Skip to main content
SpringerLink
Log in

The Ins and Outs of Thymic Epithelial Cell Differentiation and Function

  • Chapter
  • First Online:
Thymus Transcriptome and Cell Biology

Abstract

The thymus is the organ dedicated to the generation of T cells, which are key effector cells in immune clearance of pathogens and tumours. However, T cells can also react to our own tissues or turn into cancer cells, such as in the case of autoimmunity and leukaemia, respectively. Therefore, the development and selection of T cells is a tightly regulated process that proceeds within inductive thymic microenvironments formed by cortical (c) and medullary (m) thymic epithelial cells (TECs). Herein, we critically summarize our current knowledge on the molecular principles underlying the development and diversification of TEC compartments and highlight their specialized roles in specific stages of T cell development. Knowledge in this area is of fundamental and clinical relevance to understand how the immune system reaches the equilibrium between immunity and tolerance induction.

Given the importance of the thymus for T cell development and general immune function, it is hard to conceive of the time when the origin of lymphocytes – where they developed and their complexity – was completely unknown. I was fortunate to have found myself situated at the right time and place to evaluate the function of the thymus, which at the time was considered superfluous.

Jacques F. A. P. Miller (2006).

Mitsuru Matsumoto and Nuno L. Alves supervised equally to this work.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abramson J, Anderson G (2017) Thymic epithelial cells. Annu Rev Immunol 35:85–118

    Article  CAS  PubMed  Google Scholar 

  • Abramson J, Giraud M, Benoist C, Mathis D (2010) Aire’s partners in the molecular control of immunological tolerance. Cell 140(1):123–135

    Article  CAS  PubMed  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(5719):248–251

    Article  CAS  PubMed  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(3):423–437

    Article  CAS  PubMed  Google Scholar 

  • Alves NL, Huntington ND, Rodewald HR, Di Santo JP (2009a) Thymic epithelial cells: the multi-tasking framework of the T cell “cradle”. Trends Immunol 30(10):468–474

    Article  CAS  PubMed  Google Scholar 

  • Alves NL, Richard-Le Goff O, Huntington ND, Sousa AP, Ribeiro VS, Bordack A, Vives FL, Peduto L, Chidgey A, Cumano A, Boyd R, Eberl G, Di Santo JP (2009b) Characterization of the thymic IL-7 niche in vivo. Proc Natl Acad Sci U S A 106(5):1512–1517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alves NL, Huntington ND, Mention JJ, Richard-Le Goff O, Di Santo JP (2010) Cutting edge: a thymocyte-thymic epithelial cell cross-talk dynamically regulates intrathymic IL-7 expression in vivo. J Immunol 184(11):5949–5953

    Article  CAS  PubMed  Google Scholar 

  • Alves NL, Takahama Y, Ohigashi I, Ribeiro AR, Baik S, Anderson G, Jenkinson WE (2014) Serial progression of cortical and medullary thymic epithelial microenvironments. Eur J Immunol 44(1):16–22

    Article  CAS  PubMed  Google Scholar 

  • Anderson G, Takahama Y (2012) Thymic epithelial cells: working class heroes for T cell development and repertoire selection. Trends Immunol 33(6):256–263

    Article  CAS  PubMed  Google Scholar 

  • Anderson G, Jenkinson EJ, Moore NC, Owen JJ (1993) MHC class II-positive epithelium and mesenchyme cells are both required for T-cell development in the thymus. Nature 362(6415):70–73

    Article  CAS  PubMed  Google Scholar 

  • Anderson G, Anderson KL, Tchilian EZ, Owen JJ, Jenkinson EJ (1997) Fibroblast dependency during early thymocyte development maps to the CD25+ CD44+ stage and involves interactions with fibroblast matrix molecules. Eur J Immunol 27(5):1200–1206

    Article  CAS  PubMed  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(5597):1395–1401

    Article  CAS  PubMed  Google Scholar 

  • Anderson MS, Venanzi ES, Chen Z, Berzins SP, Benoist C, Mathis D (2005) The cellular mechanism of aire control of T cell tolerance. Immunity 23(2):227–239

    Article  CAS  PubMed  Google Scholar 

  • Anderson G, Lane PJ, Jenkinson EJ (2007) Generating intrathymic microenvironments to establish T-cell tolerance. Nat Rev Immunol 7(12):954–963

    Article  CAS  PubMed  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(4):351–358

    Article  CAS  PubMed  Google Scholar 

  • Aw D, Silva AB, Maddick M, von Zglinicki T, Palmer DB (2008) Architectural changes in the thymus of aging mice. Aging Cell 7(2):158–167

    Article  CAS  PubMed  Google Scholar 

  • Aw D, Taylor-Brown F, Cooper K, Palmer DB (2009) Phenotypical and morphological changes in the thymic microenvironment from ageing mice. Biogerontology 10(3):311–322

    Article  PubMed  Google Scholar 

  • Baik S, Jenkinson EJ, Lane PJ, Anderson G, Jenkinson WE (2013) Generation of both cortical and aire(+) medullary thymic epithelial compartments from CD205(+) progenitors. Eur J Immunol 43(3):589–594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baik S, Sekai M, Hamazaki Y, Jenkinson WE, Anderson G (2016) Relb acts downstream of medullary thymic epithelial stem cells and is essential for the emergence of RANK(+) medullary epithelial progenitors. Eur J Immunol 46(4):857–862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Balciunaite G, Keller MP, Balciunaite E, Piali L, Zuklys S, Mathieu YD, Gill J, Boyd R, Sussman DJ, Hollander GA (2002) Wnt glycoproteins regulate the expression of FoxN1, the gene defective in nude mice. Nat Immunol 3(11):1102–1108

    Article  CAS  PubMed  Google Scholar 

  • Banwell CM, Partington KM, Jenkinson EJ, Anderson G (2000) Studies on the role of IL-7 presentation by mesenchymal fibroblasts during early thymocyte development. Eur J Immunol 30(8):2125–2129

    Article  CAS  PubMed  Google Scholar 

  • Barr IG, Khalid BA, Pearce P, Toh BH, Bartlett PF, Scollay RG, Funder JW (1982) Dihydrotestosterone and estradiol deplete corticosensitive thymocytes lacking in receptors for these hormones. J Immunol 128(6):2825–2828

    CAS  PubMed  Google Scholar 

  • Bennett AR, Farley A, Blair NF, Gordon J, Sharp L, Blackburn CC (2002) Identification and characterization of thymic epithelial progenitor cells. Immunity 16(6):803–814

    Article  CAS  PubMed  Google Scholar 

  • Blackburn CC, Manley NR (2004) Developing a new paradigm for thymus organogenesis. Nat Rev Immunol 4(4):278–289

    Article  CAS  PubMed  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(12):5742–5746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bleul CC, Boehm T (2000) Chemokines define distinct microenvironments in the developing thymus. Eur J Immunol 30(12):3371–3379

    Article  CAS  PubMed  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(7096):992–996

    Article  CAS  PubMed  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 LT{beta}R. J Exp Med 198(5):757–769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boyd RL, Tucek CL, Godfrey DI, Izon DJ, Wilson TJ, Davidson NJ, Bean AG, Ladyman HM, Ritter MA, Hugo P (1993) The thymic microenvironment. Immunol Today 14(9):445–459

    Article  CAS  PubMed  Google Scholar 

  • Bredenkamp N, Nowell CS, Blackburn CC (2014a) Regeneration of the aged thymus by a single transcription factor. Development 141(8):1627–1637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bredenkamp N, Ulyanchenko S, O’Neill KE, Manley NR, Vaidya HJ, Blackburn CC (2014b) An organized and functional thymus generated from FOXN1-reprogrammed fibroblasts. Nat Cell Biol 16(9):902–908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buono M, Facchini R, Matsuoka S, Thongjuea S, Waithe D, Luis TC, Giustacchini A, Besmer P, Mead AJ, Jacobsen SE, Nerlov C (2016) A dynamic niche provides Kit ligand in a stage-specific manner to the earliest thymocyte progenitors. Nat Cell Biol 18(2):157–167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Calderon L, Boehm T (2011) Three chemokine receptors cooperatively regulate homing of hematopoietic progenitors to the embryonic mouse thymus. Proc Natl Acad Sci U S A 108(18):7517–7522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen L, Xiao S, Manley NR (2009) Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner. Blood 113(3):567–574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chinn IK, Blackburn CC, Manley NR, Sempowski GD (2012) Changes in primary lymphoid organs with aging. Semin Immunol 24(5):309–320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chuprin A, Avin A, Goldfarb Y, Herzig Y, Levi B, Jacob A, Sela A, Katz S, Grossman M, Guyon C, Rathaus M, Cohen HY, Sagi I, Giraud M, McBurney MW, Husebye ES, Abramson J (2015) The deacetylase Sirt1 is an essential regulator of aire-mediated induction of central immunological tolerance. Nat Immunol 16(7):737–745

    Article  CAS  PubMed  Google Scholar 

  • Ciofani M, Zuniga-Pflucker JC (2007) The thymus as an inductive site for T lymphopoiesis. Annu Rev Cell Dev Biol 23:463–493

    Article  CAS  PubMed  Google Scholar 

  • Consortium TF-GA (1997) An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet 17(4):399–403

    Article  Google Scholar 

  • Corbeaux T, Hess I, Swann JB, Kanzler B, Haas-Assenbaum A, Boehm T (2010) Thymopoiesis in mice depends on a Foxn1-positive thymic epithelial cell lineage. Proc Natl Acad Sci U S A 107(38):16613–16618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Togni P, Goellner J, Ruddle NH, Streeter PR, Fick A, Mariathasan S, Smith SC, Carlson R, Shornick LP, Strauss-Schoenberger J et al (1994) Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 264(5159):703–707

    Article  PubMed  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(11):1032–1039

    Article  CAS  PubMed  Google Scholar 

  • Edelson BT, Kc W, Juang R, Kohyama M, Benoit LA, Klekotka PA, Moon C, Albring JC, Ise W, Michael DG, Bhattacharya D, Stappenbeck TS, Holtzman MJ, Sung SS, Murphy TL, Hildner K, Murphy KM (2010) Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8alpha+ conventional dendritic cells. J Exp Med 207(4):823–836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Esashi E, Sekiguchi T, Ito H, Koyasu S, Miyajima A (2003) Cutting edge: a possible role for CD4+ thymic macrophages as professional scavengers of apoptotic thymocytes. J Immunol 171(6):2773–2777

    Article  CAS  PubMed  Google Scholar 

  • van Ewijk W, Shores EW, Singer A (1994) Crosstalk in the mouse thymus. Immunol Today 15(5):214–217

    Article  PubMed  Google Scholar 

  • 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):1583–1591

    PubMed  Google Scholar 

  • Farr AG, Anderson SK (1985) Epithelial heterogeneity in the murine thymus: fucose-specific lectins bind medullary epithelial cells. J Immunol 134(5):2971–2977

    CAS  PubMed  Google Scholar 

  • Fiorini E, Ferrero I, Merck E, Favre S, Pierres M, Luther SA, MacDonald HR (2008) Cutting edge: thymic crosstalk regulates delta-like 4 expression on cortical epithelial cells. J Immunol 181(12):8199–8203

    Article  CAS  PubMed  Google Scholar 

  • Garfin PM, Min D, Bryson JL, Serwold T, Edris B, Blackburn CC, Richie ER, Weinberg KI, Manley NR, Sage J, Viatour P (2013) Inactivation of the RB family prevents thymus involution and promotes thymic function by direct control of Foxn1 expression. J Exp Med 210(6):1087–1097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gill J, Malin M, Hollander GA, Boyd R (2002) Generation of a complete thymic microenvironment by MTS24(+) thymic epithelial cells. Nat Immunol 3(7):635–642

    Article  CAS  PubMed  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(5):3007–3015

    Article  CAS  PubMed  Google Scholar 

  • Godfrey DI, Izon DJ, Tucek CL, Wilson TJ, Boyd RL (1990) The phenotypic heterogeneity of mouse thymic stromal cells. Immunology 70(1):66–74

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gommeaux J, Gregoire C, Nguessan P, Richelme M, Malissen M, Guerder S, Malissen B, Carrier A (2009) Thymus-specific serine protease regulates positive selection of a subset of CD4+ thymocytes. Eur J Immunol 39(4):956–964

    Article  CAS  PubMed  Google Scholar 

  • Gordon J, Manley NR (2011) Mechanisms of thymus organogenesis and morphogenesis. Development 138(18):3865–3878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gordon J, Bennett AR, Blackburn CC, Manley NR (2001) Gcm2 and Foxn1 mark early parathyroid- and thymus-specific domains in the developing third pharyngeal pouch. Mech Dev 103(1-2):141–143

    Article  CAS  PubMed  Google Scholar 

  • Gossens K, Naus S, Corbel SY, Lin S, Rossi FM, Kast J, Ziltener HJ (2009) Thymic progenitor homing and lymphocyte homeostasis are linked via S1P-controlled expression of thymic P-selectin/CCL25. J Exp Med 206(4):761–778

    Article  CAS  PubMed  PubMed Central  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(12):3777–3785

    Article  CAS  PubMed  Google Scholar 

  • Greenstein BD, Fitzpatrick FT, Kendall MD, Wheeler MJ (1987) Regeneration of the thymus in old male rats treated with a stable analogue of LHRH. J Endocrinol 112(3):345–350

    Article  CAS  PubMed  Google Scholar 

  • Grossman CJ (1985) Interactions between the gonadal steroids and the immune system. Science 227(4684):257–261

    Article  CAS  PubMed  Google Scholar 

  • Gui J, Zhu X, Dohkan J, Cheng L, Barnes PF, Su DM (2007) The aged thymus shows normal recruitment of lymphohematopoietic progenitors but has defects in thymic epithelial cells. Int Immunol 19(10):1201–1211

    Article  CAS  PubMed  Google Scholar 

  • Hadden JW (1998) Thymic endocrinology. Ann N Y Acad Sci 840:352–358

    Article  CAS  PubMed  Google Scholar 

  • Hale JS, Boursalian TE, Turk GL, Fink PJ (2006) Thymic output in aged mice. Proc Natl Acad Sci U S A 103(22):8447–8452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haljasorg U, Dooley J, Laan M, Kisand K, Bichele R, Liston A, Peterson P (2017) Irf4 expression in thymic epithelium is critical for thymic regulatory T cell homeostasis. J Immunol 198(5):1952–1960

    Article  CAS  PubMed  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(3):304–311

    Article  CAS  PubMed  Google Scholar 

  • Hamazaki Y, Sekai M, Minato N (2016) Medullary thymic epithelial stem cells: role in thymic epithelial cell maintenance and thymic involution. Immunol Rev 271(1):38–55

    Article  CAS  PubMed  Google Scholar 

  • Hanahan D (1998) Peripheral-antigen-expressing cells in thymic medulla: factors in self-tolerance and autoimmunity. Curr Opin Immunol 10(6):656–662

    Article  CAS  PubMed  Google Scholar 

  • Heng TS, Goldberg GL, Gray DH, Sutherland JS, Chidgey AP, Boyd RL (2005) Effects of castration on thymocyte development in two different models of thymic involution. J Immunol 175(5):2982–2993

    Article  CAS  PubMed  Google Scholar 

  • Hince M, Sakkal S, Vlahos K, Dudakov J, Boyd R, Chidgey A (2008) The role of sex steroids and gonadectomy in the control of thymic involution. Cell Immunol 252(1-2):122–138

    Article  CAS  PubMed  Google Scholar 

  • Hofmann J, Mair F, Greter M, Schmidt-Supprian M, Becher B (2011) NIK signaling in dendritic cells but not in T cells is required for the development of effector T cells and cell-mediated immune responses. J Exp Med 208(9):1917–1929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hubert FX, Kinkel SA, Davey GM, Phipson B, Mueller SN, Liston A, Proietto AI, Cannon PZ, Forehan S, Smyth GK, Wu L, Goodnow CC, Carbone FR, Scott HS, Heath WR (2011) Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance. Blood 118(9):2462–2472

    Article  CAS  PubMed  Google Scholar 

  • Jain R, Sheridan JM, Policheni A, Heinlein M, Gandolfo LC, Dewson G, Smyth GK, Sansom SN, Fu NY, Visvader JE, Hollander GA, Strasser A, Gray DHD (2017) A critical epithelial survival axis regulated by MCL-1 maintains thymic function in mice. Blood 130(23):2504–2515

    Article  CAS  PubMed  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(3):954–960

    Article  CAS  PubMed  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-kappaB-inducing kinase establishes self-tolerance in a thymic stroma-dependent manner. J Immunol 172(4):2067–2075

    Article  CAS  PubMed  Google Scholar 

  • Kawano H, Nishijima H, Morimoto J, Hirota F, Morita R, Mouri Y, Nishioka Y, Matsumoto M (2015) Aire expression is inherent to most medullary thymic epithelial cells during their differentiation program. J Immunol 195(11):5149–5158

    Article  CAS  PubMed  Google Scholar 

  • Ki S, Park D, Selden HJ, Seita J, Chung H, Kim J, Iyer VR, Ehrlich LIR (2014) Global transcriptional profiling reveals distinct functions of thymic stromal subsets and age-related changes during thymic involution. Cell Rep 9(1):402–415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kinoshita D, Hirota F, Kaisho T, Kasai M, Izumi K, Bando Y, Mouri Y, Matsushima A, Niki S, Han H, Oshikawa K, Kuroda N, Maegawa M, Irahara M, Takeda K, Akira S, Matsumoto M (2006) Essential role of IkappaB kinase alpha in thymic organogenesis required for the establishment of self-tolerance. J Immunol 176(7):3995–4002

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  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(20):11822–11827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klug DB, Carter C, Gimenez-Conti IB, Richie ER (2002) Cutting edge: thymocyte-independent and thymocyte-dependent phases of epithelial patterning in the fetal thymus. J Immunol 169(6):2842–2845

    Article  CAS  PubMed  Google Scholar 

  • Koch U, Fiorini E, Benedito R, Besseyrias V, Schuster-Gossler K, Pierres M, Manley NR, Duarte A, Macdonald HR, Radtke F (2008) Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment. J Exp Med 205(11):2515–2523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koh AS, Miller EL, Buenrostro JD, Moskowitz DM, Wang J, Greenleaf WJ, Chang HY, Crabtree GR (2018) Rapid chromatin repression by aire provides precise control of immune tolerance. Nat Immunol 19(2):162–172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krueger A, Willenzon S, Lyszkiewicz M, Kremmer E, Forster R (2010) CC chemokine receptor 7 and 9 double-deficient hematopoietic progenitors are severely impaired in seeding the adult thymus. Blood 115(10):1906–1912

    Article  CAS  PubMed  Google Scholar 

  • Kuroda N, Mitani T, Takeda N, Ishimaru N, Arakaki R, Hayashi Y, Bando Y, Izumi K, Takahashi T, Nomura T, Sakaguchi S, Ueno T, Takahama Y, Uchida D, Sun S, Kajiura F, Mouri Y, Han H, Matsushima A, Yamada G, Matsumoto M (2005) Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of aire-deficient mice. J Immunol 174(4):1862–1870

    Article  CAS  PubMed  Google Scholar 

  • Kyewski B, Klein L (2006) A central role for central tolerance. Annu Rev Immunol 24:571–606

    Article  CAS  PubMed  Google Scholar 

  • Lee H, Kim H, Chung Y, Kim J, Yang H (2013) Thymocyte differentiation is regulated by a change in estradiol levels during the estrous cycle in mouse. Dev Reprod 17(4):441–449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liang Z, Zhang L, Su H, Luan R, Na N, Sun L, Zhao Y, Zhang X, Zhang Q, Li J, Zhang L, Zhao Y (2018) MTOR signaling is essential for the development of thymic epithelial cells and the induction of central immune tolerance. Autophagy 14(3):505–517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Linton PJ, Dorshkind K (2004) Age-related changes in lymphocyte development and function. Nat Immunol 5(2):133–139

    Article  CAS  PubMed  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(4):350–354

    Article  CAS  PubMed  Google Scholar 

  • Liu C, Saito F, Liu Z, Lei Y, Uehara S, Love P, Lipp M, Kondo S, Manley N, Takahama Y (2006) Coordination between CCR7- and CCR9-mediated chemokine signals in prevascular fetal thymus colonization. Blood 108(8):2531–2539

    Article  CAS  PubMed  Google Scholar 

  • Liu Z, Yu S, Manley NR (2007) Gcm2 is required for the differentiation and survival of parathyroid precursor cells in the parathyroid/thymus primordia. Dev Biol 305(1):333–346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lomada D, Jain M, Bolner M, Reeh KA, Kang R, Reddy MC, DiGiovanni J, Richie ER (2016) Stat3 signaling promotes survival and maintenance of medullary thymic epithelial cells. PLoS Genet 12(1):e1005777

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Love PE, Bhandoola A (2011) Signal integration and crosstalk during thymocyte migration and emigration. Nat Rev Immunol 11(7):469–477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malchow S, Leventhal DS, Nishi S, Fischer BI, Shen L, Paner GP, Amit AS, Kang C, Geddes JE, Allison JP, Socci ND, Savage PA (2013) Aire-dependent thymic development of tumor-associated regulatory T cells. Science 339(6124):1219–1224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Manley NR (2000) Thymus organogenesis and molecular mechanisms of thymic epithelial cell differentiation. Semin Immunol 12(5):421–428

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto M (2007) Transcriptional regulation in thymic epithelial cells for the establishment of self tolerance. Arch Immunol Ther Exp (Warsz) 55:27–34

    Article  CAS  Google Scholar 

  • Matsumoto M, Fu YX, Molina H, Chaplin DD (1997) Lymphotoxin-alpha-deficient and TNF receptor-I-deficient mice define developmental and functional characteristics of germinal centers. Immunol Rev 156:137–144

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto M, Iwamasa K, Rennert PD, Yamada T, Suzuki R, Matsushima A, Okabe M, Fujita S, Yokoyama M (1999) Involvement of distinct cellular compartments in the abnormal lymphoid organogenesis in lymphotoxin-alpha-deficient mice and alymphoplasia (aly) mice defined by the chimeric analysis. J Immunol 163(3):1584–1591

    CAS  PubMed  Google Scholar 

  • Matsumoto M, Nishikawa Y, Nishijima H, Morimoto J, Matsumoto M, Mouri Y (2013) Which model better fits the role of aire in the establishment of self-tolerance: the transcription model or the maturation model? Front Immunol 4:210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsushima A, Kaisho T, Rennert PD, Nakano H, Kurosawa K, Uchida D, Takeda K, Akira S, Matsumoto M (2001) Essential role of nuclear factor (NF)-kappaB-inducing kinase and inhibitor of kappaB (IkappaB) kinase alpha in NF-kappaB activation through lymphotoxin beta receptor, but not through tumor necrosis factor receptor I. J Exp Med 193(5):631–636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mayer CE, Zuklys S, Zhanybekova S, Ohigashi I, Teh HY, Sansom SN, Shikama-Dorn N, Hafen K, Macaulay IC, Deadman ME, Ponting CP, Takahama Y, Hollander GA (2016) Dynamic spatio-temporal contribution of single beta5t+ cortical epithelial precursors to the thymus medulla. Eur J Immunol 46(4):846–856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meireles C, Ribeiro AR, Pinto RD, Leitao C, Rodrigues PM, Alves NL (2017) Thymic crosstalk restrains the pool of cortical thymic epithelial cells with progenitor properties. Eur J Immunol 47(6):958–969

    Article  CAS  PubMed  Google Scholar 

  • 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):166–179

    Article  CAS  PubMed  Google Scholar 

  • Miller JFAP (1961) Imunological function of the thymus. Lancet 2(7205):748–749

    Article  CAS  PubMed  Google Scholar 

  • Miller JF (2006) Vestigial no more. Nat Immunol 7(1):3–5

    Article  CAS  PubMed  Google Scholar 

  • Moore TA, von Freeden-Jeffry U, Murray R, Zlotnik A (1996) Inhibition of gamma delta T cell development and early thymocyte maturation in IL-7 -/- mice. J Immunol 157(6):2366–2373

    CAS  PubMed  Google Scholar 

  • Morrissey PJ, Charrier K, Alpert A, Bressler L (1988) In vivo administration of IL-1 induces thymic hypoplasia and increased levels of serum corticosterone. J Immunol 141(5):1456–1463

    CAS  PubMed  Google Scholar 

  • 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 J, Akiyama T, Matsumoto M (2011) Lymphotoxin signal promotes thymic organogenesis by eliciting RANK expression in the embryonic thymic stroma. J Immunol 186(9):5047–5057

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Mouri Y, Ueda Y, Yamano T, Matsumoto M, Tsuneyama K, Kinashi T, Matsumoto M (2017) Mode of tolerance induction and requirement for aire are governed by the cell types that express self-antigen and those that present antigen. J Immunol 199(12):3959–3971

    Article  CAS  PubMed  Google Scholar 

  • Murata S, Sasaki K, Kishimoto T, Niwa S, Hayashi H, Takahama Y, Tanaka K (2007) Regulation of CD8+ T cell development by thymus-specific proteasomes. Science 316(5829):1349–1353

    Article  CAS  PubMed  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(4):393–398

    Article  CAS  PubMed  Google Scholar 

  • Nakagawa T, Roth W, Wong P, Nelson A, Farr A, Deussing J, Villadangos JA, Ploegh H, Peters C, Rudensky AY (1998) Cathepsin L: critical role in Ii degradation and CD4 T cell selection in the thymus. Science 280(5362):450–453

    Article  CAS  PubMed  Google Scholar 

  • Nedjic J, Aichinger M, Emmerich J, Mizushima N, Klein L (2008) Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature 455(7211):396–400

    Article  CAS  PubMed  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(5263):886–889

    Article  CAS  PubMed  Google Scholar 

  • Niki S, Oshikawa K, Mouri Y, Hirota F, Matsushima A, Yano M, Han H, Bando Y, Izumi K, Matsumoto M, Nakayama KI, Kuroda N, Matsumoto M (2006) Alteration of intra-pancreatic target-organ specificity by abrogation of aire in NOD mice. J Clin Invest 116(5):1292–1301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nishijima H, Kitano S, Miyachi H, Morimoto J, Kawano H, Hirota F, Morita R, Mouri Y, Masuda K, Imoto I, Ikuta K, Matsumoto M (2015) Ectopic aire expression in the thymic cortex reveals inherent properties of aire as a tolerogenic factor within the medulla. J Immunol 195(10):4641–4649

    Article  CAS  PubMed  Google Scholar 

  • Nishijima H, Kajimoto T, Matsuoka Y, Mouri Y, Morimoto J, Matsumoto M, Kawano H, Nishioka Y, Uehara H, Izumi K, Tsuneyama K, Okazaki IM, Okazaki T, Hosomichi K, Shiraki A, Shibutani M, Mitsumori K, Matsumoto M (2018) Paradoxical development of polymyositis-like autoimmunity through augmented expression of autoimmune regulator (AIRE). J Autoimmun 86:75–92

    Article  CAS  PubMed  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(5):963–971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nishikawa Y, Nishijima H, Matsumoto M, Morimoto J, Hirota F, Takahashi S, Luche H, Fehling HJ, Mouri Y, Matsumoto M (2014) Temporal lineage tracing of aire-expressing cells reveals a requirement for aire in their maturation program. J Immunol 192(6):2585–2592

    Article  CAS  PubMed  Google Scholar 

  • Nitta T, Murata S, Sasaki K, Fujii H, Ripen AM, Ishimaru N, Koyasu S, Tanaka K, Takahama Y (2010) Thymoproteasome shapes immunocompetent repertoire of CD8+ T cells. Immunity 32(1):29–40

    Article  CAS  PubMed  Google Scholar 

  • O’Neill KE, Bredenkamp N, Tischner C, Vaidya HJ, Stenhouse FH, Peddie CD, Nowell CS, Gaskell T, Blackburn CC (2016) Foxn1 is dynamically regulated in thymic epithelial cells during embryogenesis and at the onset of thymic involution. PLoS One 11(3):e0151666

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ohigashi I, Zuklys S, Sakata M, Mayer CE, Zhanybekova S, Murata S, Tanaka K, Hollander GA, Takahama Y (2013) Aire-expressing thymic medullary epithelial cells originate from beta5t-expressing progenitor cells. Proc Natl Acad Sci U S A 110(24):9885–9890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ohigashi I, Zuklys S, Sakata M, Mayer CE, Hamazaki Y, Minato N, Hollander GA, Takahama Y (2015) Adult thymic medullary epithelium is maintained and regenerated by lineage-restricted cells rather than bipotent progenitors. Cell Rep 13(7):1432–1443

    Article  CAS  PubMed  Google Scholar 

  • Ohigashi I, Kozai M, Takahama Y (2016) Development and developmental potential of cortical thymic epithelial cells. Immunol Rev 271(1):10–22

    Article  CAS  PubMed  Google Scholar 

  • Olsen NJ, Olson G, Viselli SM, Gu X, Kovacs WJ (2001) Androgen receptors in thymic epithelium modulate thymus size and thymocyte development. Endocrinology 142(3):1278–1283

    Article  CAS  PubMed  Google Scholar 

  • Onder L, Nindl V, Scandella E, Chai Q, Cheng HW, Caviezel-Firner S, Novkovic M, Bomze D, Maier R, Mair F, Ledermann B, Becher B, Waisman A, Ludewig B (2015) Alternative NF-kappaB signaling regulates mTEC differentiation from podoplanin-expressing precursors in the cortico-medullary junction. Eur J Immunol 45(8):2218–2231

    Article  CAS  PubMed  Google Scholar 

  • Org T, Rebane A, Kisand K, Laan M, Haljasorg U, Andreson R, Peterson P (2009) AIRE activated tissue specific genes have histone modifications associated with inactive chromatin. Hum Mol Genet 18(24):4699–4710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Otero DC, Baker DP, David M (2013) IRF7-dependent IFN-beta production in response to RANKL promotes medullary thymic epithelial cell development. J Immunol 190(7):3289–3298

    Article  CAS  PubMed  Google Scholar 

  • Papadopoulou AS, Dooley J, Linterman MA, Pierson W, Ucar O, Kyewski B, Zuklys S, Hollander GA, Matthys P, Gray DH, De Strooper B, Liston A (2011) The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via miR-29a mediated suppression of the IFN-alpha receptor. Nat Immunol 13(2):181–187

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Perry JS, Lio CW, Kau AL, Nutsch K, Yang Z, Gordon JI, Murphy KM, Hsieh CS (2014) Distinct contributions of aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus. Immunity 41(3):414–426

    Article  CAS  PubMed  PubMed Central  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

    Article  CAS  PubMed  Google Scholar 

  • Plotkin J, Prockop SE, Lepique A, Petrie HT (2003) Critical role for CXCR4 signaling in progenitor localization and T cell differentiation in the postnatal thymus. J Immunol 171(9):4521–4527

    Article  CAS  PubMed  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(50):19869–19874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Revest JM, Suniara RK, Kerr K, Owen JJ, Dickson C (2001) Development of the thymus requires signaling through the fibroblast growth factor receptor R2-IIIb. J Immunol 167(4):1954–1961

    Article  CAS  PubMed  Google Scholar 

  • Ribeiro AR, Rodrigues PM, Meireles C, Di Santo JP, Alves NL (2013) Thymocyte selection regulates the homeostasis of IL-7-expressing thymic cortical epithelial cells in vivo. J Immunol 191(3):1200–1209

    Article  CAS  PubMed  Google Scholar 

  • Ribeiro AR, Meireles C, Rodrigues PM, Alves NL (2014) Intermediate expression of CCRL1 reveals novel subpopulations of medullary thymic epithelial cells that emerge in the postnatal thymus. Eur J Immunol 44(10):2918–2924

    Article  CAS  PubMed  Google Scholar 

  • Riemann M, Andreas N, Fedoseeva M, Meier E, Weih D, Freytag H, Schmidt-Ullrich R, Klein U, Wang ZQ, Weih F (2017) Central immune tolerance depends on crosstalk between the classical and alternative NF-kappaB pathways in medullary thymic epithelial cells. J Autoimmun 81:56–67

    Article  CAS  PubMed  Google Scholar 

  • Rijhsinghani AG, Thompson K, Bhatia SK, Waldschmidt TJ (1996) Estrogen blocks early T cell development in the thymus. Am J Reprod Immunol 36(5):269–277

    Article  CAS  PubMed  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(3):427–437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rode I, Martins VC, Kublbeck G, Maltry N, Tessmer C, Rodewald HR (2015) Foxn1 protein expression in the developing, aging, and regenerating thymus. J Immunol 195(12):5678–5687

    Article  CAS  PubMed  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(6865):763–768

    Article  CAS  PubMed  Google Scholar 

  • Rodrigues PM, Ribeiro AR, Perrod C, Landry JJM, Araujo L, Pereira-Castro I, Benes V, Moreira A, Xavier-Ferreira H, Meireles C, Alves NL (2017) Thymic epithelial cells require p53 to support their long-term function in thymopoiesis in mice. Blood 130(4):478–488

    Article  CAS  PubMed  Google Scholar 

  • Romano R, Palamaro L, Fusco A, Giardino G, Gallo V, Del Vecchio L, Pignata C (2013) FOXN1: a master regulator gene of thymic epithelial development program. Front Immunol 4:187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ropke C, Van Soest P, Platenburg PP, Van Ewijk W (1995) A common stem cell for murine cortical and medullary thymic epithelial cells? Dev Immunol 4(2):149–156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rossi FM, Corbel SY, Merzaban JS, Carlow DA, Gossens K, Duenas J, So L, Yi L, Ziltener HJ (2005) Recruitment of adult thymic progenitors is regulated by P-selectin and its ligand PSGL-1. Nat Immunol 6(6):626–634

    Article  CAS  PubMed  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(7096):988–991

    Article  CAS  PubMed  Google Scholar 

  • Rossi SW, Chidgey AP, Parnell SM, Jenkinson WE, Scott HS, Boyd RL, Jenkinson EJ, Anderson G (2007a) Redefining epithelial progenitor potential in the developing thymus. Eur J Immunol 37(9):2411–2418

    Article  CAS  PubMed  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 (2007b) RANK signals from CD4(+)3(-) inducer cells regulate development of aire-expressing epithelial cells in the thymic medulla. J Exp Med 204(6):1267–1272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rossi SW, Jeker LT, Ueno T, Kuse S, Keller MP, Zuklys S, Gudkov AV, Takahama Y, Krenger W, Blazar BR, Hollander GA (2007c) Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells. Blood 109(9):3803–3811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sakaguchi S (2004) Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22:531–562

    Article  CAS  PubMed  Google Scholar 

  • Sano S, Takahama Y, Sugawara T, Kosaka H, Itami S, Yoshikawa K, Miyazaki J, van Ewijk W, Takeda J (2001) Stat3 in thymic epithelial cells is essential for postnatal maintenance of thymic architecture and thymocyte survival. Immunity 15(2):261–273

    Article  CAS  PubMed  Google Scholar 

  • Satoh R, Kakugawa K, Yasuda T, Yoshida H, Sibilia M, Katsura Y, Levi B, Abramson J, Koseki Y, Koseki H, van Ewijk W, Hollander GA, Kawamoto H (2016) Requirement of Stat3 signaling in the postnatal development of thymic medullary epithelial cells. PLoS Genet 12(1):e1005776

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Schuddekopf K, Schorpp M, Boehm T (1996) The whn transcription factor encoded by the nude locus contains an evolutionarily conserved and functionally indispensable activation domain. Proc Natl Acad Sci U S A 93(18):9661–9664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schuster C, Gerold KD, Schober K, Probst L, Boerner K, Kim MJ, Ruckdeschel A, Serwold T, Kissler S (2015) The autoimmunity-associated gene CLEC16A modulates thymic epithelial cell autophagy and alters T cell selection. Immunity 42(5):942–952

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scimone ML, Aifantis I, Apostolou I, von Boehmer H, von Andrian UH (2006) A multistep adhesion cascade for lymphoid progenitor cell homing to the thymus. Proc Natl Acad Sci U S A 103(18):7006–7011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sekai M, Hamazaki Y, Minato N (2014) Medullary thymic epithelial stem cells maintain a functional thymus to ensure lifelong central T cell tolerance. Immunity 41(5):753–761

    Article  CAS  PubMed  Google Scholar 

  • Sempowski GD, Hale LP, Sundy JS, Massey JM, Koup RA, Douek DC, Patel DD, Haynes BF (2000) Leukemia inhibitory factor, oncostatin M, IL-6, and stem cell factor mRNA expression in human thymus increases with age and is associated with thymic atrophy. J Immunol 164(4):2180–2187

    Article  CAS  PubMed  Google Scholar 

  • Sempowski GD, Gooding ME, Liao HX, Le PT, Haynes BF (2002) T cell receptor excision circle assessment of thymopoiesis in aging mice. Mol Immunol 38(11):841–848

    Article  CAS  PubMed  Google Scholar 

  • Senoo M, Pinto F, Crum CP, McKeon F (2007) p63 Is essential for the proliferative potential of stem cells in stratified epithelia. Cell 129(3):523–536

    Article  CAS  PubMed  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(1):130–137

    Article  CAS  PubMed  Google Scholar 

  • Shanley DP, Aw D, Manley NR, Palmer DB (2009) An evolutionary perspective on the mechanisms of immunosenescence. Trends Immunol 30(7):374–381

    Article  CAS  PubMed  Google Scholar 

  • Shinkura R, Kitada K, Matsuda F, Tashiro K, Ikuta K, Suzuki M, Kogishi K, Serikawa T, Honjo T (1999) Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-kappa b-inducing kinase. Nat Genet 22(1):74–77

    Article  CAS  PubMed  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(10):4801–4809

    Article  CAS  PubMed  Google Scholar 

  • Smith KM, Olson DC, Hirose R, Hanahan D (1997) Pancreatic gene expression in rare cells of thymic medulla: evidence for functional contribution to T cell tolerance. Int Immunol 9(9):1355–1365

    Article  CAS  PubMed  Google Scholar 

  • Soleimanpour SA, Gupta A, Bakay M, Ferrari AM, Groff DN, Fadista J, Spruce LA, Kushner JA, Groop L, Seeholzer SH, Kaufman BA, Hakonarson H, Stoffers DA (2014) The diabetes susceptibility gene Clec16a regulates mitophagy. Cell 157(7):1577–1590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Soza-Ried C, Bleul CC, Schorpp M, Boehm T (2008) Maintenance of thymic epithelial phenotype requires extrinsic signals in mouse and zebrafish. J Immunol 181(8):5272–5277

    Article  CAS  PubMed  Google Scholar 

  • Staples JE, Gasiewicz TA, Fiore NC, Lubahn DB, Korach KS, Silverstone AE (1999) Estrogen receptor alpha is necessary in thymic development and estradiol-induced thymic alterations. J Immunol 163(8):4168–4174

    CAS  PubMed  Google Scholar 

  • Steinmann GG, Klaus B, Muller-Hermelink HK (1985) The involution of the ageing human thymic epithelium is independent of puberty. A morphometric study. Scand J Immunol 22(5):563–575

    Article  CAS  PubMed  Google Scholar 

  • Sukseree S, Mildner M, Rossiter H, Pammer J, Zhang CF, Watanapokasin R, Tschachler E, Eckhart L (2012) Autophagy in the thymic epithelium is dispensable for the development of self-tolerance in a novel mouse model. PLoS One 7(6):e38933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sutherland JS, Goldberg GL, Hammett MV, Uldrich AP, Berzins SP, Heng TS, Blazar BR, Millar JL, Malin MA, Chidgey AP, Boyd RL (2005) Activation of thymic regeneration in mice and humans following androgen blockade. J Immunol 175(4):2741–2753

    Article  CAS  PubMed  Google Scholar 

  • Takada K, Van Laethem F, Xing Y, Akane K, Suzuki H, Murata S, Tanaka K, Jameson SC, Singer A, Takahama Y (2015) TCR affinity for thymoproteasome-dependent positively selecting peptides conditions antigen responsiveness in CD8(+) T cells. Nat Immunol 16(10):1069–1076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takada K, Kondo K, Takahama Y (2017) Generation of peptides that promote positive selection in the thymus. J Immunol 198(6):2215–2222

    Article  CAS  PubMed  Google Scholar 

  • Takahama Y (2006) Journey through the thymus: stromal guides for T-cell development and selection. Nat Rev Immunol 6(2):127–135

    Article  CAS  PubMed  Google Scholar 

  • Takeoka Y, Chen SY, Yago H, Boyd R, Suehiro S, Shultz LD, Ansari AA, Gershwin ME (1996) The murine thymic microenvironment: changes with age. Int Arch Allergy Immunol 111(1):5–12

    Article  CAS  PubMed  Google Scholar 

  • Taub DD, Longo DL (2005) Insights into thymic aging and regeneration. Immunol Rev 205:72–93

    Article  CAS  PubMed  Google Scholar 

  • Tsai PT, Lee RA, Wu H (2003) BMP4 acts upstream of FGF in modulating thymic stroma and regulating thymopoiesis. Blood 102(12):3947–3953

    Article  CAS  PubMed  Google Scholar 

  • Ulyanchenko S, O’Neill KE, Medley T, Farley AM, Vaidya HJ, Cook AM, Blair NF, Blackburn CC (2016) Identification of a bipotent epithelial progenitor population in the adult thymus. Cell Rep 14(12):2819–2832

    Article  CAS  PubMed  PubMed Central  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(6):524–529

    Article  PubMed  Google Scholar 

  • Velardi E, Dudakov JA, van den Brink MR (2015) Sex steroid ablation: an immunoregenerative strategy for immunocompromised patients. Bone Marrow Transplant 50(Suppl 2):S77–S81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Viselli SM, Olsen NJ, Shults K, Steizer G, Kovacs WJ (1995) Immunochemical and flow cytometric analysis of androgen receptor expression in thymocytes. Mol Cell Endocrinol 109(1):19–26

    Article  CAS  PubMed  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(March):19

    CAS  PubMed  PubMed Central  Google Scholar 

  • Williams KM, Lucas PJ, Bare CV, Wang J, Chu YW, Tayler E, Kapoor V, Gress RE (2008) CCL25 increases thymopoiesis after androgen withdrawal. Blood 112(8):3255–3263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wong K, Lister NL, Barsanti M, Lim JM, Hammett MV, Khong DM, Siatskas C, Gray DH, Boyd RL, Chidgey AP (2014) Multilineage potential and self-renewal define an epithelial progenitor cell population in the adult thymus. Cell Rep 8(4):1198–1209

    Article  CAS  PubMed  Google Scholar 

  • 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(6):1048–1061

    Article  CAS  PubMed  Google Scholar 

  • Yang H, Youm YH, Sun Y, Rim JS, Galban CJ, Vandanmagsar B, Dixit VD (2009) Axin expression in thymic stromal cells contributes to an age-related increase in thymic adiposity and is associated with reduced thymopoiesis independently of ghrelin signaling. J Leukoc Biol 85(6):928–938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  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(12):2827–2838

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Youm YH, Kanneganti TD, Vandanmagsar B, Zhu X, Ravussin A, Adijiang A, Owen JS, Thomas MJ, Francis J, Parks JS, Dixit VD (2012) The Nlrp3 inflammasome promotes age-related thymic demise and immunosenescence. Cell Rep 1(1):56–68

    Article  CAS  PubMed  Google Scholar 

  • Zhu M, Chin RK, Christiansen PA, Lo JC, Liu X, Ware C, Siebenlist U, Fu YX (2006) NF-kappaB2 is required for the establishment of central tolerance through an aire-dependent pathway. J Clin Invest 116(11):2964–2971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zlotoff DA, Sambandam A, Logan TD, Bell JJ, Schwarz BA, Bhandoola A (2010) CCR7 and CCR9 together recruit hematopoietic progenitors to the adult thymus. Blood 115(10):1897–1905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zook EC, Krishack PA, Zhang S, Zeleznik-Le NJ, Firulli AB, Witte PL, Le PT (2011) Overexpression of Foxn1 attenuates age-associated thymic involution and prevents the expansion of peripheral CD4 memory T cells. Blood 118(22):5723–5731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zuklys S, Mayer CE, Zhanybekova S, Stefanski HE, Nusspaumer G, Gill J, Barthlott T, Chappaz S, Nitta T, Dooley J, Nogales-Cadenas R, Takahama Y, Finke D, Liston A, Blazar BR, Pascual-Montano A, Hollander GA (2012) MicroRNAs control the maintenance of thymic epithelia and their competence for T lineage commitment and thymocyte selection. J Immunol 189(8):3894–3904

    Article  CAS  PubMed  Google Scholar 

  • Zuklys S, Handel A, Zhanybekova S, Govani F, Keller M, Maio S, Mayer CE, Teh HY, Hafen K, Gallone G, Barthlott T, Ponting CP, Hollander GA (2016) Foxn1 regulates key target genes essential for T cell development in postnatal thymic epithelial cells. Nat Immunol 17(10):1206–1215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zumer K, Saksela K, Peterlin BM (2013) The mechanism of tissue-restricted antigen gene expression by AIRE. J Immunol 190(6):2479–2482

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The European Research Council (ERC) under the EU’s Horizon 2020 research and innovation program (grant agreement No 637843—TEC_Pro)—starting grant attributed to N.L.A—supports the studies from the laboratory of Nuno L. Alves. The studies from the laboratory of Mitsuru Matsumoto are supported by JSPS KAKENHI Grant Numbers JP16H06496 and JP16H05342, and by the Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology. We apologize for not referring to all of the primary literature owing to the space limitations.

Author information

Author notes

  1. Minoru Matsumoto and Pedro M. Rodrigues contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular Immunology, Institute for Enzyme Research, Tokushima University, Tokushima, Japan

    Minoru Matsumoto & Mitsuru Matsumoto

  2. Department of Molecular and Environmental Pathology, Institute of Biomedical Sciences, The University of Tokushima Graduate School, Tokushima, Japan

    Minoru Matsumoto & Koichi Tsuneyama

  3. Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

    Pedro M. Rodrigues, Laura Sousa & Nuno L. Alves

  4. Thymus Development and Function Laboratory, Instituto de Biologia Molecular e Celular, Porto, Portugal

    Pedro M. Rodrigues & Nuno L. Alves

Authors
  1. Minoru Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pedro M. Rodrigues
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laura Sousa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Koichi Tsuneyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mitsuru Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nuno L. Alves
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Mitsuru Matsumoto or Nuno L. Alves .

Editor information

Editors and Affiliations

  1. Laboratory of Genetics and Molecular Biology, Department of Basic and Oral Biology, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

    Geraldo A. Passos

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Matsumoto, M., Rodrigues, P.M., Sousa, L., Tsuneyama, K., Matsumoto, M., Alves, N.L. (2019). The Ins and Outs of Thymic Epithelial Cell Differentiation and Function. In: Passos, G. (eds) Thymus Transcriptome and Cell Biology. Springer, Cham. https://doi.org/10.1007/978-3-030-12040-5_3

Download citation

Publish with us

Policies and ethics

Search

Navigation