title: Dendritic cells are specialized accessory cells along with TGF- for the differentiation of Foxp3+ CD4+ regulatory T cells from peripheral Foxp3 precursors.
abstract: Foxp3(+)CD25(+)CD4(+) regulatory T cells are produced in the thymus (natural T regs) but can also differentiate from peripheral Foxp3(-)CD4(+) precursors (induced or adaptive T regs). We assessed antigen presenting cell (APC) requirements for the latter differentiation. With added transforming growth factor (TGF)-beta, both immature and mature populations of dendritic cells (DCs) induced antigen-specific Foxp3(+) T regs from Foxp3(-) precursors. Using endogenous TGF-beta, DCs from gut-associated mesenteric lymph nodes were capable of differentiating Foxp3(+)T regs. Spleen DCs were 100-fold more potent than DC-depleted APCs for the induction of T regs and required 10-fold lower doses of peptide antigen. Interleukin-2 (IL-2) was essential, but could be provided endogenously by T cells stimulated by DCs, but not other APCs. The required IL-2 was induced by DCs that expressed CD80/CD86 costimulatory molecules. The DC-induced Foxp3(+)T regs divided up to 6 times in 6 days and were comprised of CD62L and CD103 positive and negative forms. The induced Foxp3(+)T regs exerted suppression in vitro and blocked tumor immunity in vivo. These results indicate that DCs are specialized to differentiate functional peripheral Foxp3(+)T regs and help set the stage to use DCs to actively suppress the immune response in an antigen-specific manner.
authors: Laboratory of Cellular Physiology and Immunology and Chris Browne Center of Immunology and Immune Disease, Rockefeller University, New York, NY 10021-6399, USA. yamazas@rockefeller.edu
authors: Sayuri
authors: S
authors: Yamazaki
authors: Anthony J
authors: AJ
authors: Bonito
authors: Radek
authors: R
authors: Spisek
authors: Madhav
authors: M
authors: Dhodapkar
authors: Kayo
authors: K
authors: Inaba
authors: Ralph M
authors: RM
authors: Steinman
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D003713:Dendritic Cells / Q000502:physiology*; D005260:Female; D051858:Forkhead Transcription Factors; D006412:Hematopoietic Stem Cells / Q000166:cytology; D007109:Immunity; D051379:Mice; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D015291:Transforming Growth Factors / Q000494:pharmacology / Q000502:physiology*
chemical_list: D000941:Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015291:Transforming Growth Factors
references: J Immunol. 2004 Jun 1;172(11):6598-606
references: 15153474
references: J Exp Med. 2001 Jan 15;193(2):233-8
references: 11208863
references: Nat Rev Immunol. 2002 Jun;2(6):389-400
references: 12093005
references: Nat Immunol. 2003 Apr;4(4):330-6
references: 12612578
references: J Exp Med. 2005 Mar 7;201(5):723-35
references: 15753206
references: Nature. 2006 May 11;441(7090):231-4
references: 16648837
references: J Immunol. 2017 Feb 1;198(3):981-985
references: 28115586
references: Nature. 1997 Oct 16;389(6652):737-42
references: 9338786
references: J Immunol. 2001 Aug 1;167(3):1188-97
references: 11466333
references: J Exp Med. 2003 Dec 15;198(12):1875-86
references: 14676299
references: Nat Immunol. 2002 Jul;3(7):673-80
references: 12055625
references: Immunity. 2006 Aug;25(2):195-201
references: 16920638
references: Nature. 2006 May 11;441(7090):235-8
references: 16648838
references: Immunity. 2006 Feb;24(2):179-89
references: 16473830
references: Nat Rev Immunol. 2005 Apr;5(4):343-9
references: 15775994
references: Int Immunol. 2004 Aug;16(8):1203-13
references: 15237111
references: Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):351-8
references: 11773639
references: J Immunol. 2004 May 1;172(9):5149-53
references: 15100250
references: Nat Immunol. 2005 Dec;6(12):1219-27
references: 16244650
references: Nat Immunol. 2003 Apr;4(4):337-42
references: 12612581
references: Trends Immunol. 2004 Oct;25(10):513-7
references: 15364052
references: J Exp Med. 2006 Jul 10;203(7):1693-700
references: 16818676
references: J Immunol. 2002 Jan 15;168(2):537-40
references: 11777943
references: Immunity. 2006 Jun;24(6):677-688
references: 16782025
references: J Immunol. 2007 Feb 15;178(4):2018-27
references: 17277105
references: J Immunol. 2005 Dec 1;175(11):7332-40
references: 16301639
references: J Exp Med. 2004 Jun 7;199(11):1467-77
references: 15184500
references: J Exp Med. 2003 Jul 21;198(2):267-79
references: 12874260
references: J Exp Med. 2007 Aug 6;204(8):1775-85
references: 17620362
references: Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2758-63
references: 16473944
references: J Exp Med. 2005 Oct 17;202(8):1051-61
references: 16216886
references: Science. 1990 Dec 21;250(4988):1720-3
references: 2125367
references: J Exp Med. 2004 Feb 2;199(3):303-13
references: 14757740
references: J Exp Med. 2005 Oct 3;202(7):919-29
references: 16186184
references: Immunity. 1998 Mar;8(3):275-83
references: 9529145
references: Nature. 1996 Oct 31;383(6603):787-93
references: 8893001
references: J Exp Med. 2003 Jul 21;198(2):235-47
references: 12874257
references: Immunol Rev. 2004 Dec;202:157-74
references: 15546392
references: J Exp Med. 1999 Feb 1;189(3):587-92
references: 9927520
references: Nat Rev Immunol. 2002 Feb;2(2):116-26
references: 11910893
references: Eur J Immunol. 2004 Jul;34(7):1861-9
references: 15214034
references: J Exp Med. 2000 Jul 17;192(2):295-302
references: 10899916
references: J Immunol. 2006 Apr 15;176(8):4730-9
references: 16585566
references: Immunity. 2000 Apr;12(4):431-40
references: 10795741
references: Proc Natl Acad Sci U S A. 1999 Feb 2;96(3):1036-41
references: 9927689
references: Blood. 2001 Sep 1;98(5):1512-23
references: 11520802
references: J Exp Med. 2007 Aug 6;204(8):1765-74
references: 17620363
references: Immunity. 2004 Oct;21(4):467-76
references: 15485625
references: J Immunol. 2005 May 1;174(9):5444-55
references: 15845457
references: J Immunol. 2007 Apr 1;178(7):4022-6
references: 17371955
references: Nat Immunol. 2005 Mar;6(3):280-6
references: 15685176
references: Immunogenetics. 1998 Aug;48(3):184-95
references: 9683663
references: Nat Immunol. 2002 Feb;3(2):135-42
references: 11812990
references: J Immunol. 2006 Mar 15;176(6):3321-9
references: 16517699
references: Science. 2007 Jul 13;317(5835):256-60
references: 17569825
references: J Exp Med. 2005 Mar 7;201(5):769-77
references: 15753210
references: Immunol Rev. 2006 Aug;212:86-98
references: 16903908
references: Nat Immunol. 2001 Sep;2(9):882-8
references: 11526406
references: Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5126-31
references: 15795373
references: J Exp Med. 2006 Jul 10;203(7):1701-11
references: 16818678
references: J Exp Med. 2007 Aug 6;204(8):1757-64
references: 17620361
references: J Exp Med. 2002 Sep 16;196(6):851-7
references: 12235217
references: Blood. 2006 Oct 15;108(8):2655-61
references: 16763205
references: Nat Immunol. 2005 Nov;6(11):1142-51
references: 16227984
references: Int Immunol. 2000 Aug;12(8):1145-55
references: 10917889
references: J Exp Med. 2001 Sep 17;194(6):769-79
references: 11560993
references: Nat Rev Immunol. 2004 Aug;4(8):583-94
references: 15286725
references: Immunity. 2005 Mar;22(3):329-41
references: 15780990
references: J Exp Med. 2000 Jul 17;192(2):303-10
references: 10899917
references: Annu Rev Immunol. 2004;22:531-62
references: 15032588
references: J Exp Med. 2007 Jan 22;204(1):191-201
references: 17210729
references: Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13031-6
references: 12242333
references: J Exp Med. 1992 Oct 1;176(4):1091-8
references: 1328464
references: Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2821-6
references: 17307871
references: J Exp Med. 2005 Jan 3;201(1):127-37
references: 15630140
references: J Immunol. 2002 Sep 1;169(5):2461-5
references: 12193715
references: Nat Immunol. 2007 Feb;8(2):172-80
references: 17206145
references: Blood. 2005 Feb 1;105(3):1162-9
references: 15479730
references: Immunity. 2002 Feb;16(2):311-23
references: 11869690
references: Int Immunol. 2004 Dec;16(12):1769-80
references: 15520045