title: Thymic stromal cell subsets for T cell development.
abstract: The thymus provides a specialized microenvironment in which a variety of stromal cells of both hematopoietic and non-hematopoietic origin regulate development and repertoire selection of T cells. Recent studies have been unraveling the inter- and intracellular signals and transcriptional networks for spatiotemporal regulation of development of thymic stromal cells, mainly thymic epithelial cells (TECs), and the molecular mechanisms of how different TEC subsets control T cell development and selection. TECs are classified into two functionally different subsets: cortical TECs (cTECs) and medullary TECs (mTECs). cTECs induce positive selection of diverse and functionally distinct T cells by virtue of unique antigen-processing systems, while mTECs are essential for establishing T cell tolerance via ectopic expression of peripheral tissue-restricted antigens and cooperation with dendritic cells. In addition to reviewing the role of the thymic stroma in conventional T cell development, we will discuss recently discovered novel functions of TECs in the development of unconventional T cells, such as natural killer T cells and γδT cells.
authors.affiliation: Department of Immunology and Pathology, Research Institute, National Center for Global Health and Medicine, Chiba, 272-8516, Japan. nit-im@m.u-tokyo.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nitta
authors.affiliation: Department of Immunology and Pathology, Research Institute, National Center for Global Health and Medicine, Chiba, 272-8516, Japan. hsuzuki@ri.ncgm.go.jp.
authors.forename: Harumi
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D006801:Humans; D017154:Stromal Cells / Q000166:cytology*; D013601:T-Lymphocytes / Q000166:cytology*; D013950:Thymus Gland / Q000033:anatomy & histology / Q000166:cytology*
keywords: Repertoire selection; T cell; Thymic epithelial cell; Thymus; cTEC; mTEC
references.citation: PLoS One. 2012;7(12):e52591
references.pmid: 23300712
references.citation: Nature. 2006 Jun 22;441(7096):992-6
references.pmid: 16791198
references.citation: J Immunol. 2013 Apr 1;190(7):3289-98
references.pmid: 23440417
references.citation: Eur J Immunol. 1991 Jul;21(7):1657-61
references.pmid: 2060577
references.citation: Proc Natl Acad Sci U S A. 2014 Jan 28;111(4):1491-6
references.pmid: 24434558
references.citation: Blood. 2006 Dec 1;108(12):3777-85
references.pmid: 16896157
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 6;106(40):17129-33
references.pmid: 19805112
references.citation: Nat Immunol. 2001 Oct;2(10):971-8
references.pmid: 11550008
references.citation: Proc Natl Acad Sci U S A. 2008 Oct 14;105(41):15860-5
references.pmid: 18838677
references.citation: Annu Rev Immunol. 2012;30:531-64
references.pmid: 22224781
references.citation: Nat Genet. 1997 Dec;17(4):393-8
references.pmid: 9398839
references.citation: Immunity. 2010 Jan 29;32(1):29-40
references.pmid: 20045355
references.citation: Nat Immunol. 2004 May;5(5):546-53
references.pmid: 15098031
references.citation: J Exp Med. 2007 Jun 11;204(6):1267-72
references.pmid: 17502664
references.citation: Nature. 1995 Aug 3;376(6539):435-8
references.pmid: 7630421
references.citation: J Immunol. 2007 Jun 1;178(11):7173-80
references.pmid: 17513766
references.citation: Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):E3497-505
references.pmid: 23980163
references.citation: J Exp Med. 2004 Oct 18;200(8):1039-49
references.pmid: 15492126
references.citation: Biochem Biophys Res Commun. 1999 Apr 21;257(3):821-5
references.pmid: 10208866
references.citation: J Immunol. 2003 Nov 1;171(9):4521-7
references.pmid: 14568925
references.citation: Proc Natl Acad Sci U S A. 2013 Dec 24;110(52):21107-12
references.pmid: 24324158
references.citation: Adv Immunol. 2004;84:201-38
references.pmid: 15246254
references.citation: Nat Med. 2000 Jan;6(1):56-61
references.pmid: 10613824
references.citation: Immunol Today. 1993 Sep;14(9):445-59
references.pmid: 8216723
references.citation: Microbiol Mol Biol Rev. 2001 Sep;65(3):390-403, table of contents
references.pmid: 11528002
references.citation: J Immunol. 2013 Jun 15;190(12):6173-9
references.pmid: 23686483
references.citation: J Biol Chem. 2004 Apr 9;279(15):15396-401
references.pmid: 14732704
references.citation: Immunobiology. 2013 Apr;218(4):554-60
references.pmid: 22883565
references.citation: J Immunol. 2004 Apr 1;172(7):3999-4007
references.pmid: 15034011
references.citation: Science. 2007 Jun 1;316(5829):1349-53
references.pmid: 17540904
references.citation: J Exp Med. 2009 Jul 6;206(7):1505-13
references.pmid: 19564355
references.citation: J Exp Med. 2005 Oct 3;202(7):901-6
references.pmid: 16203863
references.citation: Blood. 2009 May 21;113(21):5186-91
references.pmid: 19289856
references.citation: Nat Commun. 2014 Jun 09;5:3986
references.pmid: 24909159
references.citation: Nature. 1994 Nov 3;372(6501):103-7
references.pmid: 7969402
references.citation: J Immunol. 2006 Apr 1;176(7):3995-4002
references.pmid: 16547234
references.citation: Nat Immunol. 2010 Jun;11(6):512-9
references.pmid: 20431619
references.citation: Cell Immunol. 1999 Sep 15;196(2):80-6
references.pmid: 10527559
references.citation: J Immunol. 2014 Mar 15;192(6):2585-92
references.pmid: 24516201
references.citation: Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20572-7
references.pmid: 23188800
references.citation: J Exp Med. 2007 Oct 29;204(11):2513-20
references.pmid: 17908937
references.citation: J Immunol. 2007 Mar 1;178(5):3007-15
references.pmid: 17312146
references.citation: J Exp Med. 2007 Oct 29;204(11):2521-8
references.pmid: 17908938
references.citation: Eur J Immunol. 2000 Jul;30(7):1884-93
references.pmid: 10940877
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):11999-2004
references.pmid: 17626181
references.citation: J Immunol. 2007 Apr 15;178(8):5018-27
references.pmid: 17404284
references.citation: J Exp Med. 2004 Aug 16;200(4):493-505
references.pmid: 15302902
references.citation: Cell Mol Life Sci. 2011 May;68(9):1491-502
references.pmid: 21387144
references.citation: Eur J Immunol. 2009 Apr;39(4):956-64
references.pmid: 19283781
references.citation: J Immunol. 2008 Apr 15;180(8):5384-92
references.pmid: 18390720
references.citation: Science. 2010 May 28;328(5982):1129-35
references.pmid: 20413455
references.citation: Nature. 2005 Aug 25;436(7054):1181-5
references.pmid: 16121185
references.citation: Lancet. 1961 Sep 30;2(7205):748-9
references.pmid: 14474038
references.citation: Nat Immunol. 2004 Apr;5(4):426-34
references.pmid: 14991051
references.citation: J Immunol. 2013 May 15;190(10):5110-7
references.pmid: 23585674
references.citation: Nature. 1995 Jan 26;373(6512):350-3
references.pmid: 7830770
references.citation: J Exp Med. 2011 Feb 14;208(2):383-94
references.pmid: 21300913
references.citation: J Exp Med. 2013 Apr 8;210(4):675-81
references.pmid: 23530124
references.citation: J Immunol. 2008 Oct 15;181(8):5225-32
references.pmid: 18832676
references.citation: Nat Immunol. 2014 Jun;15(6):554-61
references.pmid: 24728352
references.citation: Nat Rev Immunol. 2014 Jun;14(6):377-91
references.pmid: 24830344
references.citation: Nat Immunol. 2007 Apr;8(4):351-8
references.pmid: 17322887
references.citation: Eur J Immunol. 2014 Oct;44(10):2918-24
references.pmid: 25070355
references.citation: Immunity. 2008 Sep 19;29(3):423-37
references.pmid: 18799149
references.citation: Nature. 2006 Jun 22;441(7096):988-91
references.pmid: 16791197
references.citation: Int Immunol. 2007 Feb;19(2):127-32
references.pmid: 17158094
references.citation: Nat Rev Immunol. 2007 Dec;7(12):954-63
references.pmid: 17992179
references.citation: Science. 2007 Apr 13;316(5822):295-8
references.pmid: 17363629
references.citation: J Exp Med. 2005 Jul 4;202(1):15-9
references.pmid: 15983067
references.citation: J Immunol. 2014 Jan 15;192(2):630-40
references.pmid: 24337745
references.citation: J Exp Med. 1994 May 1;179(5):1495-506
references.pmid: 8163934
references.citation: Eur J Immunol. 1997 Jun;27(6):1392-7
references.pmid: 9209490
references.citation: Immunity. 2006 Feb;24(2):165-77
references.pmid: 16473829
references.citation: J Immunol. 1996 Sep 15;157(6):2366-73
references.pmid: 8805634
references.citation: PLoS One. 2012;7(7):e41154
references.pmid: 22815949
references.citation: Nat Immunol. 2002 May;3(5):469-76
references.pmid: 11967541
references.citation: Nat Immunol. 2003 Apr;4(4):350-4
references.pmid: 12612579
references.citation: Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4679-84
references.pmid: 23487759
references.citation: Eur J Immunol. 2009 Sep;39(9):2395-402
references.pmid: 19662637
references.citation: Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5742-6
references.pmid: 8650163
references.citation: Science. 2005 Apr 8;308(5719):248-51
references.pmid: 15705807
references.citation: J Immunol. 2006 Jul 1;177(1):290-7
references.pmid: 16785524
references.citation: Nat Immunol. 2002 Nov;3(11):1102-8
references.pmid: 12379851
references.citation: J Immunol. 2014 Mar 15;192(6):2659-66
references.pmid: 24510964
references.citation: Science. 2013 Mar 8;339(6124):1219-24
references.pmid: 23471412
references.citation: Science. 1992 Jun 5;256(5062):1448-52
references.pmid: 1604321
references.citation: Immunity. 2011 Jul 22;35(1):59-68
references.pmid: 21737317
references.citation: J Immunol. 2007 Dec 15;179(12):8069-75
references.pmid: 18056347
references.citation: Nat Rev Immunol. 2010 Jul;10(7):490-500
references.pmid: 20559327
references.citation: Nat Immunol. 2014 Sep;15(9):815-23
references.pmid: 25137456
references.citation: Cancer Res. 2005 Jul 15;65(14):6443-9
references.pmid: 16024649
references.citation: Nat Immunol. 2006 Oct;7(10):1092-100
references.pmid: 16951687
references.citation: Immunity. 2008 Jan;28(1):100-11
references.pmid: 18199417
references.citation: J Immunol. 2014 Apr 1;192(7):3228-38
references.pmid: 24591366
references.citation: J Exp Med. 2011 Jan 17;208(1):3-11
references.pmid: 21173102
references.citation: J Immunol. 2009 Dec 15;183(12):7682-91
references.pmid: 19923453
references.citation: Eur J Immunol. 2013 Mar;43(3):589-94
references.pmid: 23299414
references.citation: Nature. 2008 Sep 18;455(7211):396-400
references.pmid: 18701890
references.citation: Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9885-90
references.pmid: 23720310
references.citation: Nat Rev Immunol. 2002 May;2(5):336-45
references.pmid: 12033739
references.citation: Cell. 2007 May 4;129(3):523-36
references.pmid: 17482546
references.citation: J Immunol. 2002 Oct 15;169(8):4354-61
references.pmid: 12370368
references.citation: J Immunol. 1994 May 15;152(10):4826-31
references.pmid: 8176205
references.citation: J Immunol. 2009 Dec 15;183(12):7909-18
references.pmid: 19933868
references.citation: J Immunol. 2012 Oct 15;189(8):3894-904
references.pmid: 22972926
references.citation: J Clin Invest. 2011 May;121(5):1810-21
references.pmid: 21505262
references.citation: J Immunol. 2015 Sep 15;195(6):2675-82
references.pmid: 26254339
references.citation: Proc Natl Acad Sci U S A. 2011 Feb 22;108(8):3330-5
references.pmid: 21300860
references.citation: Cell. 2012 Mar 30;149(1):159-72
references.pmid: 22464328
references.citation: Immunity. 2012 Mar 23;36(3):438-50
references.pmid: 22444632
references.citation: Nature. 1980 Jan 24;283(5745):402-4
references.pmid: 6965423
references.citation: Immunity. 2007 Sep;27(3):438-52
references.pmid: 17869136
references.citation: J Exp Med. 2008 Oct 27;205(11):2515-23
references.pmid: 18824585
references.citation: Immunity. 2001 Aug;15(2):261-73
references.pmid: 11520461
references.citation: Eur J Immunol. 2004 Dec;34(12):3652-63
references.pmid: 15484191
references.citation: Eur J Immunol. 2008 Apr;38(4):942-7
references.pmid: 18350550
references.citation: J Exp Med. 2003 Sep 1;198(5):757-69
references.pmid: 12953095
references.citation: J Immunol. 2010 Oct 15;185(8):4769-76
references.pmid: 20861360
references.citation: Immunity. 2014 Sep 18;41(3):414-426
references.pmid: 25220213
references.citation: Cancer Res. 2007 Apr 15;67(8):3919-26
references.pmid: 17440107
references.citation: Curr Opin Immunol. 2008 Apr;20(2):178-84
references.pmid: 18403191
references.citation: Nat Rev Immunol. 2011 Jun 24;11(7):469-77
references.pmid: 21701522
references.citation: Eur J Immunol. 2011 May;41(5):1278-87
references.pmid: 21469133
references.citation: Curr Opin Immunol. 2005 Apr;17(2):137-43
references.pmid: 15766672
references.citation: Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3463-8
references.pmid: 22331880
references.citation: Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):535-40
references.pmid: 22203960
references.citation: Science. 1996 May 10;272(5263):886-9
references.pmid: 8629026
references.citation: Semin Immunol. 2005 Aug;17(4):304-12
references.pmid: 15946853
references.citation: J Immunol. 2009 Jan 1;182(1):130-7
references.pmid: 19109143
references.citation: Nat Rev Immunol. 2006 Feb;6(2):127-35
references.pmid: 16491137
references.citation: EMBO Rep. 2015 May;16(5):638-53
references.pmid: 25770130
references.citation: J Exp Med. 2014 Nov 17;211(12):2425-38
references.pmid: 25385757
references.citation: Nat Immunol. 2015 Oct;16(10):1069-76
references.pmid: 26301566
references.citation: J Immunol. 2000 Aug 15;165(4):1976-83
references.pmid: 10925280
references.citation: J Immunol. 2003 May 1;170(9):4649-55
references.pmid: 12707343
references.citation: J Immunol. 2007 Apr 15;178(8):4956-65
references.pmid: 17404277
references.citation: J Immunol. 2006 Jul 15;177(2):804-13
references.pmid: 16818734
references.citation: J Exp Med. 1992 Aug 1;176(2):611-6
references.pmid: 1500862
references.citation: J Exp Med. 2005 Jul 4;202(1):33-45
references.pmid: 15983066
references.citation: Immunity. 2013 Jun 27;38(6):1116-28
references.pmid: 23746651
references.citation: J Immunol. 2009 Aug 15;183(4):2213-6
references.pmid: 19620294
references.citation: Cell. 1995 Jan 27;80(2):331-40
references.pmid: 7834753
references.citation: J Biol Chem. 2006 Dec 15;281(50):38617-24
references.pmid: 17046818
references.citation: Blood. 2007 Feb 1;109(3):886-95
references.pmid: 17018859
references.citation: Nat Immunol. 2011 Dec 18;13(2):181-7
references.pmid: 22179202
references.citation: Science. 2002 Jun 7;296(5574):1876-80
references.pmid: 12052962
references.citation: Science. 1998 Apr 17;280(5362):450-3
references.pmid: 9545226
references.citation: Nat Genet. 1997 Dec;17(4):399-403
references.pmid: 9398840
references.citation: Immunity. 2005 Aug;23(2):227-39
references.pmid: 16111640
references.citation: Nature. 1995 Feb 9;373(6514):531-6
references.pmid: 7845467
references.citation: Nat Immunol. 2009 Oct;10(10):1125-32
references.pmid: 19734905
references.citation: J Immunol. 2009 Mar 1;182(5):2997-3007
references.pmid: 19234195
references.citation: Eur J Immunol. 2007 Mar;37(3):613-22
references.pmid: 17304629
references.citation: Nat Immunol. 2005 Feb;6(2):143-51
references.pmid: 15654342
references.citation: Hum Mol Genet. 2002 Feb 15;11(4):397-409
references.pmid: 11854172
references.citation: Blood. 1997 Sep 1;90(5):1943-51
references.pmid: 9292528
references.citation: Nat Rev Immunol. 2013 Feb;13(2):88-100
references.pmid: 23348415
references.citation: Nat Rev Immunol. 2003 Jun;3(6):472-82
references.pmid: 12776207
references.citation: J Exp Med. 1980 Apr 1;151(4):925-44
references.pmid: 6966312
references.citation: J Exp Med. 2008 Oct 27;205(11):2507-13
references.pmid: 18824583
references.citation: J Immunol. 1997 Mar 15;158(6):2558-66
references.pmid: 9058787
references.citation: Eur J Immunol. 2014 Jan;44(1):16-22
references.pmid: 24214487
references.citation: J Immunol. 2013 Jan 15;190(2):586-96
references.pmid: 23248258
references.citation: J Exp Med. 2004 Aug 16;200(4):481-91
references.pmid: 15302903
references.citation: Nat Commun. 2015 Jun 23;6:7484
references.pmid: 26099460
references.citation: J Clin Invest. 2006 Nov;116(11):2964-71
references.pmid: 17039258
references.citation: J Mol Med (Berl). 2000;78(9):483-94
references.pmid: 11140374
references.citation: Immunol Lett. 2013 Jul-Aug;154(1-2):31-41
references.pmid: 23912054
references.citation: Semin Immunol. 2010 Oct;22(5):287-93
references.pmid: 20510627
references.citation: Nat Rev Mol Cell Biol. 2001 Mar;2(3):179-87
references.pmid: 11265247
references.citation: Cancer Res. 2013 Apr 1;73(7):2104-16
references.pmid: 23370329
references.citation: Immunity. 2012 Jul 27;37(1):48-59
references.pmid: 22770884
references.citation: J Exp Med. 2008 Oct 27;205(11):2575-84
references.pmid: 18936237
references.citation: Nat Immunol. 2001 Nov;2(11):1032-9
references.pmid: 11600886
references.citation: Eur J Immunol. 2013 Jul;43(7):1769-78
references.pmid: 23589212
references.citation: Nature. 2004 Jan 22;427(6972):355-60
references.pmid: 14737169
references.citation: J Autoimmun. 2015 Sep;63:13-22
references.pmid: 26143957
references.citation: Blood. 2013 Jan 3;121(1):118-28
references.pmid: 23152546
references.citation: Eur J Immunol. 2008 May;38(5):1257-63
references.pmid: 18412162
references.citation: Proc Natl Acad Sci U S A. 2013 Apr 23;110(17):6979-84
references.pmid: 23569244
references.citation: Eur J Immunol. 2015 Feb;45(2):574-83
references.pmid: 25521433
references.citation: J Exp Med. 2011 Oct 24;208(11):2201-7
references.pmid: 21948082
references.citation: Genome Res. 2014 Dec;24(12):1918-31
references.pmid: 25224068
references.citation: J Immunol. 2013 Aug 1;191(3):1200-9
references.pmid: 23794633
references.citation: Nat Immunol. 2010 Feb;11(2):162-70
references.pmid: 20010845
references.citation: J Immunol. 2003 Dec 1;171(11):5653-8
references.pmid: 14634069
references.citation: J Immunol. 2014 Aug 15;193(4):1778-86
references.pmid: 25015825
references.citation: J Exp Med. 2002 May 20;195(10):1349-58
references.pmid: 12021314
references.citation: Nat Immunol. 2014 Mar;15(3):258-65
references.pmid: 24464130
references.citation: Nat Immunol. 2015 Apr;16(4):397-405
references.pmid: 25729925
references.citation: Science. 2002 Nov 15;298(5597):1395-401
references.pmid: 12376594
references.citation: J Immunol. 2015 Jul 15;195(2):498-506
references.pmid: 26034170
references.citation: J Immunol. 2002 Sep 15;169(6):2842-5
references.pmid: 12218095
references.citation: J Immunol. 2012 Aug 15;189(4):1577-84
references.pmid: 22786774
references.citation: J Exp Med. 2004 Oct 18;200(8):1015-26
references.pmid: 15492124
references.citation: J Immunol. 2004 Feb 15;172(4):2067-75
references.pmid: 14764671
references.citation: Nat Immunol. 2007 Mar;8(3):304-11
references.pmid: 17277780
references.citation: Immunity. 2005 Mar;22(3):329-41
references.pmid: 15780990
references.citation: Immunity. 2008 Jul 18;29(1):90-100
references.pmid: 18585064
references.citation: Cell Rep. 2013 Oct 17;5(1):166-79
references.pmid: 24095736
references.citation: J Exp Med. 2014 May 5;211(5):761-8
references.pmid: 24752296
references.citation: J Immunol. 2005 Feb 15;174(4):1862-70
references.pmid: 15699112
references.citation: Development. 2013 Feb;140(4):780-8
references.pmid: 23362346
references.citation: Science. 2015 May 1;348(6234):589-94
references.pmid: 25791085
references.citation: J Med Genet. 2011 Jun;48(6):413-6
references.pmid: 21507891
references.citation: Immunity. 2008 Sep 19;29(3):438-50
references.pmid: 18799150
references.citation: Nat Immunol. 2010 Jun;11(6):503-11
references.pmid: 20431621
references.citation: Eur J Immunol. 2007 Dec;37(12):3363-72
references.pmid: 18000951
references.citation: Nat Genet. 2008 May;40(5):656-62
references.pmid: 18408721
references.citation: Cell. 2010 Jan 8;140(1):123-35
references.pmid: 20085707
references.citation: Immunol Rev. 1998 Jun;163:161-76
references.pmid: 9700509
references.citation: Eur J Immunol. 2014 May;44(5):1320-9
references.pmid: 24500801
references.citation: Immunity. 2012 Mar 23;36(3):427-37
references.pmid: 22425250
references.citation: J Exp Med. 2008 Nov 24;205(12):2827-38
references.pmid: 19015306
references.citation: Trends Immunol. 2012 Jun;33(6):256-63
references.pmid: 22591984
references.citation: J Immunol. 2010 Mar 15;184(6):2999-3007
references.pmid: 20173030
references.citation: J Immunol. 2011 May 1;186(9):5047-57
references.pmid: 21441458
references.citation: Curr Opin Immunol. 2007 Apr;19(2):186-93
references.pmid: 17303398
references.citation: Immunity. 2008 Sep 19;29(3):451-63
references.pmid: 18799151