Thymic Crosstalk: An Overview of the Complex Cellular Interactions That Control the Establishment of T-Cell Tolerance

  • Magali IrlaEmail author


The thymus ensures the generation of a self-tolerant T-cell repertoire capable of recognizing foreign antigens. The selection of the T-cell repertoire is dictated by the thymic microenvironment. Among stromal cells, medullary thymic epithelial cells (mTECs) play a pivotal role in this process through their unique ability to express thousands of tissue-restricted self-antigens. In turn, developing T cells control the pool and maturation of mTECs. This phenomenon of bidirectional interactions between TECs and thymocytes is referred to as thymic crosstalk. In this chapter, I discuss the discovery of thymic crosstalk and our current understanding of bidirectional interactions between mTECs and thymocytes. Finally, I summarize recent advances indicating that thymic crosstalk is not restricted to TECs and thymocytes but also occurs between TECs and dendritic cells, as well as B cells and thymocytes. This complex cellular interplay is essential for efficient T-cell selection.


Thymic crosstalk Thymic medulla Medullary thymic epithelial cells Dendritic cells B cells Negative selection Central tolerance 



Autoimmune Regulator


Conventional dendritic cells


Cortical thymic epithelial cells


Double negative cells


Double positive cells


Fez family zinc-finger 2


Lymphotoxin α


Lymphotoxin beta receptor


Medullary thymic epithelial cells


Natural regulatory T cells




Plasmacytoid dendritic cells


Receptor Activator of Nuclear factor Kappa-B Ligand


Single positive cells


Thymic epithelial cells


T-cell receptor


Tissue-restricted self-antigens





I gratefully thank Prof. Arnauld Sergé (Centre de Recherche en Cancérologie de Marseille) and Teshika Jayewickreme (Harvard University) for constructive comments. This work was supported by the Marie Curie Actions (Career Integration Grants, CIG_SIGnEPI4Tol_618541 to MI), institutional grants from Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique and Aix-Marseille Université.


  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(10):3373–3379PubMedGoogle Scholar
  2. Akirav EM, Xu Y, Ruddle NH (2011) Resident B cells regulate thymic expression of myelin oligodendrocyte glycoprotein. J Neuroimmunol 235(1-2):33–39. 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(3):423–437PubMedCrossRefGoogle Scholar
  4. 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(5597):1395–1401PubMedCrossRefGoogle Scholar
  5. 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(5):3053–3063. Scholar
  6. 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(5):757–769PubMedPubMedCentralCrossRefGoogle Scholar
  7. Bonasio R, Scimone ML, Schaerli P, Grabie N, Lichtman AH, von Andrian UH (2006) Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nat Immunol 7(10):1092–1100. Scholar
  8. Deng X, Xu M, Yuan C, Yin L, Chen X, Zhou X, Li G, Fu Y, Feghali-Bostwick CA, Pang L (2013) Transcriptional regulation of increased CCL2 expression in pulmonary fibrosis involves nuclear factor-kappaB and activator protein-1. Int J Biochem Cell Biol 45(7):1366–1376. Scholar
  9. Derbinski J, Kyewski B (2010) How thymic antigen presenting cells sample the body’s self-antigens. Curr Opin Immunol 22(5):592–600. Scholar
  10. Derbinski J, Schulte A, Kyewski B, Klein L (2001) Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol 2(11):1032–1039PubMedCrossRefGoogle Scholar
  11. 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(2):657–662. Scholar
  12. 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(12):5519–5526. Scholar
  13. van Ewijk W, Shores EW, Singer A (1994) Crosstalk in the mouse thymus. Immunol Today 15(5):214–217PubMedCrossRefGoogle Scholar
  14. van Ewijk W, Hollander G, Terhorst C, Wang B (2000) Stepwise development of thymic microenvironments in vivo is regulated by thymocyte subsets. Development 127(8):1583–1591PubMedGoogle Scholar
  15. Farr AG, Anderson SK (1985) Epithelial heterogeneity in the murine thymus: fucose-specific lectins bind medullary epithelial cells. J Immunol 134(5):2971–2977PubMedGoogle Scholar
  16. Ferrero I, Anjuere F, Martin P, Martinez del Hoyo G, Fraga ML, Wright N, Varona R, Marquez G, Ardavin C (1999) Functional and phenotypic analysis of thymic B cells: role in the induction of T cell negative selection. Eur J Immunol 29(5):1598–1609.<1598::AID-IMMU1598>3.0.CO;2-OPubMedCrossRefGoogle Scholar
  17. Fink PJ, Bevan MJ (1978) H-2 antigens of the thymus determine lymphocyte specificity. J Exp Med 148(3):766–775PubMedPubMedCentralCrossRefGoogle Scholar
  18. Frommer F, Waisman A (2010) B cells participate in thymic negative selection of murine auto-reactive CD4+ T cells. PLoS One 5(10):e15372. Scholar
  19. Fujihara C, Williams JA, Watanabe M, Jeon H, Sharrow SO, Hodes RJ (2014) T cell-B cell thymic cross-talk: maintenance and function of thymic B cells requires cognate CD40-CD40 ligand interaction. J Immunol 193(11):5534–5544. Scholar
  20. Gabler J, Arnold J, Kyewski B (2007) Promiscuous gene expression and the developmental dynamics of medullary thymic epithelial cells. Eur J Immunol 37(12):3363–3372PubMedCrossRefGoogle Scholar
  21. Gallegos AM, Bevan MJ (2004) Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J Exp Med 200(8):1039–1049PubMedPubMedCentralCrossRefGoogle Scholar
  22. Gies V, Guffroy A, Danion F, Billaud P, Keime C, Fauny JD, Susini S, Soley A, Martin T, Pasquali JL, Gros F, Andre-Schmutz I, Soulas-Sprauel P, Korganow AS (2017) B cells differentiate in human thymus and express AIRE. J Allergy Clin Immunol 139(3):1049–1052 e1012. Scholar
  23. Godfrey DI, Izon DJ, Tucek CL, Wilson TJ, Boyd RL (1990) The phenotypic heterogeneity of mouse thymic stromal cells. Immunology 70(1):66–74PubMedPubMedCentralGoogle Scholar
  24. Godfrey DI, Kennedy J, Suda T, Zlotnik A (1993) A developmental pathway involving four phenotypically and functionally distinct subsets of CD3-CD4-CD8- triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. J Immunol 150(10):4244–4252PubMedGoogle Scholar
  25. 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(12):3777–3785PubMedCrossRefGoogle Scholar
  26. Gray D, Abramson J, Benoist C, Mathis D (2007) Proliferative arrest and rapid turnover of thymic epithelial cells expressing aire. J Exp Med 204(11):2521–2528PubMedPubMedCentralCrossRefGoogle Scholar
  27. 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(6):1245–1252. Scholar
  28. 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(3):438–450. Scholar
  29. 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(3):438–450PubMedCrossRefGoogle Scholar
  30. Hollander GA, Wang B, Nichogiannopoulou A, Platenburg PP, van Ewijk W, Burakoff SJ, Gutierrez-Ramos JC, Terhorst C (1995) Developmental control point in induction of thymic cortex regulated by a subpopulation of prothymocytes. Nature 373(6512):350–353PubMedCrossRefGoogle Scholar
  31. 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(3):451–463PubMedCrossRefGoogle Scholar
  32. Irla M, Hollander G, Reith W (2010) Control of central self-tolerance induction by autoreactive CD4+ thymocytes. Trends Immunol 31(2):71–79. Scholar
  33. Irla M, Guerri L, Guenot J, Serge A, Lantz O, Liston A, Imhof BA, Palmer E, Reith W (2012) Antigen recognition by autoreactive cd4(+) thymocytes drives homeostasis of the thymic medulla. PLoS One 7(12):e52591. Scholar
  34. Irla M, Guenot J, Sealy G, Reith W, Imhof BA, Serge A (2013) Three-dimensional visualization of the mouse thymus organization in health and immunodeficiency. J Immunol 190(2):586–596. Scholar
  35. Josefowicz SZ, Lu LF, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564. Scholar
  36. 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(4):2067–2075PubMedCrossRefGoogle Scholar
  37. 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(2):263–270PubMedPubMedCentralGoogle Scholar
  38. Khan IS, Mouchess ML, Zhu ML, Conley B, Fasano KJ, Hou Y, Fong L, Su MA, Anderson MS (2014) Enhancement of an anti-tumor immune response by transient blockade of central T cell tolerance. J Exp Med 211(5):761–768. Scholar
  39. Klein L, Hinterberger M, Wirnsberger G, Kyewski B (2009) Antigen presentation in the thymus for positive selection and central tolerance induction. Nat Rev Immunol 9(12):833–844. Scholar
  40. Klein L, Kyewski B, Allen PM, Hogquist KA (2014) Positive and negative selection of the T cell repertoire: what thymocytes see (and don’t see). Nat Rev Immunol 14(6):377–391. Scholar
  41. Kleindienst P, Chretien I, Winkler T, Brocker T (2000) Functional comparison of thymic B cells and dendritic cells in vivo. Blood 95(8):2610–2616PubMedCrossRefGoogle Scholar
  42. 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(20):11822–11827PubMedPubMedCentralCrossRefGoogle Scholar
  43. Koble C, Kyewski B (2009) The thymic medulla: a unique microenvironment for intercellular self-antigen transfer. J Exp Med 206(7):1505–1513PubMedPubMedCentralCrossRefGoogle Scholar
  44. Kurts C, Heath WR, Carbone FR, Allison J, Miller JF, Kosaka H (1996) Constitutive class I-restricted exogenous presentation of self antigens in vivo. J Exp Med 184(3):923–930PubMedCrossRefGoogle Scholar
  45. Kyewski BA, Schirrmacher V, Allison JP (1989) Antibodies against the T cell receptor/CD3 complex interfere with distinct intra-thymic cell-cell interactions in vivo: correlation with arrest of T cell differentiation. Eur J Immunol 19(5):857–863. Scholar
  46. 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(2):383–394. Scholar
  47. Lind EF, Prockop SE, Porritt HE, Petrie HT (2001) Mapping precursor movement through the postnatal thymus reveals specific microenvironments supporting defined stages of early lymphoid development. J Exp Med 194(2):127–134PubMedPubMedCentralCrossRefGoogle Scholar
  48. Lkhagvasuren E, Sakata M, Ohigashi I, Takahama Y (2013) Lymphotoxin beta receptor regulates the development of CCL21-expressing subset of postnatal medullary thymic epithelial cells. J Immunol 190(10):5110–5117. Scholar
  49. Lopes N, Serge A, Ferrier P, Irla M (2015) Thymic crosstalk coordinates medulla organization and T-cell tolerance induction. Front Immunol 6:365. Scholar
  50. Lopes N, Vachon H, Marie J, Irla M (2017) Administration of RANKL boosts thymic regeneration upon bone marrow transplantation. EMBO Mol Med 9:835. Scholar
  51. Lopes N, Charaix J, Cedile O, Serge A, Irla M (2018) Lymphotoxin alpha fine-tunes T cell clonal deletion by regulating thymic entry of antigen-presenting cells. Nat Commun 9(1):1262. Scholar
  52. Meredith M, Zemmour D, Mathis D, Benoist C (2015) Aire controls gene expression in the thymic epithelium with ordered stochasticity. Nat Immunol 16(9):942–949. Scholar
  53. Metzger TC, Khan IS, Gardner JM, Mouchess ML, Johannes KP, Krawisz AK, Skrzypczynska KM, Anderson MS (2013) Lineage tracing and cell ablation identify a post-aire-expressing thymic epithelial cell population. Cell Rep 5(1):166–179PubMedCrossRefGoogle Scholar
  54. Miller JF (1961) Immunological function of the thymus. Lancet 2(7205):748–749PubMedPubMedCentralCrossRefGoogle Scholar
  55. Miller JF (2002) The discovery of thymus function and of thymus-derived lymphocytes. Immunol Rev 185:7–14PubMedCrossRefGoogle Scholar
  56. Mouri Y, Yano M, Shinzawa M, Shimo Y, Hirota F, Nishikawa Y, Nii T, Kiyonari H, Abe T, Uehara H, Izumi K, Tamada K, Chen L, Penninger JM, Inoue JI, Akiyama T, Matsumoto M (2011) Lymphotoxin signal promotes thymic organogenesis by eliciting RANK expression in the embryonic thymic stroma. J Immunol 186:5047PubMedCrossRefGoogle Scholar
  57. Mouri Y, Nishijima H, Kawano H, Hirota F, Sakaguchi N, Morimoto J, Matsumoto M (2014) NF-kappaB-inducing kinase in thymic stroma establishes central tolerance by orchestrating cross-talk with not only thymocytes but also dendritic cells. J Immunol 193(9):4356–4367. Scholar
  58. Nasreen M, Ueno T, Saito F, Takahama Y (2003) In vivo treatment of class II MHC-deficient mice with anti-TCR antibody restores the generation of circulating CD4 T cells and optimal architecture of thymic medulla. J Immunol 171(7):3394–3400PubMedCrossRefGoogle Scholar
  59. Negishi I, Motoyama N, Nakayama K, Nakayama K, Senju S, Hatakeyama S, Zhang Q, Chan AC, Loh DY (1995) Essential role for ZAP-70 in both positive and negative selection of thymocytes. Nature 376(6539):435–438PubMedCrossRefGoogle Scholar
  60. 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(5):963–971. Scholar
  61. 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(3):549–559. Scholar
  62. Palmer E (2003) Negative selection--clearing out the bad apples from the T-cell repertoire. Nat Rev Immunol 3(5):383–391. Scholar
  63. 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(3):175–179PubMedPubMedCentralCrossRefGoogle Scholar
  64. Passos GA, Mendes-da-Cruz DA, Oliveira EH (2015) The thymic orchestration involving aire, miRNAs, and cell-cell interactions during the induction of central tolerance. Front Immunol 6:352. Scholar
  65. Perera J, Meng L, Meng F, Huang H (2013) Autoreactive thymic B cells are efficient antigen-presenting cells of cognate self-antigens for T cell negative selection. Proc Natl Acad Sci U S A 110(42):17011–17016. Scholar
  66. Perniola R (2018) Twenty years of AIRE. Front Immunol 9:98. Scholar
  67. Petrie HT, Zuniga-Pflucker JC (2007) Zoned out: functional mapping of stromal signaling microenvironments in the thymus. Annu Rev Immunol 25:649–679PubMedCrossRefGoogle Scholar
  68. Ping D, Jones PL, Boss JM (1996) TNF regulates the in vivo occupancy of both distal and proximal regulatory regions of the MCP-1/JE gene. Immunity 4(5):455–469PubMedCrossRefGoogle Scholar
  69. 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(6):957–962. Scholar
  70. 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(50):19869–19874PubMedPubMedCentralCrossRefGoogle Scholar
  71. 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(6865):763–768PubMedCrossRefGoogle Scholar
  72. 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(6):1267–1272PubMedPubMedCentralCrossRefGoogle Scholar
  73. Saade M, Irla M, Yammine M, Boulanger N, Victorero G, Vincentelli R, Penninger JM, Hollander GA, Chauvet S, Nguyen C (2010) Spatial (Tbata) expression in mature medullary thymic epithelial cells. Eur J Immunol 40(2):530–538. Scholar
  74. Sansom SN, Shikama-Dorn N, Zhanybekova S, Nusspaumer G, Macaulay IC, Deadman ME, Heger A, Ponting CP, Hollander GA (2014) Population and single-cell genomics reveal the aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia. Genome Res 24:1918. Scholar
  75. 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(8):5384–5392PubMedPubMedCentralCrossRefGoogle Scholar
  76. Senelar R, Escola MJ, Escola R, Serrou B, Serre A (1976) Relationship between Hassall’s corpuscles and thymocytes fate in guinea-pig foetus. Biomedicine 24(2):112–122PubMedGoogle Scholar
  77. Serge A, Bailly AL, Aurrand-Lions M, Imhof BA, Irla M (2015) For3D: full organ reconstruction in 3D, an automatized tool for deciphering the complexity of lymphoid organs. J Immunol Methods 424:32. Scholar
  78. 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(7):1657–1661PubMedCrossRefGoogle Scholar
  79. Shores EW, Van Ewijk W, Singer A (1994) Maturation of medullary thymic epithelium requires thymocytes expressing fully assembled CD3-TCR complexes. Int Immunol 6(9):1393–1402PubMedCrossRefGoogle Scholar
  80. Spidale NA, Wang B, Tisch R (2014) Cutting edge: antigen-specific thymocyte feedback regulates homeostatic thymic conventional dendritic cell maturation. J Immunol 193(1):21–25. Scholar
  81. 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(2):611–616PubMedCrossRefGoogle Scholar
  82. Takaba H, Morishita Y, Tomofuji Y, Danks L, Nitta T, Komatsu N, Kodama T, Takayanagi H (2015) Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. Cell 163(4):975–987. Scholar
  83. Takahama Y (2006) Journey through the thymus: stromal guides for T-cell development and selection. Nat Rev Immunol 6(2):127–135PubMedCrossRefGoogle Scholar
  84. Takahama Y, Nitta T, Mat Ripen A, Nitta S, Murata S, Tanaka K (2010) Role of thymic cortex-specific self-peptides in positive selection of T cells. Semin Immunol 22(5):287–293. Scholar
  85. Ueda A, Okuda K, Ohno S, Shirai A, Igarashi T, Matsunaga K, Fukushima J, Kawamoto S, Ishigatsubo Y, Okubo T (1994) NF-kappa B and Sp1 regulate transcription of the human monocyte chemoattractant protein-1 gene. J Immunol 153(5):2052–2063PubMedGoogle Scholar
  86. Van Vliet E, Melis M, Van Ewijk W (1984) Monoclonal antibodies to stromal cell types of the mouse thymus. Eur J Immunol 14(6):524–529. Scholar
  87. Venanzi ES, Gray DH, Benoist C, Mathis D (2007) Lymphotoxin pathway and aire influences on thymic medullary epithelial cells are unconnected. J Immunol 179(9):5693–5700PubMedCrossRefGoogle Scholar
  88. Waldburger JM, Suter T, Fontana A, Acha-Orbea H, Reith W (2001) Selective abrogation of major histocompatibility complex class II expression on extrahematopoietic cells in mice lacking promoter IV of the class II transactivator gene. J Exp Med 194(4):393–406PubMedPubMedCentralCrossRefGoogle Scholar
  89. Walters SN, Webster KE, Daley S, Grey ST (2014) A role for intrathymic B cells in the generation of natural regulatory T cells. J Immunol 193(1):170–176. Scholar
  90. Wang B, Biron C, She J, Higgins K, Sunshine MJ, Lacy E, Lonberg N, Terhorst C (1994) A block in both early T lymphocyte and natural killer cell development in transgenic mice with high-copy numbers of the human CD3E gene. Proc Natl Acad Sci U S A 91(20):9402–9406PubMedPubMedCentralCrossRefGoogle Scholar
  91. Watanabe N, Wang YH, Lee HK, Ito T, Cao W, Liu YJ (2005) Hassall’s corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature 436(7054):1181–1185. Scholar
  92. 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(8):4769–4776. Scholar
  93. Williams JA, Zhang J, Jeon H, Nitta T, Ohigashi I, Klug D, Kruhlak MJ, Choudhury B, Sharrow SO, Granger L, Adams A, Eckhaus MA, Jenkinson SR, Richie ER, Gress RE, Takahama Y, Hodes RJ (2014) Thymic medullary epithelium and thymocyte self-tolerance require cooperation between CD28-CD80/86 and CD40-CD40L costimulatory pathways. J Immunol 192(2):630–640. Scholar
  94. Wu L, Shortman K (2005) Heterogeneity of thymic dendritic cells. Semin Immunol 17(4):304–312. Scholar
  95. Xing C, Ma N, Xiao H, Wang X, Zheng M, Han G, Chen G, Hou C, Shen B, Li Y, Wang R (2015) Critical role for thymic CD19+CD5+CD1dhiIL-10+ regulatory B cells in immune homeostasis. J Leukoc Biol 97(3):547–556. Scholar
  96. Yamano T, Nedjic J, Hinterberger M, Steinert M, Koser S, Pinto S, Gerdes N, Lutgens E, Ishimaru N, Busslinger M, Brors B, Kyewski B, Klein L (2015) Thymic B cells are licensed to present self antigens for central T cell tolerance induction. Immunity 42:1048. Scholar
  97. Yang S, Fujikado N, Kolodin D, Benoist C, Mathis D (2015) Immune tolerance. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance. Science 348(6234):589–594. Scholar
  98. 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(12):2827–2838. Scholar
  99. Zhu M, Fu YX (2008) Coordinating development of medullary thymic epithelial cells. Immunity 29(3):386–388PubMedCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Centre d’Immunologie de Marseille-Luminy (CIML), INSERM U1104, CNRS UMR7280Aix-Marseille Université UM2Marseille Cedex 09France

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