differentiation of effector and effector-memory CD8+ T cells at the expense of central-memory cells. We also found T-bet to be overexpressed in CD8+ T cells that differentiated in the absence of CD4+ T cell help, a condition that is associated with defective central-memory formation. Finally, deletion of T-bet corrected the abnormal phenotypic and functional properties of "unhelped" memory CD8+ T cells. T-bet, thus, appears to function as a molecular switch between central- and effector-memory cell differentiation. Antagonism of T-bet may, therefore, represent a novel strategy to offset dysfunctional programming of memory CD8+ T cells.
authors: Abramson Family Cancer Research Institute, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Andrew M
authors: AM
authors: Intlekofer
authors: Naofumi
authors: N
authors: Takemoto
authors: Charlly
authors: C
authors: Kao
authors: Arnob
authors: A
authors: Banerjee
authors: Felix
authors: F
authors: Schambach
authors: John K
authors: JK
authors: Northrop
authors: Hao
authors: H
authors: Shen
authors: E John
authors: EJ
authors: Wherry
authors: Steven L
authors: SL
authors: Reiner
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002454:Cell Differentiation; D007156:Immunologic Memory / Q000276:immunology*; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D051379:Mice; D012097:Repressor Proteins / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: D053699:Interleukin-7 Receptor alpha Subunit; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor
references: Immunity. 2004 Apr;20(4):477-94
references: 15084276
references: Science. 2002 Jan 11;295(5553):338-42
references: 11786644
references: Science. 1997 Apr 25;276(5312):596-9
references: 9110979
references: Science. 2002 Sep 20;297(5589):2060-3
references: 12242444
references: Nature. 2003 Feb 20;421(6925):852-6
references: 12594515
references: Nat Immunol. 2003 Mar;4(3):225-34
references: 12563257
references: Science. 2003 Apr 11;300(5617):337-9
references: 12690201
references: Science. 2003 Apr 11;300(5617):339-42
references: 12690202
references: Nat Immunol. 2003 Dec;4(12):1191-8
references: 14625547
references: Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5610-5
references: 15044705
references: Nat Immunol. 2004 Sep;5(9):927-33
references: 15300249
references: Nat Rev Immunol. 2004 Aug;4(8):595-602
references: 15286726
references: Eur J Immunol. 2005 Mar;35(3):757-65
references: 15719366
references: Nat Immunol. 2005 Aug;6(8):793-9
references: 16025119
references: J Exp Med. 2005 Nov 7;202(9):1289-300
references: 16275766
references: J Immunol. 2005 Dec 15;175(12):7837-47
references: 16339519
references: Nat Immunol. 2005 Dec;6(12):1236-44
references: 16273099
references: Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3304-9
references: 16492737
references: Nature. 2006 Apr 13;440(7086):890-5
references: 16612374
references: Nat Immunol. 2006 May;7(5):466-74
references: 16565720
references: Nat Immunol. 2006 May;7(5):457-65
references: 16565721
references: Nature. 2006 Jun 15;441(7095):890-3
references: 16778891
references: J Immunol. 2006 Dec 1;177(11):7515-9
references: 17114419
references: Dev Cell. 2006 Dec;11(6):775-89
references: 17141154
references: Annu Rev Immunol. 2007;25:171-92
references: 17129182
references: Science. 2007 Mar 23;315(5819):1687-91
references: 17332376
references: Nature. 1999 Oct 14;401(6754):708-12
references: 10537110
references: J Clin Invest. 2001 Sep;108(6):871-8
references: 11560956
references: J Immunol. 2001 Nov 1;167(9):4838-43
references: 11673487
references: J Exp Med. 2004 Apr 19;199(8):1153-62
references: 15096540