title: FoxP3 and Bcl-xL cooperatively promote regulatory T cell persistence and prevention of arthritis development.
abstract: BACKGROUND
  Forkhead box p3 (FoxP3)-expressing regulatory T cells (Tregs) have been clearly implicated in the control of autoimmune disease in murine models. In addition, ectopic expression of FoxP3 conveys a Treg phenotype to CD4(+) T cells, lending itself to therapeutic use in the prevention of rheumatoid arthritis (RA). In this study, we generated therapeutically active Tregs with an increased life span and hence greater therapeutic potential.
  
  
  METHODS
  We used retrovirus-mediated transduction to introduce FoxP3 or FoxP3 with anti-apoptotic Bcl-2 family molecule Bcl-xL linked by a 2A picornavirus self-cleaving peptide into CD4(+) T cells to generate Tregs. In addition, by using in vitro functional analyses and adoptive immunotherapy in a murine model of RA, we demonstrated that these Tregs were highly reactive.
  
  
  RESULTS
  We found that CD4(+) T cells expressing both FoxP3 and Bcl-xL were able to differentiate into functional Tregs, which have a long-term survival advantage over cells transduced with FoxP3 alone. In an in vivo murine model, adoptive transfer of Tregs expressing both FoxP3 and Bcl-xL demonstrated more effective suppression of RA than CD4(+) T cells expressing FoxP3 alone.
  
  
  CONCLUSIONS
  FoxP3 and Bcl-xL can cooperatively promote the differentiation and persistence of Tregs, with the capacity to prevent arthritis. Our results provide a novel approach for generating highly reactive Tregs for augmenting cellular immunotherapy for autoimmune disease.
authors.affiliation: Department of Microbiology & Immunology and Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
authors.forename: Rizwanul
authors.initials: R
authors.lastname: Haque
authors.forename: Fengyang
authors.initials: F
authors.lastname: Lei
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Xiong
authors.forename: Yuzhang
authors.initials: Y
authors.lastname: Wu
authors.forename: Jianxun
authors.initials: J
authors.lastname: Song
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D051858:Forkhead Transcription Factors / Q000235:genetics*; D016219:Immunotherapy, Adoptive; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology*; D014161:Transduction, Genetic; D051020:bcl-X Protein / Q000235:genetics*
chemical_list: C494812:Bcl2l1 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D051020:bcl-X Protein
references.citation: J Clin Invest. 2006 Sep;116(9):2325-7
references.pmid: 16955134
references.citation: J Immunol. 2005 Sep 1;175(5):3075-83
references.pmid: 16116196
references.citation: Nat Immunol. 2007 Jan;8(1):64-73
references.pmid: 17128276
references.citation: Nat Immunol. 2005 Feb;6(2):152-62
references.pmid: 15640801
references.citation: J Immunol. 2008 Aug 1;181(3):2220-6
references.pmid: 18641362
references.citation: J Exp Med. 2004 Jun 7;199(11):1479-89
references.pmid: 15184501
references.citation: J Immunol. 2017 Feb 1;198(3):981-985
references.pmid: 28115586
references.citation: Cell Death Differ. 2003 Sep;10(9):1059-67
references.pmid: 12934080
references.citation: J Immunol. 2008 Jan 15;180(2):774-82
references.pmid: 18178815
references.citation: J Exp Med. 2005 Apr 4;201(7):1061-7
references.pmid: 15809351
references.citation: Nat Immunol. 2009 Jul;10(7):689-95
references.pmid: 19536194
references.citation: J Immunol. 2009 Jun 1;182(11):6744-52
references.pmid: 19454669
references.citation: Blood. 2008 Sep 1;112(5):1813-21
references.pmid: 18550850
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 10;106(45):19078-83
references.pmid: 19884493
references.citation: Immunity. 2005 May;22(5):621-31
references.pmid: 15894279
references.citation: Biol Direct. 2008 Feb 27;3:6
references.pmid: 18304352
references.citation: J Immunol. 2008 Jun 1;180(11):7240-8
references.pmid: 18490723
references.citation: Eur J Immunol. 2001 Apr;31(4):1122-31
references.pmid: 11298337
references.citation: J Exp Med. 2006 Jul 10;203(7):1693-700
references.pmid: 16818676
references.citation: J Immunol. 2009 Jun 1;182(11):6648-52
references.pmid: 19454658
references.citation: Eur J Immunol. 2010 Jan;40(1):71-80
references.pmid: 19877010
references.citation: Nat Immunol. 2003 Apr;4(4):330-6
references.pmid: 12612578
references.citation: Blood. 2008 Oct 15;112(8):3283-92
references.pmid: 18664628
references.citation: J Immunol. 2008 Aug 15;181(4):2855-68
references.pmid: 18684977
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18169-74
references.pmid: 17978190
references.citation: Immunol Rev. 2009 May;229(1):41-66
references.pmid: 19426214
references.citation: J Immunol. 2004 Feb 1;172(3):1341-5
references.pmid: 14734708
references.citation: Ann N Y Acad Sci. 2005 Jun;1051:506-14
references.pmid: 16126991
references.citation: Arthritis Res Ther. 2004;6(3):R239-49
references.pmid: 15142270
references.citation: Arthritis Rheum. 2007 Sep;56(9):2947-56
references.pmid: 17763426
references.citation: J Immunol. 2006 Dec 1;177(11):8140-7
references.pmid: 17114489
references.citation: Arthritis Rheum. 2006 Jun;54(6):1759-71
references.pmid: 16736518
references.citation: J Autoimmun. 2010 Jun;34(4):390-9
references.pmid: 19880290
references.citation: Nat Immunol. 2004 Feb;5(2):150-8
references.pmid: 14730361
references.citation: Nat Immunol. 2007 Dec;8(12):1353-62
references.pmid: 17982458
references.citation: PLoS Biol. 2008 Nov 11;6(11):e276
references.pmid: 18998771
references.citation: Nat Methods. 2006 Mar;3(3):162-4
references.pmid: 16489331
references.citation: Nat Protoc. 2006;1(1):406-17
references.pmid: 17406263
references.citation: Br J Cancer. 2005 Mar 14;92(5):913-20
references.pmid: 15714205
references.citation: Nat Immunol. 2009 Nov;10(11):1178-84
references.pmid: 19783988
references.citation: Arthritis Rheum. 2005 Jul;52(7):2212-21
references.pmid: 15986351
references.citation: Nature. 2007 Nov 22;450(7169):566-9
references.pmid: 18033300
references.citation: J Clin Invest. 2005 Oct;115(10):2904-13
references.pmid: 16167085
references.citation: J Exp Med. 2009 Feb 16;206(2):421-34
references.pmid: 19188497
references.citation: Immunity. 2001 Sep;15(3):445-55
references.pmid: 11567634
references.citation: Arthritis Res Ther. 2005;7(2):R291-301
references.pmid: 15743476
references.citation: Eur J Immunol. 2006 Oct;36(10):2601-12
references.pmid: 17013990
references.citation: J Immunol. 2009 Jan 1;182(1):102-10
references.pmid: 19109140
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19396-401
references.pmid: 19036923