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Thymic Development and Selection of T Lymphocytes pp 19–47Cite as

Mechanisms of Thymus Medulla Development and Function

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Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 373))

Abstract

The development of CD4+ helper and CD8+ cytotoxic T-cells expressing the αβ form of the T-cell receptor (αβTCR) takes place in the thymus, a primary lymphoid organ containing distinct cortical and medullary microenvironments. While the cortex represents a site of early T-cell precursor development, and the positive selection of CD4+8+ thymocytes, the thymic medulla plays a key role in tolerance induction, ensuring that thymic emigrants are purged of autoreactive αβTCR specificities. In recent years, advances have been made in understanding the development and function of thymic medullary epithelial cells, most notably the subset defined by expression of the Autoimmune Regulator (Aire) gene. Here, we summarize current knowledge of the developmental mechanisms regulating thymus medulla development, and examine the role of the thymus medulla in recessive (negative selection) and dominant (T-regulatory cell) tolerance.

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References

  • Adkins B, Gandour D, Strober S, Weissman I (1988) Total lymphoid irradiation leads to transient depletion of the mouse thymic medulla and persistent abnormalities among medullary stromal cells. J Immunol 140:3373–3379

    CAS  Google Scholar 

  • Akiyama T, Maeda S, Yamane S, Ogino K, Kasai M, Kajiura F, Matsumoto M, Inoue J (2005) Dependence of self-tolerance on TRAF6-directed development of thymic stroma. Science 308:248–251

    CAS  Google Scholar 

  • Akiyama T, Shimo Y, Yanai H, Qin J, Ohshima D, Maruyama Y, Asaumi Y, Kitazawa J, Takayanagi H, Penninger JM, Matsumoto M, Nitta T, Takahama Y, Inoue J (2008) The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 29:423–437

    CAS  Google Scholar 

  • Allende ML, Sasaki T, Kawai H, Olivera A, Mi Y, van Echten-Deckert G, Hajdu R, Rosenbach M, Keohane CA, Mandala S, Spiegel S, Proia RL (2004) Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720. J Biol Chem 279:52487–52492

    CAS  Google Scholar 

  • Alves NL, Huntington ND, Rodewald HR, Di Santo JP (2009) Thymic epithelial cells: the multi-tasking framework of the T cell “cradle”. Trends Immunol 30:468–474

    CAS  Google Scholar 

  • Anderson G, Takahama Y (2012) Thymic epithelial cells: working class heroes for T cell development and repertoire selection. Trends Immunol 33:256–263

    CAS  Google Scholar 

  • Anderson G, Partington KM, Jenkinson EJ (1998) Differential effects of peptide diversity and stromal cell type in positive and negative selection in the thymus. J Immunol 161:6599–6603

    CAS  Google Scholar 

  • Anderson M, Anderson SK, Farr AG (2000) Thymic vasculature: organizer of the medullary epithelial compartment? Int Immunol 12:1105–1110

    CAS  Google Scholar 

  • Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D (2002) Projection of an immunological self shadow within the thymus by the aire protein. Science 298:1395–1401

    CAS  Google Scholar 

  • Anderson G, Lane PJ, Jenkinson EJ (2007) Generating intrathymic microenvironments to establish T-cell tolerance. Nat Rev Immunol 7:954–963

    CAS  Google Scholar 

  • Aschenbrenner K, D’Cruz LM, Vollmann EH, Hinterberger M, Emmerich J, Swee LK, Rolink A, Klein L (2007) Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat Immunol 8:351–358

    CAS  Google Scholar 

  • Baba T, Nakamoto Y, Mukaida N (2009) Crucial contribution of thymic Sirp alpha+ conventional dendritic cells to central tolerance against blood-borne antigens in a CCR2-dependent manner. J Immunol 183:3053–3063

    CAS  Google Scholar 

  • Bai A, Hu H, Yeung M, Chen J (2007) Kruppel-like factor 2 controls T cell trafficking by activating L-selectin (CD62L) and sphingosine-1-phosphate receptor 1 transcription. J Immunol 178:7632–7639

    CAS  Google Scholar 

  • Bautista JL, Lio CW, Lathrop SK, Forbush K, Liang Y, Luo J, Rudensky AY, Hsieh CS (2009) Intraclonal competition limits the fate determination of regulatory T cells in the thymus. Nat Immunol 10:610–617

    CAS  Google Scholar 

  • Bensinger SJ, Bandeira A, Jordan MS, Caton AJ, Laufer TM (2001) Major histocompatibility complex class II-positive cortical epithelium mediates the selection of CD4(+)25(+) immunoregulatory T cells. J Exp Med 194:427–438

    CAS  Google Scholar 

  • Blackburn CC, Augustine CL, Li R, Harvey RP, Malin MA, Boyd RL, Miller JF, Morahan G (1996) The nu gene acts cell-autonomously and is required for differentiation of thymic epithelial progenitors. Proc Natl Acad Sci U S A 93:5742–5746

    CAS  Google Scholar 

  • Bleul CC, Corbeaux T, Reuter A, Fisch P, Monting JS, Boehm T (2006) Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature 441:992–996

    CAS  Google Scholar 

  • Boehm T, Scheu S, Pfeffer K, Bleul CC (2003) Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LTbetaR. J Exp Med 198:757–769

    CAS  Google Scholar 

  • Bonifaz L, Bonnyay D, Mahnke K, Rivera M, Nussenzweig MC, Steinman RM (2002) Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J Exp Med 196:1627–1638

    CAS  Google Scholar 

  • Bonifaz LC, Bonnyay DP, Charalambous A, Darguste DI, Fujii S, Soares H, Brimnes MK, Moltedo B, Moran TM, Steinman RM (2004) In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T cell vaccination. J Exp Med 199:815–824

    CAS  Google Scholar 

  • Boursalian TE, Golob J, Soper DM, Cooper CJ, Fink PJ (2004) Continued maturation of thymic emigrants in the periphery. Nat Immunol 5:418–425

    CAS  Google Scholar 

  • Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA (2007) IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J Immunol 178:280–290

    CAS  Google Scholar 

  • Burkly L, Hession C, Ogata L, Reilly C, Marconi LA, Olson D, Tizard R, Cate R, Lo D (1995) Expression of relB is required for the development of thymic medulla and dendritic cells. Nature 373:531–536

    CAS  Google Scholar 

  • Carlson CM, Endrizzi BT, Wu J, Ding X, Weinreich MA, Walsh ER, Wani MA, Lingrel JB, Hogquist KA, Jameson SC (2006) Kruppel-like factor 2 regulates thymocyte and T-cell migration. Nature 442:299–302

    CAS  Google Scholar 

  • Chin RK, Lo JC, Kim O, Blink SE, Christiansen PA, Peterson P, Wang Y, Ware C, Fu YX (2003) Lymphotoxin pathway directs thymic Aire expression. Nat Immunol 4:1121–1127

    CAS  Google Scholar 

  • Chin RK, Zhu M, Christiansen PA, Liu W, Ware C, Peltonen L, Zhang X, Guo L, Han S, Zheng B, Fu YX (2006) Lymphotoxin pathway-directed, autoimmune regulator-independent central tolerance to arthritogenic collagen. J Immunol 177:290–297

    CAS  Google Scholar 

  • Cowan JE, Parnell SM, Nakamura K, Caamano JH, Lane PJ, Jenkinson EJ, Jenkinson WE, Anderson G (2013) The thymic medulla is required for Foxp3+ regulatory but not conventional CD4+ thymocyte development. J Exp Med 210:675–681

    Google Scholar 

  • Cupedo T, Kraal G, Mebius RE (2002) The role of CD45+CD4+CD3− cells in lymphoid organ development. Immunol Rev 189:41–50

    CAS  Google Scholar 

  • Derbinski J, Kyewski B (2005) Linking signalling pathways, thymic stroma integrity and autoimmunity. Trends Immunol 26:503–506

    CAS  Google Scholar 

  • Derbinski J, Schulte A, Kyewski B, Klein L (2001) Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol 2:1032–1039

    CAS  Google Scholar 

  • Derbinski J, Gabler J, Brors B, Tierling S, Jonnakuty S, Hergenhahn M, Peltonen L, Walter J, Kyewski B (2005) Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J Exp Med 202:33–45

    CAS  Google Scholar 

  • Derbinski J, Pinto S, Rosch S, Hexel K, Kyewski B (2008) Promiscuous gene expression patterns in single medullary thymic epithelial cells argue for a stochastic mechanism. Proc Natl Acad Sci U S A 105:657–662

    CAS  Google Scholar 

  • Desanti GE, Cowan JE, Baik S, Parnell SM, White AJ, Penninger JM, Lane PJ, Jenkinson EJ, Jenkinson WE, Anderson G (2012) Developmentally regulated availability of RANKL and CD40 ligand reveals distinct mechanisms of fetal and adult cross-talk in the thymus medulla. J Immunol 189:5519–5526

    CAS  Google Scholar 

  • DeVoss J, Hou Y, Johannes K, Lu W, Liou GI, Rinn J, Chang H, Caspi RR, Fong L, Anderson MS (2006) Spontaneous autoimmunity prevented by thymic expression of a single self-antigen. J Exp Med 203:2727–2735

    CAS  Google Scholar 

  • Dooley J, Erickson M, Farr AG (2008) Alterations of the medullary epithelial compartment in the Aire-deficient thymus: Implications for programs of thymic epithelial differentiation. J Immunol 181:5225–5232

    CAS  Google Scholar 

  • Dresch C, Ackermann M, Vogt B, de Andrade Pereira B, Shortman K, Fraefel C (2011) Thymic but not splenic CD8(+) DCs can efficiently cross-prime T cells in the absence of licensing factors. Eur J Immunol 41:2544–2555

    CAS  Google Scholar 

  • Drumea-Mirancea M, Wessels JT, Muller CA, Essl M, Eble JA, Tolosa E, Koch M, Reinhardt DP, Sixt M, Sorokin L, Stierhof YD, Schwarz H, Klein G (2006) Characterization of a conduit system containing laminin-5 in the human thymus: a potential transport system for small molecules. J Cell Sci 119:1396–1405

    CAS  Google Scholar 

  • Dudakov JA, Hanash AM, Jenq RR, Young LF, Ghosh A, Singer NV, West ML, Smith OM, Holland AM, Tsai JJ, Boyd RL, van den Brink MR (2012) Interleukin-22 drives endogenous thymic regeneration in mice. Science 336:91–95

    CAS  Google Scholar 

  • Egerton M, Scollay R, Shortman K (1990) Kinetics of mature T-cell development in the thymus. Proc Natl Acad Sci U S A 87:2579–2582

    CAS  Google Scholar 

  • Farr AG, Anderson SK (1985) Epithelial heterogeneity in the murine thymus: fucose-specific lectins bind medullary epithelial cells. J Immunol 134:2971–2977

    CAS  Google Scholar 

  • Farr AG, Braddy SC (1989) Patterns of keratin expression in the murine thymus. Anat Rec 224:374–378

    CAS  Google Scholar 

  • Foster K, Sheridan J, Veiga-Fernandes H, Roderick K, Pachnis V, Adams R, Blackburn C, Kioussis D, Coles M (2008) Contribution of neural crest-derived cells in the embryonic and adult thymus. J Immunol 180:3183–3189

    CAS  Google Scholar 

  • Gabler J, Arnold J, Kyewski B (2007) Promiscuous gene expression and the developmental dynamics of medullary thymic epithelial cells. Eur J Immunol 37:3363–3372

    Google Scholar 

  • Gallegos AM, Bevan MJ (2004) Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J Exp Med 200:1039–1049

    CAS  Google Scholar 

  • Gillard GO, Farr AG (2005) Contrasting models of promiscuous gene expression by thymic epithelium. J Exp Med 202:15–19

    CAS  Google Scholar 

  • Gillard GO, Dooley J, Erickson M, Peltonen L, Farr AG (2007) Aire-dependent alterations in medullary thymic epithelium indicate a role for Aire in thymic epithelial differentiation. J Immunol 178:3007–3015

    CAS  Google Scholar 

  • Godfrey DI, Izon DJ, Tucek CL, Wilson TJ, Boyd RL (1990) The phenotypic heterogeneity of mouse thymic stromal cells. Immunology 70:66–74

    CAS  Google Scholar 

  • Gray DH, Abramson J, Benoist C, Mathis D (2007) Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire. J Exp Med 204:2521–2528

    CAS  Google Scholar 

  • Gray DH, Seach N, Ueno T, Milton MK, Liston A, Lew AM, Goodnow CC, Boyd RL (2006) Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood 108:3777–3785

    CAS  Google Scholar 

  • Guerau-de-Arellano M, Martinic M, Benoist C, Mathis D (2009) Neonatal tolerance revisited: a perinatal window for Aire control of autoimmunity. J Exp Med 206:1245–1252

    CAS  Google Scholar 

  • Hadeiba H, Lahl K, Edalati A, Oderup C, Habtezion A, Pachynski R, Nguyen L, Ghodsi A, Adler S, Butcher EC (2012) Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance. Immunity 36:438–450

    CAS  Google Scholar 

  • Hamazaki Y, Fujita H, Kobayashi T, Choi Y, Scott HS, Matsumoto M, Minato N (2007) Medullary thymic epithelial cells expressing Aire represent a unique lineage derived from cells expressing claudin. Nat Immunol 8:304–311

    CAS  Google Scholar 

  • Heino M, Peterson P, Sillanpaa N, Guerin S, Wu L, Anderson G, Scott HS, Antonarakis SE, Kudoh J, Shimizu N, Jenkinson EJ, Naquet P, Krohn KJ (2000) RNA and protein expression of the murine autoimmune regulator gene (Aire) in normal, RelB-deficient and in NOD mouse. Eur J Immunol 30:1884–1893

    CAS  Google Scholar 

  • Hikosaka Y, Nitta T, Ohigashi I, Yano K, Ishimaru N, Hayashi Y, Matsumoto M, Matsuo K, Penninger JM, Takayanagi H, Yokota Y, Yamada H, Yoshikai Y, Inoue J, Akiyama T, Takahama Y (2008) The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity 29:438–450

    CAS  Google Scholar 

  • Hinterberger M, Aichinger M, Prazeres da Costa O, Voehringer D, Hoffmann R, Klein L (2010) Autonomous role of medullary thymic epithelial cells in central CD4(+) T cell tolerance. Nat Immunol 11:512–519

    CAS  Google Scholar 

  • Hsieh CS, Liang Y, Tyznik AJ, Self SG, Liggitt D, Rudensky AY (2004) Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 21:267–277

    CAS  Google Scholar 

  • Hubert FX, Kinkel SA, Webster KE, Cannon P, Crewther PE, Proeitto AI, Wu L, Heath WR, Scott HS (2008) A specific anti-Aire antibody reveals aire expression is restricted to medullary thymic epithelial cells and not expressed in periphery. J Immunol 180:3824–3832

    CAS  Google Scholar 

  • Irla M, Hugues S, Gill J, Nitta T, Hikosaka Y, Williams IR, Hubert FX, Scott HS, Takahama Y, Hollander GA, Reith W (2008) Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity. Immunity 29:451–463

    CAS  Google Scholar 

  • Itoh M, Takahashi T, Sakaguchi N, Kuniyasu Y, Shimizu J, Otsuka F, Sakaguchi S (1999) Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol 162:5317–5326

    CAS  Google Scholar 

  • Izon DJ, Nieland JD, Godfrey DI, Boyd RL, Kruisbeek AM (1994) Flow cytometric analysis reveals unexpected shared antigens between histologically defined populations of thymic stromal cells. Int Immunol 6:31–39

    CAS  Google Scholar 

  • Jenkinson WE, Jenkinson EJ, Anderson G (2003) Differential requirement for mesenchyme in the proliferation and maturation of thymic epithelial progenitors. J Exp Med 198:325–332

    CAS  Google Scholar 

  • Jenkinson WE, Rossi SW, Parnell SM, Jenkinson EJ, Anderson G (2007) PDGFRalpha-expressing mesenchyme regulates thymus growth and the availability of intrathymic niches. Blood 109:954–960

    CAS  Google Scholar 

  • Jordan MS, Boesteanu A, Reed AJ, Petrone AL, Holenbeck AE, Lerman MA, Naji A, Caton AJ (2001) Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat Immunol 2:301–306

    CAS  Google Scholar 

  • Josefowicz SZ, Lu LF, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564

    CAS  Google Scholar 

  • Kajiura F, Sun S, Nomura T, Izumi K, Ueno T, Bando Y, Kuroda N, Han H, Li Y, Matsushima A, Takahama Y, Sakaguchi S, Mitani T, Matsumoto M (2004) NF-kappa B-inducing kinase establishes self-tolerance in a thymic stroma-dependent manner. J Immunol 172:2067–2075

    CAS  Google Scholar 

  • Kanariou M, Huby R, Ladyman H, Colic M, Sivolapenko G, Lampert I, Ritter M (1989) Immunosuppression with cyclosporin A alters the thymic microenvironment. Clin Exp Immunol 78:263–270

    CAS  Google Scholar 

  • Kerdiles YM, Beisner DR, Tinoco R, Dejean AS, Castrillon DH, DePinho RA, Hedrick SM (2009) Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat Immunol 10:176–184

    CAS  Google Scholar 

  • Kim JM, Rasmussen JP, Rudensky AY (2007) Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 8:191–197

    CAS  Google Scholar 

  • Kishimoto H, Sprent J (1997) Negative selection in the thymus includes semimature T cells. J Exp Med 185:263–271

    CAS  Google Scholar 

  • Klein L, Hinterberger M, von Rohrscheidt J, Aichinger M (2011) Autonomous versus dendritic cell-dependent contributions of medullary thymic epithelial cells to central tolerance. Trends Immunol 32:188–193

    CAS  Google Scholar 

  • Klug DB, Carter C, Crouch E, Roop D, Conti CJ, Richie ER (1998) Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment. Proc Natl Acad Sci U S A 95:11822–11827

    CAS  Google Scholar 

  • Klug DB, Carter C, Gimenez-Conti IB, Richie ER (2002) Thymocyte-independent and thymocyte-dependent phases of epithelial patterning in the fetal thymus. J Immunol 169:2842–2845

    CAS  Google Scholar 

  • Koble C, Kyewski B (2009) The thymic medulla: a unique microenvironment for intercellular self-antigen transfer. J Exp Med 206:1505–1513

    CAS  Google Scholar 

  • Laan M, Kisand K, Kont V, Moll K, Tserel L, Scott HS, Peterson P (2009) Autoimmune regulator deficiency results in decreased expression of CCR4 and CCR7 ligands and in delayed migration of CD4+ thymocytes. J Immunol 183:7682–7691

    CAS  Google Scholar 

  • Ladi E, Schwickert TA, Chtanova T, Chen Y, Herzmark P, Yin X, Aaron H, Chan SW, Lipp M, Roysam B, Robey EA (2008) Thymocyte-dendritic cell interactions near sources of CCR7 ligands in the thymic cortex. J Immunol 181:7014–7023

    CAS  Google Scholar 

  • Le Borgne M, Ladi E, Dzhagalov I, Herzmark P, Liao YF, Chakraborty AK, Robey EA (2009) The impact of negative selection on thymocyte migration in the medulla. Nat Immunol 10:823–830

    Google Scholar 

  • Lee HM, Hsieh CS (2009) Rare development of Foxp3+ thymocytes in the CD4+CD8+ subset. J Immunol 183:2261–2266

    CAS  Google Scholar 

  • Lei Y, Ripen AM, Ishimaru N, Ohigashi I, Nagasawa T, Jeker LT, Bosl MR, Hollander GA, Hayashi Y, Malefyt Rde W, Nitta T, Takahama Y (2011) Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development. J Exp Med 208:383–394

    CAS  Google Scholar 

  • Li J, Li Y, Yao JY, Jin R, Zhu MZ, Qian XP, Zhang J, Fu YX, Wu L, Zhang Y, Chen WF (2007) Developmental pathway of CD4+CD8− medullary thymocytes during mouse ontogeny and its defect in Aire−/− mice. Proc Natl Acad Sci U S A 104:18175–18180

    CAS  Google Scholar 

  • Li J, Park J, Foss D, Goldschneider I (2009) Thymus-homing peripheral dendritic cells constitute two of the three major subsets of dendritic cells in the steady-state thymus. J Exp Med 206:607–622

    CAS  Google Scholar 

  • Lio CW, Hsieh CS (2008) A two-step process for thymic regulatory T cell development. Immunity 28:100–111

    CAS  Google Scholar 

  • Liston A, Rudensky AY (2007) Thymic development and peripheral homeostasis of regulatory T cells. Curr Opin Immunol 19:176–185

    CAS  Google Scholar 

  • Liston A, Lesage S, Wilson J, Peltonen L, Goodnow CC (2003) Aire regulates negative selection of organ-specific T cells. Nat Immunol 4:350–354

    CAS  Google Scholar 

  • Liston A, Nutsch KM, Farr AG, Lund JM, Rasmussen JP, Koni PA, Rudensky AY (2008) Differentiation of regulatory Foxp3+ T cells in the thymic cortex. Proc Natl Acad Sci U S A 105:11903–11908

    CAS  Google Scholar 

  • Manley NR, Blackburn CC (2003) A developmental look at thymus organogenesis: where do the non-hematopoietic cells in the thymus come from? Curr Opin Immunol 15:225–232

    CAS  Google Scholar 

  • Martins VC, Boehm T, Bleul CC (2008) Ltbetar signaling does not regulate Aire-dependent transcripts in medullary thymic epithelial cells. J Immunol 181:400–407

    CAS  Google Scholar 

  • Mathis D, Benoist C (2009) Aire. Annu Rev Immunol 27:287–312

    CAS  Google Scholar 

  • Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, Brinkmann V, Allende ML, Proia RL, Cyster JG (2004) Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427:355–360

    CAS  Google Scholar 

  • Matsumoto M (2011) Contrasting models for the roles of Aire in the differentiation program of epithelial cells in the thymic medulla. Eur J Immunol 41:12–17

    CAS  Google Scholar 

  • McCaughtry TM, Wilken MS, Hogquist KA (2007) Thymic emigration revisited. J Exp Med 204:2513–2520

    CAS  Google Scholar 

  • Moran AE, Holzapfel KL, Xing Y, Cunningham NR, Maltzman JS, Punt J, Hogquist KA (2011) T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J Exp Med 208:1279–1289

    CAS  Google Scholar 

  • Mori K, Itoi M, Tsukamoto N, Kubo H, Amagai T (2007) The perivascular space as a path of hematopoietic progenitor cells and mature T cells between the blood circulation and the thymic parenchyma. Int Immunol 19:745–753

    CAS  Google Scholar 

  • Muller SM, Terszowski G, Blum C, Haller C, Anquez V, Kuschert S, Carmeliet P, Augustin HG, Rodewald HR (2005) Gene targeting of VEGF-A in thymus epithelium disrupts thymus blood vessel architecture. Proc Natl Acad Sci U S A 102:10587–10592

    Google Scholar 

  • Muller SM, Stolt CC, Terszowski G, Blum C, Amagai T, Kessaris N, Iannarelli P, Richardson WD, Wegner M, Rodewald HR (2008) Neural crest origin of perivascular mesenchyme in the adult thymus. J Immunol 180:5344–5351

    Google Scholar 

  • Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, Krohn KJ, Lalioti MD, Mullis PE, Antonarakis SE, Kawasaki K, Asakawa S, Ito F, Shimizu N (1997) Positional cloning of the APECED gene. Nat Genet 17:393–398

    CAS  Google Scholar 

  • Nehls M, Pfeifer D, Schorpp M, Hedrich H, Boehm T (1994) New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature 372:103–107

    CAS  Google Scholar 

  • Nehls M, Kyewski B, Messerle M, Waldschutz R, Schuddekopf K, Smith AJ, Boehm T (1996) Two genetically separable steps in the differentiation of thymic epithelium. Science 272:886–889

    CAS  Google Scholar 

  • Nelson AJ, Dunn RJ, Peach R, Aruffo A, Farr AG (1996) The murine homolog of human Ep-CAM, a homotypic adhesion molecule, is expressed by thymocytes and thymic epithelial cells. Eur J Immunol 26:401–408

    CAS  Google Scholar 

  • Nishikawa Y, Hirota F, Yano M, Kitajima H, Miyazaki J, Kawamoto H, Mouri Y, Matsumoto M (2010) Biphasic Aire expression in early embryos and in medullary thymic epithelial cells before end-stage terminal differentiation. J Exp Med 207:963–971

    CAS  Google Scholar 

  • Nitta T, Ohigashi I, Nakagawa Y, Takahama Y (2011) Cytokine crosstalk for thymic medulla formation. Curr Opin Immunol 23:190–197

    CAS  Google Scholar 

  • Nowell CS, Bredenkamp N, Tetelin S, Jin X, Tischner C, Vaidya H, Sheridan JM, Stenhouse FH, Heussen R, Smith AJ, Blackburn CC (2011) Foxn1 regulates lineage progression in cortical and medullary thymic epithelial cells but is dispensable for medullary sublineage divergence. PLoS Genet 7:e1002348

    CAS  Google Scholar 

  • Odaka C (2009) Localization of mesenchymal cells in adult mouse thymus: their abnormal distribution in mice with disorganization of thymic medullary epithelium. J Histochem Cytochem 57:373–382

    CAS  Google Scholar 

  • Odaka C, Morisada T, Oike Y, Suda T (2006) Distribution of lymphatic vessels in mouse thymus: immunofluorescence analysis. Cell Tissue Res 325:13–22

    Google Scholar 

  • Ohnmacht C, Pullner A, King SB, Drexler I, Meier S, Brocker T, Voehringer D (2009) Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J Exp Med 206:549–559

    CAS  Google Scholar 

  • Pacholczyk R, Ignatowicz H, Kraj P, Ignatowicz L (2006) Origin and T cell receptor diversity of Foxp3+CD4+CD25+ T cells. Immunity 25:249–259

    CAS  Google Scholar 

  • Palmer DB, Viney JL, Ritter MA, Hayday AC, Owen MJ (1993) Expression of the alpha beta T-cell receptor is necessary for the generation of the thymic medulla. Dev Immunol 3:175–179

    CAS  Google Scholar 

  • Petrie HT, Zuniga-Pflucker JC (2007) Zoned out: functional mapping of stromal signaling microenvironments in the thymus. Annu Rev Immunol 25:649–679

    CAS  Google Scholar 

  • Pham TH, Baluk P, Xu Y, Grigorova I, Bankovich AJ, Pappu R, Coughlin SR, McDonald DM, Schwab SR, Cyster JG (2010) Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning. J Exp Med 207:17–27

    CAS  Google Scholar 

  • Porritt HE, Gordon K, Petrie HT (2003) Kinetics of steady-state differentiation and mapping of intrathymic-signaling environments by stem cell transplantation in nonirradiated mice. J Exp Med 198:957–962

    CAS  Google Scholar 

  • Proietto AI, van Dommelen S, Zhou P, Rizzitelli A, D’Amico A, Steptoe RJ, Naik SH, Lahoud MH, Liu Y, Zheng P, Shortman K, Wu L (2008) Dendritic cells in the thymus contribute to T-regulatory cell induction. Proc Natl Acad Sci U S A 105:19869–19874

    CAS  Google Scholar 

  • Ramsdell F, Jenkins M, Dinh Q, Fowlkes BJ (1991) The majority of CD4+8− thymocytes are functionally immature. J Immunol 147:1779–1785

    CAS  Google Scholar 

  • Ramsey C, Winqvist O, Puhakka L, Halonen M, Moro A, Kampe O, Eskelin P, Pelto-Huikko M, Peltonen L (2002) Aire deficient mice develop multiple features of APECED phenotype and show altered immune response. Hum Mol Genet 11:397–409

    CAS  Google Scholar 

  • Ripen AM, Nitta T, Murata S, Tanaka K, Takahama Y (2011) Ontogeny of thymic cortical epithelial cells expressing the thymoproteasome subunit beta5t. Eur J Immunol 41:1278–1287

    CAS  Google Scholar 

  • Roberts NA, White AJ, Jenkinson WE, Turchinovich G, Nakamura K, Withers DR, McConnell FM, Desanti GE, Benezech C, Parnell SM, Cunningham AF, Paolino M, Penninger JM, Simon AK, Nitta T, Ohigashi I, Takahama Y, Caamano JH, Hayday AC, Lane PJ, Jenkinson EJ, Anderson G (2012) Rank signaling links the development of invariant gammadelta T cell progenitors and Aire(+) medullary epithelium. Immunity 36:427–437

    CAS  Google Scholar 

  • Rodewald HR (2008) Thymus organogenesis. Annu Rev Immunol 26:355–388

    CAS  Google Scholar 

  • Rodewald HR, Paul S, Haller C, Bluethmann H, Blum C (2001) Thymus medulla consisting of epithelial islets each derived from a single progenitor. Nature 414:763–768

    CAS  Google Scholar 

  • Romagnoli P, Dooley J, Enault G, Vicente R, Malissen B, Liston A, van Meerwijk JP (2012) The thymic niche does not limit development of the naturally diverse population of mouse regulatory T lymphocytes. J Immunol 189:3831–3837

    CAS  Google Scholar 

  • Roman E, Shino H, Qin FX, Liu YJ (2010) Cutting edge: Hematopoietic-derived APCs select regulatory T cells in thymus. J Immunol 185:3819–3823

    CAS  Google Scholar 

  • Rossi SW, Jenkinson WE, Anderson G, Jenkinson EJ (2006) Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature 441:988–991

    CAS  Google Scholar 

  • Rossi SW, Kim MY, Leibbrandt A, Parnell SM, Jenkinson WE, Glanville SH, McConnell FM, Scott HS, Penninger JM, Jenkinson EJ, Lane PJ, Anderson G (2007) RANK signals from CD4(+)3(−) inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J Exp Med 204:1267–1272

    CAS  Google Scholar 

  • Scollay R, Godfrey DI (1995) Thymic emigration: conveyor belts or lucky dips? Immunol Today 16:268–273, discussion 273–274

    CAS  Google Scholar 

  • Seach N, Ueno T, Fletcher AL, Lowen T, Mattesich M, Engwerda CR, Scott HS, Ware CF, Chidgey AP, Gray DH, Boyd RL (2008) The lymphotoxin pathway regulates Aire-independent expression of ectopic genes and chemokines in thymic stromal cells. J Immunol 180:5384–5392

    CAS  Google Scholar 

  • Seach N, Wong K, Hammett M, Boyd RL, Chidgey AP (2012) Purified enzymes improve isolation and characterization of the adult thymic epithelium. J Immunol Methods 385:23–34

    CAS  Google Scholar 

  • Shakib S, Desanti GE, Jenkinson WE, Parnell SM, Jenkinson EJ, Anderson G (2009) Checkpoints in the development of thymic cortical epithelial cells. J Immunol 182:130–137

    CAS  Google Scholar 

  • Shores EW, Van Ewijk W, Singer A (1991) Disorganization and restoration of thymic medullary epithelial cells in T cell receptor-negative scid mice: evidence that receptor-bearing lymphocytes influence maturation of the thymic microenvironment. Eur J Immunol 21:1657–1661

    CAS  Google Scholar 

  • Shores EW, Van Ewijk W, Singer A (1994) Maturation of medullary thymic epithelium requires thymocytes expressing fully assembled CD3-TCR complexes. Int Immunol 6:1393–1402

    CAS  Google Scholar 

  • Sitnik KM, Kotarsky K, White AJ, Jenkinson WE, Anderson G, Agace WW (2012) Mesenchymal cells regulate retinoic acid receptor-dependent cortical thymic epithelial cell homeostasis. J Immunol 188:4801–4809

    CAS  Google Scholar 

  • Spence PJ, Green EA (2008) Foxp3+ regulatory T cells promiscuously accept thymic signals critical for their development. Proc Natl Acad Sci U S A 105:973–978

    CAS  Google Scholar 

  • Surh CD, Ernst B, Sprent J (1992) Growth of epithelial cells in the thymic medulla is under the control of mature T cells. J Exp Med 176:611–616

    CAS  Google Scholar 

  • Tai X, Cowan M, Feigenbaum L, Singer A (2005) CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Nat Immunol 6:152–162

    CAS  Google Scholar 

  • Takahama Y (2006) Journey through the thymus: stromal guides for T-cell development and selection. Nat Rev Immunol 6:127–135

    CAS  Google Scholar 

  • Teng F, Zhou Y, Jin R, Chen Y, Pei X, Liu Y, Dong J, Wang W, Pang X, Qian X, Chen WF, Zhang Y, Ge Q (2011) The molecular signature underlying the thymic migration and maturation of TCRalphabeta+ CD4+ CD8 thymocytes. PLoS One 6:e25567

    CAS  Google Scholar 

  • Tough DF, Sprent J (1994) Turnover of naive- and memory-phenotype T cells. J Exp Med 179:1127–1135

    CAS  Google Scholar 

  • Ueno T, Saito F, Gray DH, Kuse S, Hieshima K, Nakano H, Kakiuchi T, Lipp M, Boyd RL, Takahama Y (2004) CCR7 signals are essential for cortex-medulla migration of developing thymocytes. J Exp Med 200:493–505

    CAS  Google Scholar 

  • van Ewijk W, Shores EW, Singer A (1994) Crosstalk in the mouse thymus. Immunol Today 15:214–217

    Google Scholar 

  • Van Vliet E, Melis M, Van Ewijk W (1984) Monoclonal antibodies to stromal cell types of the mouse thymus. Eur J Immunol 14:524–529

    Google Scholar 

  • Venanzi ES, Gray DH, Benoist C, Mathis D (2007) Lymphotoxin pathway and Aire influences on thymic medullary epithelial cells are unconnected. J Immunol 179:5693–5700

    CAS  Google Scholar 

  • Vicari A, Abehsira-Amar O, Papiernik M, Boyd RL, Tucek CL (1994) MTS-32 monoclonal antibody defines CD4+8− thymocyte subsets that differ in their maturation level, lymphokine secretion, and selection patterns. J Immunol 152:2207–2213

    CAS  Google Scholar 

  • Wang X, Laan M, Bichele R, Kisand K, Scott HS, Peterson P (2012) Post-Aire maturation of thymic medullary epithelial cells involves selective expression of keratinocyte-specific autoantigens. Front Immunol 3:19

    CAS  Google Scholar 

  • Weih F, Caamano J (2003) Regulation of secondary lymphoid organ development by the nuclear factor-kappaB signal transduction pathway. Immunol Rev 195:91–105

    CAS  Google Scholar 

  • Weih F, Carrasco D, Durham SK, Barton DS, Rizzo CA, Ryseck RP, Lira SA, Bravo R (1995) Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. Cell 80:331–340

    CAS  Google Scholar 

  • Weinreich MA, Hogquist KA (2008) Thymic emigration: when and how T cells leave home. J Immunol 181:2265–2270

    CAS  Google Scholar 

  • Weinreich MA, Jameson SC, Hogquist KA (2011) Postselection thymocyte maturation and emigration are independent of IL-7 and ERK5. J Immunol 186:1343–1347

    CAS  Google Scholar 

  • White AJ, Withers DR, Parnell SM, Scott HS, Finke D, Lane PJ, Jenkinson EJ, Anderson G (2008) Sequential phases in the development of Aire-expressing medullary thymic epithelial cells involve distinct-cellular input. Eur J Immunol 38:942–947

    CAS  Google Scholar 

  • White AJ, Nakamura K, Jenkinson WE, Saini M, Sinclair C, Seddon B, Narendran P, Pfeffer K, Nitta T, Takahama Y, Caamano JH, Lane PJ, Jenkinson EJ, Anderson G (2010) Lymphotoxin signals from positively selected thymocytes regulate the terminal differentiation of medullary thymic epithelial cells. J Immunol 185:4769–4776

    CAS  Google Scholar 

  • Wilson A, Day LM, Scollay R, Shortman K (1988) Subpopulations of mature murine thymocytes: properties of CD4−CD8+ and CD4+CD8− thymocytes lacking the heat-stable antigen. Cell Immunol 117:312–326

    CAS  Google Scholar 

  • Wu L, D’Amico A, Winkel KD, Suter M, Lo D, Shortman K (1998) RelB is essential for the development of myeloid-related CD8alpha− dendritic cells but not of lymphoid-related CD8alpha+ dendritic cells. Immunity 9:839–847

    CAS  Google Scholar 

  • Yamazaki H, Sakata E, Yamane T, Yanagisawa A, Abe K, Yamamura KI, Hayashi SI, Kunisada T (2005) Presence and distribution of neural crest-derived cells in the murine developing thymus and their potential for differentiation. Int Immunol 17:549–558

    CAS  Google Scholar 

  • Yano M, Kuroda N, Han H, Meguro-Horike M, Nishikawa Y, Kiyonari H, Maemura K, Yanagawa Y, Obata K, Takahashi S, Ikawa T, Satoh R, Kawamoto H, Mouri Y, Matsumoto M (2008) Aire controls the differentiation program of thymic epithelial cells in the medulla for the establishment of self-tolerance. J Exp Med 205:2827–2838

    CAS  Google Scholar 

  • Zachariah MA, Cyster JG (2010) Neural crest-derived pericytes promote egress of mature thymocytes at the corticomedullary junction. Science 328:1129–1135

    CAS  Google Scholar 

  • Zhu M, Chin RK, Tumanov AV, Liu X, Fu YX (2007) Lymphotoxin beta receptor is required for the migration and selection of autoreactive T cells in thymic medulla. J Immunol 179:8069–8075

    CAS  Google Scholar 

  • Zuklys S, Balciunaite G, Agarwal A, Fasler-Kan E, Palmer E, Hollander GA (2000) Normal thymic architecture and negative selection are associated with Aire expression, the gene defective in the autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). J Immunol 165:1976–1983

    CAS  Google Scholar 

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Authors and Affiliations

  1. MRC Centre for Immune Regulation, Institute for Biomedical Research, Medical School, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK

    Graham Anderson, Song Baik, Jennifer E. Cowan, Amanda M. Holland, Nicholas I. McCarthy, Kyoko Nakamura, Sonia M. Parnell, Andrea J. White, Peter J. L. Lane, Eric J. Jenkinson & William E. Jenkinson

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  1. Graham Anderson
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  2. Song Baik
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  3. Jennifer E. Cowan
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  7. Sonia M. Parnell
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Correspondence to Graham Anderson .

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  1. Department of Developmental Immunology, Max-Planck-Institute of Immunobiology and Epigenetics, Freiburg, Germany

    Thomas Boehm

  2. Institute for Genome Research, Division of Experimental Immunology, University of Tokushima, Tokushima, Japan

    Yousuke Takahama

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Anderson, G. et al. (2013). Mechanisms of Thymus Medulla Development and Function. In: Boehm, T., Takahama, Y. (eds) Thymic Development and Selection of T Lymphocytes. Current Topics in Microbiology and Immunology, vol 373. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2013_320

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