Rapid and Efficient Generation of Regulatory T Cells to Commensal Antigens in the Periphery.
Commensal bacteria shape the colonic regulatory T (Treg) cell population required for intestinal tolerance. However, little is known about this process. Here, we use the transfer of naive commensal-reactive transgenic T cells expressing colonic Treg T cell receptors (TCRs) to study peripheral Treg (pTreg) cell development in normal hosts. We found that T cells were activated primarily in the distal mesenteric lymph node. Treg cell induction was rapid, generating >40% Foxp3(+) cells 1 week after transfer. Contrary to prior reports, Foxp3(+) cells underwent the most cell divisions, demonstrating that pTreg cell generation can be the dominant outcome from naive T cell activation. Moreover, Notch2-dependent, but not Batf3-dependent, dendritic cells were involved in Treg cell selection. Finally, neither deletion of the conserved nucleotide sequence 1 (CNS1) region in Foxp3 nor blockade of TGF-β (transforming growth factor-β)-receptor signaling completely abrogated Foxp3 induction. Thus, these data show that pTreg cell selection to commensal bacteria is rapid, is robust, and may be specified by TGF-β-independent signals.
Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Katherine
K
Nutsch
Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Jiani N
JN
Chai
Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Teresa L
TL
Ai
Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Emilie
E
Russler-Germain
Committee on Immunology, Department of Pathology, The University of Chicago, JFK R120, 924 E. 57th Street, Chicago, IL 60637, USA.
Taylor
T
Feehley
Committee on Immunology, Department of Pathology, The University of Chicago, JFK R120, 924 E. 57th Street, Chicago, IL 60637, USA.
Cathryn R
CR
Nagler
Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: chsieh@wustl.edu.
Chyi-Song
CS
Hsieh
D019264:Adoptive Transfer; D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology; D003106:Colon / Q000276:immunology / Q000382:microbiology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000382:microbiology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D000069196:Gastrointestinal Microbiome / Q000276:immunology*; D015870:Gene Expression; D007108:Immune Tolerance; D016130:Immunophenotyping; D008198:Lymph Nodes / Q000276:immunology; D008643:Mesentery / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D051883:Receptor, Notch2 / Q000235:genetics / Q000276:immunology; D013559:Symbiosis / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology* / Q000382:microbiology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000382:microbiology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology
D000942:Antigens, Bacterial; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C497765:Notch2 protein, mouse; D051883:Receptor, Notch2; D016212:Transforming Growth Factor beta
CNS1 Foxp3; Notch2-dependent dendritic cells; TGFβ; commensal microbiota; pTreg; peripheral regulatory T cells
Nature. 2013 Dec 19;504(7480):446-50
24226770
Nat Immunol. 2013 Sep;14 (9):937-48
23913046
J Exp Med. 2011 Jun 6;208(6):1279-89
21606508
Cell Host Microbe. 2015 May 13;17(5):672-80
25974305
Autoimmun Rev. 2013 Apr;12(6):661-5
23201924
PLoS One. 2011;6(8):e24226
21918685
J Exp Med. 2012 Jun 4;209(6):1153-65
22615130
J Immunol. 2013 Jun 15;190(12):6340-50
23686479
J Exp Med. 2003 Dec 15;198(12):1875-86
14676299
J Exp Med. 2007 Aug 6;204(8):1775-85
17620362
Nat Immunol. 2007 Apr;8(4):359-68
17273171
J Exp Med. 2012 Sep 24;209(10):1713-22, S1-19
22966003
Nat Immunol. 2005 Dec;6(12):1219-27
16244650
Nature. 2013 Dec 19;504(7480):451-5
24226773
J Exp Med. 2006 Mar 20;203(3):519-27
16533884
J Exp Med. 2010 Aug 2;207(8):1701-11
20660617
Nat Immunol. 2009 Jun;10(6):610-7
19430476
J Immunol. 2015 Apr 15;194(8):3784-97
25780041
Nature. 2010 Feb 11;463(7282):808-12
20072126
Immunity. 2011 May 27;34(5):794-806
21596591
Nature. 2012 Nov 1;491(7422):119-24
23128233
Immunity. 2013 May 23;38(5):958-69
23664832
Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5919-24
20231436
J Exp Med. 2005 Apr 4;201(7):1061-7
15809351
Immunity. 2000 Feb;12(2):171-81
10714683
Cell. 2009 Oct 30;139(3):485-98
19836068
Science. 2008 Nov 14;322(5904):1097-100
19008445
Science. 2011 Jan 21;331(6015):337-41
21205640
Immunity. 2008 Nov 14;29(5):758-70
19006694
Nat Rev Immunol. 2014 Oct;14(10):667-85
25234148
J Exp Med. 2009 Sep 28;206(10):2121-30
19737865
Cell. 2014 Mar 27;157(1):121-41
24679531
ISME J. 2013 Jun;7(6):1112-5
23535917
Science. 2013 Aug 2;341(6145):569-73
23828891
J Exp Med. 2012 Aug 27;209(9):1529-35
22908322
J Immunol. 2012 Feb 1;188(3):976-80
22198953
Immunity. 2011 Feb 25;34(2):237-46
21333554
Nature. 2013 May 9;497(7448):258-62
23624374
J Exp Med. 2007 Aug 6;204(8):1757-64
17620361
J Exp Med. 2013 Sep 23;210(10):2011-24
24019552
Immunity. 2011 Nov 23;35(5):780-91
22018469
Proc Natl Acad Sci U S A. 2014 Sep 9;111(36):13145-50
25157157
Science. 2012 Sep 21;337(6101):1553-6
22923434
Mucosal Immunol. 2015 Jan;8(1):198-210
25005358
Cell Host Microbe. 2007 Nov 15;2(5):328-39
18005754
Nature. 2011 Jun 15;474(7351):298-306
21677746
Immunity. 2011 Jul 22;35(1):109-22
21723159
Nat Immunol. 2007 Sep;8(9):931-41
17694059
J Exp Med. 2012 Sep 24;209(10):1723-42, S1
22966001
Nature. 2012 Feb 08;482(7385):395-9
22318520
Trends Mol Med. 2011 Nov;17(11):668-76
21890412
Cell. 2004 Jul 23;118(2):229-41
15260992
Gut Microbes. 2012 Jul-Aug;3(4):332-44
22572873
Annu Rev Microbiol. 2014;68:217-35
24995874
Nature. 2011 Sep 21;478(7368):250-4
21937990