title: Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27-CD70 pathway.
abstract: CD4(+)Foxp3(+) regulatory T cells (Treg cells) are largely autoreactive yet escape clonal deletion in the thymus. We demonstrate here that CD27-CD70 co-stimulation in the thymus rescues developing Treg cells from apoptosis and thereby promotes Treg cell generation. Genetic ablation of CD27 or its ligand CD70 reduced Treg cell numbers in the thymus and peripheral lymphoid organs, whereas it did not alter conventional CD4(+)Foxp3(-) T cell numbers. The CD27-CD70 pathway was not required for pre-Treg cell generation, Foxp3 induction, or mature Treg cell function. Rather, CD27 signaling enhanced positive selection of Treg cells within the thymus in a cell-intrinsic manner. CD27 signals promoted the survival of thymic Treg cells by inhibiting the mitochondrial apoptosis pathway. CD70 was expressed on Aire(-) and Aire(+) medullary thymic epithelial cells (mTECs) and on dendritic cells (DCs) in the thymic medulla. CD70 on both mTECs and DCs contributed to Treg cell development as shown in BM chimera experiments with CD70-deficient mice. In vitro experiments indicated that CD70 on the CD8α(+) subset of thymic DCs promoted Treg cell development. Our data suggest that mTECs and DCs form dedicated niches in the thymic medulla, in which CD27-CD70 co-stimulation rescues developing Treg cells from apoptosis, subsequent to Foxp3 induction by TCR and CD28 signals.
authors.affiliation: Division of Immunology and 2 Division of Biological Stress Responses, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Coquet
authors.forename: Julie C
authors.initials: JC
authors.lastname: Ribot
authors.forename: Nikolina
authors.initials: N
authors.lastname: Bąbała
authors.forename: Sabine
authors.initials: S
authors.lastname: Middendorp
authors.forename: Gerda
authors.initials: G
authors.lastname: van der Horst
authors.forename: Yanling
authors.initials: Y
authors.lastname: Xiao
authors.forename: Joana F
authors.initials: JF
authors.lastname: Neves
authors.forename: Diogo
authors.initials: D
authors.lastname: Fonseca-Pereira
authors.forename: Heinz
authors.initials: H
authors.lastname: Jacobs
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Pennington
authors.forename: Bruno
authors.initials: B
authors.lastname: Silva-Santos
authors.forename: Jannie
authors.initials: J
authors.lastname: Borst
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D053282:CD27 Ligand / Q000235:genetics / Q000276:immunology*; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D054504:Precursor Cells, T-Lymphoid / Q000166:cytology / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology; D018183:Transplantation Chimera / Q000235:genetics / Q000276:immunology; D014184:Transplantation, Homologous; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000235:genetics / Q000276:immunology*; D000096927:AIRE Protein
chemical_list: D053282:CD27 Ligand; D016827:CD8 Antigens; D051858:Forkhead Transcription Factors; D014157:Transcription Factors; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D000096927:AIRE Protein; C409469:CD8 antigen, alpha chain; C498833:Foxp3 protein, mouse
references.citation: Immunity. 2009 Nov 20;31(5):823-33
references.pmid: 19913446
references.citation: Eur J Immunol. 1984 Jun;14(6):524-9
references.pmid: 6734714
references.citation: Cell. 2008 May 30;133(5):775-87
references.pmid: 18510923
references.citation: Cell. 1988 May 6;53(3):357-70
references.pmid: 3259162
references.citation: J Exp Med. 2009 Mar 16;206(3):607-22
references.pmid: 19273629
references.citation: Nature. 1995 May 11;375(6527):151-5
references.pmid: 7753172
references.citation: J Immunol. 1995 Aug 1;155(3):1151-64
references.pmid: 7636184
references.citation: J Immunol. 1990 Sep 1;145(5):1356-63
references.pmid: 1974563
references.citation: J Immunol. 2010 Dec 1;185(11):6670-8
references.pmid: 21048108
references.citation: J Exp Med. 2004 Oct 18;200(8):1039-49
references.pmid: 15492126
references.citation: J Immunol. 2005 Aug 1;175(3):1665-76
references.pmid: 16034107
references.citation: Adv Immunol. 2004;84:201-38
references.pmid: 15246254
references.citation: Nat Immunol. 2003 Apr;4(4):337-42
references.pmid: 12612581
references.citation: Science. 2003 Feb 14;299(5609):1057-61
references.pmid: 12522256
references.citation: Nat Genet. 2001 Jan;27(1):20-1
references.pmid: 11137993
references.citation: J Exp Med. 2005 Oct 3;202(7):901-6
references.pmid: 16203863
references.citation: J Exp Med. 2007 Oct 29;204(11):2521-8
references.pmid: 17908938
references.citation: Immunity. 2008 Jan;28(1):112-21
references.pmid: 18199418
references.citation: J Exp Med. 2011 Feb 14;208(2):383-94
references.pmid: 21300913
references.citation: Nat Immunol. 2002 Aug;3(8):756-63
references.pmid: 12089509
references.citation: J Immunol. 2007 Feb 1;178(3):1564-72
references.pmid: 17237405
references.citation: Nat Immunol. 2006 Apr;7(4):401-10
references.pmid: 16532000
references.citation: Nature. 2005 Aug 25;436(7054):1181-5
references.pmid: 16121185
references.citation: Immunol Rev. 2009 May;229(1):216-31
references.pmid: 19426224
references.citation: J Exp Med. 2004 Nov 15;200(10):1221-30
references.pmid: 15534371
references.citation: J Clin Invest. 2010 Jan;120(1):168-78
references.pmid: 19955658
references.citation: Immunity. 2013 Jan 24;38(1):53-65
references.pmid: 23159439
references.citation: Nat Immunol. 2007 Apr;8(4):351-8
references.pmid: 17322887
references.citation: J Immunol. 2007 Mar 15;178(6):3474-82
references.pmid: 17339442
references.citation: J Immunol. 2006 Jul 15;177(2):1101-7
references.pmid: 16818767
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11903-8
references.pmid: 18695219
references.citation: J Immunol. 2010 Oct 1;185(7):3819-23
references.pmid: 20802149
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5989-94
references.pmid: 17389361
references.citation: Adv Immunol. 1997;65:139-243
references.pmid: 9238510
references.citation: Nat Immunol. 2003 Apr;4(4):330-6
references.pmid: 12612578
references.citation: J Exp Med. 2007 May 14;204(5):1095-106
references.pmid: 17438065
references.citation: Nat Immunol. 2009 Jun;10(6):610-7
references.pmid: 19430476
references.citation: J Immunol. 2007 Jan 15;178(2):829-37
references.pmid: 17202344
references.citation: J Immunol. 2001 Jan 1;166(1):353-60
references.pmid: 11123312
references.citation: Immunity. 2008 Jan;28(1):100-11
references.pmid: 18199417
references.citation: J Immunol. 2007 Jan 1;178(1):280-90
references.pmid: 17182565
references.citation: Nat Immunol. 2005 Feb;6(2):152-62
references.pmid: 15640801
references.citation: Nat Rev Immunol. 2010 Sep;10(9):657-63
references.pmid: 20725107
references.citation: Nat Genet. 2001 Jan;27(1):68-73
references.pmid: 11138001
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19869-74
references.pmid: 19073916
references.citation: Nat Immunol. 2001 Apr;2(4):301-6
references.pmid: 11276200
references.citation: Nat Genet. 2001 Jan;27(1):18-20
references.pmid: 11137992
references.citation: J Immunol. 2001 Mar 1;166(5):3468-75
references.pmid: 11207305
references.citation: Curr Opin Immunol. 2007 Apr;19(2):176-85
references.pmid: 17306520
references.citation: Int Immunol. 1998 Apr;10(4):517-26
references.pmid: 9620608
references.citation: J Immunol. 2002 Feb 15;168(4):1644-8
references.pmid: 11823492
references.citation: Int Immunol. 1994 Mar;6(3):477-80
references.pmid: 8186199
references.citation: Immunity. 2002 Aug;17(2):117-30
references.pmid: 12196284
references.citation: J Exp Med. 1996 Aug 1;184(2):675-85
references.pmid: 8760821
references.citation: Nat Rev Immunol. 2003 Dec;3(12):939-51
references.pmid: 14647476
references.citation: J Exp Med. 2003 Nov 3;198(9):1369-80
references.pmid: 14581610
references.citation: J Immunol. 2003 Jan 1;170(1):33-40
references.pmid: 12496380
references.citation: Science. 2011 Jan 21;331(6015):337-41
references.pmid: 21205640
references.citation: Immunity. 2009 May;30(5):636-45
references.pmid: 19464986
references.citation: Nucleic Acids Res. 2003 Dec 1;31(23):e153
references.pmid: 14627843
references.citation: Immunity. 2010 May 28;32(5):642-53
references.pmid: 20471291
references.citation: J Exp Med. 2005 Jul 4;202(1):33-45
references.pmid: 15983066
references.citation: Immunity. 2006 Aug;25(2):249-59
references.pmid: 16879995
references.citation: Trends Immunol. 2006 May;27(5):215-21
references.pmid: 16580260
references.citation: Proc Natl Acad Sci U S A. 2008 Jan 22;105(3):973-8
references.pmid: 18198277
references.citation: Nat Immunol. 2009 Apr;10(4):427-36
references.pmid: 19270712
references.citation: J Immunol. 2002 May 1;168(9):4399-405
references.pmid: 11970982
references.citation: Science. 2002 Nov 15;298(5597):1395-401
references.pmid: 12376594
references.citation: Nat Immunol. 2005 Nov;6(11):1142-51
references.pmid: 16227984
references.citation: J Immunol. 2010 Jun 1;184(11):6007-13
references.pmid: 20421644
references.citation: J Immunol. 2010 Apr 15;184(8):4074-7
references.pmid: 20228198
references.citation: Immunol Cell Biol. 2010 Jul;88(5):523-8
references.pmid: 20142839
references.citation: Nat Immunol. 2000 Nov;1(5):433-40
references.pmid: 11062504
references.citation: Cancer Res. 2012 Jul 15;72(14):3664-76
references.pmid: 22628427
references.citation: J Exp Med. 2008 Nov 24;205(12):2827-38
references.pmid: 19015306
references.citation: J Immunol. 2008 Jul 15;181(2):1071-82
references.pmid: 18606659