FoxP3 and Bcl-xL cooperatively promote regulatory T cell persistence and prevention of arthritis development.
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.
Haque
Rizwanul
R
Department of Microbiology & Immunology and Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
Lei
Fengyang
F
Xiong
Xiaofang
X
Wu
Yuzhang
Y
Song
Jianxun
J
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*
C494812:Bcl2l1 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D051020:bcl-X Protein
J Clin Invest. 2006 Sep;116(9):2325-7
16955134
J Immunol. 2005 Sep 1;175(5):3075-83
16116196
Nat Immunol. 2007 Jan;8(1):64-73
17128276
Nat Immunol. 2005 Feb;6(2):152-62
15640801
J Immunol. 2008 Aug 1;181(3):2220-6
18641362
J Exp Med. 2004 Jun 7;199(11):1479-89
15184501
J Immunol. 2017 Feb 1;198(3):981-985
28115586
Cell Death Differ. 2003 Sep;10(9):1059-67
12934080
J Immunol. 2008 Jan 15;180(2):774-82
18178815
J Exp Med. 2005 Apr 4;201(7):1061-7
15809351
Nat Immunol. 2009 Jul;10(7):689-95
19536194
J Immunol. 2009 Jun 1;182(11):6744-52
19454669
Blood. 2008 Sep 1;112(5):1813-21
18550850
Proc Natl Acad Sci U S A. 2009 Nov 10;106(45):19078-83
19884493
Immunity. 2005 May;22(5):621-31
15894279
Biol Direct. 2008 Feb 27;3:6
18304352
J Immunol. 2008 Jun 1;180(11):7240-8
18490723
Eur J Immunol. 2001 Apr;31(4):1122-31
11298337
J Exp Med. 2006 Jul 10;203(7):1693-700
16818676
J Immunol. 2009 Jun 1;182(11):6648-52
19454658
Eur J Immunol. 2010 Jan;40(1):71-80
19877010
Nat Immunol. 2003 Apr;4(4):330-6
12612578
Blood. 2008 Oct 15;112(8):3283-92
18664628
J Immunol. 2008 Aug 15;181(4):2855-68
18684977
Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18169-74
17978190
Immunol Rev. 2009 May;229(1):41-66
19426214
J Immunol. 2004 Feb 1;172(3):1341-5
14734708
Ann N Y Acad Sci. 2005 Jun;1051:506-14
16126991
Arthritis Res Ther. 2004;6(3):R239-49
15142270
Arthritis Rheum. 2007 Sep;56(9):2947-56
17763426
J Immunol. 2006 Dec 1;177(11):8140-7
17114489
Arthritis Rheum. 2006 Jun;54(6):1759-71
16736518
J Autoimmun. 2010 Jun;34(4):390-9
19880290
Nat Immunol. 2004 Feb;5(2):150-8
14730361
Nat Immunol. 2007 Dec;8(12):1353-62
17982458
PLoS Biol. 2008 Nov 11;6(11):e276
18998771
Nat Methods. 2006 Mar;3(3):162-4
16489331
Nat Protoc. 2006;1(1):406-17
17406263
Br J Cancer. 2005 Mar 14;92(5):913-20
15714205
Nat Immunol. 2009 Nov;10(11):1178-84
19783988
Arthritis Rheum. 2005 Jul;52(7):2212-21
15986351
Nature. 2007 Nov 22;450(7169):566-9
18033300
J Clin Invest. 2005 Oct;115(10):2904-13
16167085
J Exp Med. 2009 Feb 16;206(2):421-34
19188497
Immunity. 2001 Sep;15(3):445-55
11567634
Arthritis Res Ther. 2005;7(2):R291-301
15743476
Eur J Immunol. 2006 Oct;36(10):2601-12
17013990
J Immunol. 2009 Jan 1;182(1):102-10
19109140
Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19396-401
19036923