Dendritic cells are specialized accessory cells along with TGF- for the differentiation of Foxp3+ CD4+ regulatory T cells from peripheral Foxp3 precursors.
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.
Yamazaki
Sayuri
S
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
Bonito
Anthony J
AJ
Spisek
Radek
R
Dhodapkar
Madhav
M
Inaba
Kayo
K
Steinman
Ralph M
RM
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*
D000941:Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015291:Transforming Growth Factors
J Immunol. 2004 Jun 1;172(11):6598-606
15153474
J Exp Med. 2001 Jan 15;193(2):233-8
11208863
Nat Rev Immunol. 2002 Jun;2(6):389-400
12093005
Nat Immunol. 2003 Apr;4(4):330-6
12612578
J Exp Med. 2005 Mar 7;201(5):723-35
15753206
Nature. 2006 May 11;441(7090):231-4
16648837
J Immunol. 2017 Feb 1;198(3):981-985
28115586
Nature. 1997 Oct 16;389(6652):737-42
9338786
J Immunol. 2001 Aug 1;167(3):1188-97
11466333
J Exp Med. 2003 Dec 15;198(12):1875-86
14676299
Nat Immunol. 2002 Jul;3(7):673-80
12055625
Immunity. 2006 Aug;25(2):195-201
16920638
Nature. 2006 May 11;441(7090):235-8
16648838
Immunity. 2006 Feb;24(2):179-89
16473830
Nat Rev Immunol. 2005 Apr;5(4):343-9
15775994
Int Immunol. 2004 Aug;16(8):1203-13
15237111
Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):351-8
11773639
J Immunol. 2004 May 1;172(9):5149-53
15100250
Nat Immunol. 2005 Dec;6(12):1219-27
16244650
Nat Immunol. 2003 Apr;4(4):337-42
12612581
Trends Immunol. 2004 Oct;25(10):513-7
15364052
J Exp Med. 2006 Jul 10;203(7):1693-700
16818676
J Immunol. 2002 Jan 15;168(2):537-40
11777943
Immunity. 2006 Jun;24(6):677-688
16782025
J Immunol. 2007 Feb 15;178(4):2018-27
17277105
J Immunol. 2005 Dec 1;175(11):7332-40
16301639
J Exp Med. 2004 Jun 7;199(11):1467-77
15184500
J Exp Med. 2003 Jul 21;198(2):267-79
12874260
J Exp Med. 2007 Aug 6;204(8):1775-85
17620362
Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2758-63
16473944
J Exp Med. 2005 Oct 17;202(8):1051-61
16216886
Science. 1990 Dec 21;250(4988):1720-3
2125367
J Exp Med. 2004 Feb 2;199(3):303-13
14757740
J Exp Med. 2005 Oct 3;202(7):919-29
16186184
Immunity. 1998 Mar;8(3):275-83
9529145
Nature. 1996 Oct 31;383(6603):787-93
8893001
J Exp Med. 2003 Jul 21;198(2):235-47
12874257
Immunol Rev. 2004 Dec;202:157-74
15546392
J Exp Med. 1999 Feb 1;189(3):587-92
9927520
Nat Rev Immunol. 2002 Feb;2(2):116-26
11910893
Eur J Immunol. 2004 Jul;34(7):1861-9
15214034
J Exp Med. 2000 Jul 17;192(2):295-302
10899916
J Immunol. 2006 Apr 15;176(8):4730-9
16585566
Immunity. 2000 Apr;12(4):431-40
10795741
Proc Natl Acad Sci U S A. 1999 Feb 2;96(3):1036-41
9927689
Blood. 2001 Sep 1;98(5):1512-23
11520802
J Exp Med. 2007 Aug 6;204(8):1765-74
17620363
Immunity. 2004 Oct;21(4):467-76
15485625
J Immunol. 2005 May 1;174(9):5444-55
15845457
J Immunol. 2007 Apr 1;178(7):4022-6
17371955
Nat Immunol. 2005 Mar;6(3):280-6
15685176
Immunogenetics. 1998 Aug;48(3):184-95
9683663
Nat Immunol. 2002 Feb;3(2):135-42
11812990
J Immunol. 2006 Mar 15;176(6):3321-9
16517699
Science. 2007 Jul 13;317(5835):256-60
17569825
J Exp Med. 2005 Mar 7;201(5):769-77
15753210
Immunol Rev. 2006 Aug;212:86-98
16903908
Nat Immunol. 2001 Sep;2(9):882-8
11526406
Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5126-31
15795373
J Exp Med. 2006 Jul 10;203(7):1701-11
16818678
J Exp Med. 2007 Aug 6;204(8):1757-64
17620361
J Exp Med. 2002 Sep 16;196(6):851-7
12235217
Blood. 2006 Oct 15;108(8):2655-61
16763205
Nat Immunol. 2005 Nov;6(11):1142-51
16227984
Int Immunol. 2000 Aug;12(8):1145-55
10917889
J Exp Med. 2001 Sep 17;194(6):769-79
11560993
Nat Rev Immunol. 2004 Aug;4(8):583-94
15286725
Immunity. 2005 Mar;22(3):329-41
15780990
J Exp Med. 2000 Jul 17;192(2):303-10
10899917
Annu Rev Immunol. 2004;22:531-62
15032588
J Exp Med. 2007 Jan 22;204(1):191-201
17210729
Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13031-6
12242333
J Exp Med. 1992 Oct 1;176(4):1091-8
1328464
Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2821-6
17307871
J Exp Med. 2005 Jan 3;201(1):127-37
15630140
J Immunol. 2002 Sep 1;169(5):2461-5
12193715
Nat Immunol. 2007 Feb;8(2):172-80
17206145
Blood. 2005 Feb 1;105(3):1162-9
15479730
Immunity. 2002 Feb;16(2):311-23
11869690
Int Immunol. 2004 Dec;16(12):1769-80
15520045