Advertisement

Mechanisms of Thymus Medulla Development and Function

  • 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
Chapter
Part of the Current Topics in Microbiology and Immunology book series (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.

Keywords

Single Positive Lymphoid Tissue Inducer Thymic Medulla Thymic Microenvironment Lymphoid Tissue Inducer Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 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 140:3373–3379Google Scholar
  2. 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 308:248–251Google Scholar
  3. 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 29:423–437Google Scholar
  4. 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 279:52487–52492Google Scholar
  5. Alves NL, Huntington ND, Rodewald HR, Di Santo JP (2009) Thymic epithelial cells: the multi-tasking framework of the T cell “cradle”. Trends Immunol 30:468–474Google Scholar
  6. Anderson G, Takahama Y (2012) Thymic epithelial cells: working class heroes for T cell development and repertoire selection. Trends Immunol 33:256–263Google Scholar
  7. 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 Google Scholar
  8. Anderson M, Anderson SK, Farr AG (2000) Thymic vasculature: organizer of the medullary epithelial compartment? Int Immunol 12:1105–1110Google Scholar
  9. 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 298:1395–1401Google Scholar
  10. Anderson G, Lane PJ, Jenkinson EJ (2007) Generating intrathymic microenvironments to establish T-cell tolerance. Nat Rev Immunol 7:954–963Google Scholar
  11. 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 8:351–358Google Scholar
  12. 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 183:3053–3063Google Scholar
  13. 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 178:7632–7639Google Scholar
  14. 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 10:610–617Google Scholar
  15. 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 194:427–438Google Scholar
  16. 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 93:5742–5746Google Scholar
  17. 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 441:992–996Google Scholar
  18. 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 198:757–769Google Scholar
  19. 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 196:1627–1638Google Scholar
  20. 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 199:815–824Google Scholar
  21. Boursalian TE, Golob J, Soper DM, Cooper CJ, Fink PJ (2004) Continued maturation of thymic emigrants in the periphery. Nat Immunol 5:418–425Google Scholar
  22. 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 178:280–290Google Scholar
  23. 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 373:531–536Google Scholar
  24. 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 442:299–302Google Scholar
  25. 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 4:1121–1127Google Scholar
  26. 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 177:290–297Google Scholar
  27. 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 210:675–681Google Scholar
  28. Cupedo T, Kraal G, Mebius RE (2002) The role of CD45+CD4+CD3− cells in lymphoid organ development. Immunol Rev 189:41–50Google Scholar
  29. Derbinski J, Kyewski B (2005) Linking signalling pathways, thymic stroma integrity and autoimmunity. Trends Immunol 26:503–506Google Scholar
  30. Derbinski J, Schulte A, Kyewski B, Klein L (2001) Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol 2:1032–1039Google Scholar
  31. 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 202:33–45Google Scholar
  32. 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 105:657–662Google Scholar
  33. 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 189:5519–5526Google Scholar
  34. 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 203:2727–2735Google Scholar
  35. 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 181:5225–5232Google Scholar
  36. 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 41:2544–2555Google Scholar
  37. 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 119:1396–1405Google Scholar
  38. 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 336:91–95Google Scholar
  39. Egerton M, Scollay R, Shortman K (1990) Kinetics of mature T-cell development in the thymus. Proc Natl Acad Sci U S A 87:2579–2582Google Scholar
  40. Farr AG, Anderson SK (1985) Epithelial heterogeneity in the murine thymus: fucose-specific lectins bind medullary epithelial cells. J Immunol 134:2971–2977Google Scholar
  41. Farr AG, Braddy SC (1989) Patterns of keratin expression in the murine thymus. Anat Rec 224:374–378Google Scholar
  42. 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 180:3183–3189Google Scholar
  43. Gabler J, Arnold J, Kyewski B (2007) Promiscuous gene expression and the developmental dynamics of medullary thymic epithelial cells. Eur J Immunol 37:3363–3372Google Scholar
  44. Gallegos AM, Bevan MJ (2004) Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J Exp Med 200:1039–1049Google Scholar
  45. Gillard GO, Farr AG (2005) Contrasting models of promiscuous gene expression by thymic epithelium. J Exp Med 202:15–19Google Scholar
  46. 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 178:3007–3015Google Scholar
  47. Godfrey DI, Izon DJ, Tucek CL, Wilson TJ, Boyd RL (1990) The phenotypic heterogeneity of mouse thymic stromal cells. Immunology 70:66–74Google Scholar
  48. Gray DH, Abramson J, Benoist C, Mathis D (2007) Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire. J Exp Med 204:2521–2528Google Scholar
  49. 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 108:3777–3785Google Scholar
  50. 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 206:1245–1252Google Scholar
  51. 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 36:438–450Google Scholar
  52. 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 8:304–311Google Scholar
  53. 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 30:1884–1893Google Scholar
  54. 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 29:438–450Google Scholar
  55. 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 11:512–519Google Scholar
  56. 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 21:267–277Google Scholar
  57. 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 180:3824–3832Google Scholar
  58. 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 29:451–463Google Scholar
  59. 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 162:5317–5326Google Scholar
  60. 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 6:31–39Google Scholar
  61. Jenkinson WE, Jenkinson EJ, Anderson G (2003) Differential requirement for mesenchyme in the proliferation and maturation of thymic epithelial progenitors. J Exp Med 198:325–332Google Scholar
  62. Jenkinson WE, Rossi SW, Parnell SM, Jenkinson EJ, Anderson G (2007) PDGFRalpha-expressing mesenchyme regulates thymus growth and the availability of intrathymic niches. Blood 109:954–960Google Scholar
  63. 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 2:301–306Google Scholar
  64. Josefowicz SZ, Lu LF, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564Google Scholar
  65. 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 172:2067–2075Google Scholar
  66. 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 78:263–270Google Scholar
  67. 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 10:176–184Google Scholar
  68. Kim JM, Rasmussen JP, Rudensky AY (2007) Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 8:191–197Google Scholar
  69. Kishimoto H, Sprent J (1997) Negative selection in the thymus includes semimature T cells. J Exp Med 185:263–271Google Scholar
  70. 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 32:188–193Google Scholar
  71. 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 95:11822–11827Google Scholar
  72. 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 169:2842–2845Google Scholar
  73. Koble C, Kyewski B (2009) The thymic medulla: a unique microenvironment for intercellular self-antigen transfer. J Exp Med 206:1505–1513Google Scholar
  74. 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 183:7682–7691Google Scholar
  75. 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 181:7014–7023Google Scholar
  76. 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 10:823–830Google Scholar
  77. Lee HM, Hsieh CS (2009) Rare development of Foxp3+ thymocytes in the CD4+CD8+ subset. J Immunol 183:2261–2266Google Scholar
  78. 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 208:383–394Google Scholar
  79. 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 104:18175–18180Google Scholar
  80. 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 206:607–622Google Scholar
  81. Lio CW, Hsieh CS (2008) A two-step process for thymic regulatory T cell development. Immunity 28:100–111Google Scholar
  82. Liston A, Rudensky AY (2007) Thymic development and peripheral homeostasis of regulatory T cells. Curr Opin Immunol 19:176–185Google Scholar
  83. Liston A, Lesage S, Wilson J, Peltonen L, Goodnow CC (2003) Aire regulates negative selection of organ-specific T cells. Nat Immunol 4:350–354Google Scholar
  84. 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 105:11903–11908Google Scholar
  85. 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 15:225–232Google Scholar
  86. Martins VC, Boehm T, Bleul CC (2008) Ltbetar signaling does not regulate Aire-dependent transcripts in medullary thymic epithelial cells. J Immunol 181:400–407Google Scholar
  87. Mathis D, Benoist C (2009) Aire. Annu Rev Immunol 27:287–312Google Scholar
  88. 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 427:355–360Google Scholar
  89. Matsumoto M (2011) Contrasting models for the roles of Aire in the differentiation program of epithelial cells in the thymic medulla. Eur J Immunol 41:12–17Google Scholar
  90. McCaughtry TM, Wilken MS, Hogquist KA (2007) Thymic emigration revisited. J Exp Med 204:2513–2520Google Scholar
  91. 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 208:1279–1289Google Scholar
  92. 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 19:745–753Google Scholar
  93. 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 102:10587–10592Google Scholar
  94. 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 180:5344–5351Google Scholar
  95. 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 17:393–398Google Scholar
  96. 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 372:103–107Google Scholar
  97. 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 272:886–889Google Scholar
  98. 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 26:401–408Google Scholar
  99. 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 207:963–971Google Scholar
  100. Nitta T, Ohigashi I, Nakagawa Y, Takahama Y (2011) Cytokine crosstalk for thymic medulla formation. Curr Opin Immunol 23:190–197Google Scholar
  101. 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:e1002348Google Scholar
  102. 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 57:373–382Google Scholar
  103. Odaka C, Morisada T, Oike Y, Suda T (2006) Distribution of lymphatic vessels in mouse thymus: immunofluorescence analysis. Cell Tissue Res 325:13–22Google Scholar
  104. 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 206:549–559Google Scholar
  105. Pacholczyk R, Ignatowicz H, Kraj P, Ignatowicz L (2006) Origin and T cell receptor diversity of Foxp3+CD4+CD25+ T cells. Immunity 25:249–259Google Scholar
  106. 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 3:175–179Google Scholar
  107. Petrie HT, Zuniga-Pflucker JC (2007) Zoned out: functional mapping of stromal signaling microenvironments in the thymus. Annu Rev Immunol 25:649–679Google Scholar
  108. 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 207:17–27Google Scholar
  109. 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 198:957–962Google Scholar
  110. 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 105:19869–19874Google Scholar
  111. Ramsdell F, Jenkins M, Dinh Q, Fowlkes BJ (1991) The majority of CD4+8− thymocytes are functionally immature. J Immunol 147:1779–1785Google Scholar
  112. 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 11:397–409Google Scholar
  113. 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 41:1278–1287Google Scholar
  114. 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 36:427–437Google Scholar
  115. Rodewald HR (2008) Thymus organogenesis. Annu Rev Immunol 26:355–388Google Scholar
  116. Rodewald HR, Paul S, Haller C, Bluethmann H, Blum C (2001) Thymus medulla consisting of epithelial islets each derived from a single progenitor. Nature 414:763–768Google Scholar
  117. 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 189:3831–3837Google Scholar
  118. Roman E, Shino H, Qin FX, Liu YJ (2010) Cutting edge: Hematopoietic-derived APCs select regulatory T cells in thymus. J Immunol 185:3819–3823Google Scholar
  119. Rossi SW, Jenkinson WE, Anderson G, Jenkinson EJ (2006) Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature 441:988–991Google Scholar
  120. 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 204:1267–1272Google Scholar
  121. Scollay R, Godfrey DI (1995) Thymic emigration: conveyor belts or lucky dips? Immunol Today 16:268–273, discussion 273–274Google Scholar
  122. 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 180:5384–5392Google Scholar
  123. 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 385:23–34Google Scholar
  124. Shakib S, Desanti GE, Jenkinson WE, Parnell SM, Jenkinson EJ, Anderson G (2009) Checkpoints in the development of thymic cortical epithelial cells. J Immunol 182:130–137Google Scholar
  125. 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 21:1657–1661Google Scholar
  126. Shores EW, Van Ewijk W, Singer A (1994) Maturation of medullary thymic epithelium requires thymocytes expressing fully assembled CD3-TCR complexes. Int Immunol 6:1393–1402Google Scholar
  127. 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 188:4801–4809Google Scholar
  128. Spence PJ, Green EA (2008) Foxp3+ regulatory T cells promiscuously accept thymic signals critical for their development. Proc Natl Acad Sci U S A 105:973–978Google Scholar
  129. 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 176:611–616Google Scholar
  130. 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 6:152–162Google Scholar
  131. Takahama Y (2006) Journey through the thymus: stromal guides for T-cell development and selection. Nat Rev Immunol 6:127–135Google Scholar
  132. 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:e25567Google Scholar
  133. Tough DF, Sprent J (1994) Turnover of naive- and memory-phenotype T cells. J Exp Med 179:1127–1135Google Scholar
  134. 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 200:493–505Google Scholar
  135. van Ewijk W, Shores EW, Singer A (1994) Crosstalk in the mouse thymus. Immunol Today 15:214–217Google Scholar
  136. Van Vliet E, Melis M, Van Ewijk W (1984) Monoclonal antibodies to stromal cell types of the mouse thymus. Eur J Immunol 14:524–529Google Scholar
  137. Venanzi ES, Gray DH, Benoist C, Mathis D (2007) Lymphotoxin pathway and Aire influences on thymic medullary epithelial cells are unconnected. J Immunol 179:5693–5700Google Scholar
  138. 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 152:2207–2213Google Scholar
  139. 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 3:19Google Scholar
  140. Weih F, Caamano J (2003) Regulation of secondary lymphoid organ development by the nuclear factor-kappaB signal transduction pathway. Immunol Rev 195:91–105Google Scholar
  141. 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 80:331–340Google Scholar
  142. Weinreich MA, Hogquist KA (2008) Thymic emigration: when and how T cells leave home. J Immunol 181:2265–2270Google Scholar
  143. Weinreich MA, Jameson SC, Hogquist KA (2011) Postselection thymocyte maturation and emigration are independent of IL-7 and ERK5. J Immunol 186:1343–1347Google Scholar
  144. 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 38:942–947Google Scholar
  145. 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 185:4769–4776Google Scholar
  146. 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 117:312–326Google Scholar
  147. 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 9:839–847Google Scholar
  148. 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 17:549–558Google Scholar
  149. 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 205:2827–2838Google Scholar
  150. Zachariah MA, Cyster JG (2010) Neural crest-derived pericytes promote egress of mature thymocytes at the corticomedullary junction. Science 328:1129–1135Google Scholar
  151. 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 179:8069–8075Google Scholar
  152. 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 165:1976–1983Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Graham Anderson
    • 1
  • Song Baik
    • 1
  • Jennifer E. Cowan
    • 1
  • Amanda M. Holland
    • 1
  • Nicholas I. McCarthy
    • 1
  • Kyoko Nakamura
    • 1
  • Sonia M. Parnell
    • 1
  • Andrea J. White
    • 1
  • Peter J. L. Lane
    • 1
  • Eric J. Jenkinson
    • 1
  • William E. Jenkinson
    • 1
  1. 1.MRC Centre for Immune Regulation, Institute for Biomedical Research, Medical School University of BirminghamEdgbaston, BirminghamUK

Personalised recommendations