Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Generation of diversity in thymic epithelial cells

Nature Reviews Immunology volume 17, pages 295–305 (2017)Cite this article

Subjects

Key Points

  • Cortical thymic epithelial cells (cTECs) are functionally heterogeneous, although T cell-lineage-specifying and positive-selection-inducing functions seem to overlap between individual cTECs.

  • Thymic nurse cells are a subpopulation of cTECs that are morphologically and functionally specialized for optimizing the positive selection of thymocytes.

  • Promiscuous gene expression in individual medullary TECs (mTECs) is heterogeneous, and mosaic expression across all mTECs constitutes a pool of the promiscuously expressed genes.

  • CC-chemokine ligand 21 (CCL21)-expressing mTECs represent a functionally mature mTEClow subpopulation and resemble post-autoimmune regulator (AIRE) mTECs.

  • Embryonic TEC progenitors acquire hallmarks of the cTEC lineage and then the mTEC lineage in a stepwise manner during initial thymus cortex and medulla formation.

  • A self-renewing subset of embryonic TECs, referred to as mTEC stem cells, has been identified that are capable of long-term and specific generation of mTECs.

Abstract

In the thymus, diverse populations of thymic epithelial cells (TECs), including cortical and medullary TECs and their subpopulations, have distinct roles in coordinating the development and repertoire selection of functionally competent and self-tolerant T cells. Here, we review the expanding diversity in TEC subpopulations in relation to their functions in T cell development and selection as well as their origins and development.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Diverse TECs constitute multiple thymic microenvironments.
Figure 2: cTEC heterogeneity.
Figure 3: mTEC heterogeneity.
Figure 4: Origin and development of TECs: lessons from the embryonic thymus.

Similar content being viewed by others

References

  1. Golub, E. S. in The Cellular Basis of the Immune Response 2nd edn 314–317 (Sinauer Associates, 1981).

    Google Scholar 

  2. Silverstein, A. M. in A History of Immunology 2nd edn 69–84 (Academic Press, 2009).

    Book  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Griffith, A. V. et al. Spatial mapping of thymic stromal microenvironments reveals unique features influencing T lymphoid differentiation. Immunity 31, 999–1009 (2009). Provides direct evidence for anatomical specialization of the thymic cortex and medulla at the molecular level.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Petrie, H. T. & Zúñiga-Pflücker, J. C. Zoned out: Functional mapping of stromal signaling microenvironments in the thymus. Annu. Rev. Immunol. 25, 649–679 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Shakib, S. et al. Checkpoints in development of thymic cortical epithelial cells. J. Immunol. 182, 130–137 (2009). Gives the first indication that embryonic TEC subsets identified by cTEC markers may have a developmental association with mTECs.

    Article  CAS  PubMed  Google Scholar 

  7. Ripen, A. M., Nitta, T., Murata, S., Tanaka, K. & Takahama, Y. Ontogeny of thymic cortical epithelial cells expressing the thymoproteasome subunit β5t. Eur. J. Immunol. 41, 1289–1287 (2011).

    Article  CAS  Google Scholar 

  8. Ribeiro, A. R., Rodrigues, P. M., Meireles, C., Di Santo, J. P. & Alves, N. L. Thymocyte selection regulates the homeostasis of IL-7-expressing thymic cortical epithelial cells in vivo. J. Immunol. 191, 1200–1209 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Takada, K., Ohigashi, I., Kasai, M., Nakase, H. & Takahama, Y. Development and function of cortical thymic epithelial cells. Curr. Top. Microbiol. Immunol. 373, 1–17 (2014).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Ribeiro, A. R., Meireles, C., Rodrigues, P. M. & Alves, N. L. The intermediate expression of CCRL1 reveals novel subpopulations of medullary thymic epithelial cells that emerge in the postnatal thymus. Eur. J. Immunol. 44, 2918–2924 (2014).

    Article  CAS  PubMed  Google Scholar 

  12. Holländer, G. A. et al. Developmental control point in induction of thymic cortex regulated by a subpopulation of prothymocytes. Nature 373, 350–353 (1995).

    Article  PubMed  Google Scholar 

  13. Alves, N. L., Huntington, N. D., Mention, J. J., Richard-Le Goff, O. & Di Santo, J. P. A thymocyte-thymic epithelial cell cross-talk dynamically regulates intrathymic IL-7 expression in vivo. J. Immunol. 184, 5949–5953 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Roberts, N. A. et al. Absence of thymus crosstalk in the fetus does not preclude hematopoietic induction of a functional thymus in the adult. Eur. J. Immunol. 39, 2395–2402 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Klein, L., Kyewski, B., Allen, P. M. & Hogquist, K. A. Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat. Rev. Immunol. 14, 377–391 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nakagawa, T. et al. Cathepsin L: critical role in Ii degradation and CD4 T cell selection in the thymus. Science 280, 450–453 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Gommeaux, J. et al. Thymus-specific serine protease regulates positive selection of a subset of CD4+ thymocytes. Eur. J. Immunol. 39, 956–964 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. von Rohrscheidt, J. et al. Thymic CD4 T cell selection requires attenuation of March8-mediated MHCII turnover in cortical epithelial cells through CD83. J. Exp. Med. 213, 1685–1694 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Liu, H. et al. Ubiquitin ligase MARCH 8 cooperates with CD83 to control surface MHC II expression in thymic epithelium and CD4 T cell selection. J. Exp. Med. 213, 1695–1703 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Koch, U. et al. Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment. J. Exp. Med. 205, 2515–2523 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fiorini, E. et al. Thymic crosstalk regulates delta-like 4 expression on cortical epithelial cells. J. Immunol. 181, 8199–8203 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Hara, T. et al. Identification of IL-7-producing cells in primary and secondary lymphoid organs using IL-7-GFP knock-in mice. J. Immunol. 189, 1577–1584 (2012).

    Article  CAS  PubMed  Google Scholar 

  24. Alves, N. et al. Characterization of the thymic IL-7 niche in vivo. Proc. Natl Acad. Sci. USA 106, 1512–1517 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wekerle, H. & Ketelsen, U. P. Thymic nurse cells—Ia-bearing epithelium involved in T-lymphocyte differentiation? Nature 283, 402–404 (1980).

    Article  CAS  PubMed  Google Scholar 

  26. Kyewski, B. A. & Kaplan, H. S. Lymphoepithelial interactions in the mouse thymus: phenotypic and kinetic studies on thymic nurse cells. J. Immunol. 128, 2287–2294 (1982).

    CAS  PubMed  Google Scholar 

  27. Nakagawa, Y. et al. Thymic nurse cells provide microenvironment for secondary TCRα rearrangement in cortical thymocytes. Proc. Natl Acad. Sci. USA 109, 20572–20577 (2012). Provides evidence for specialization within the cTEC population and for the functional importance of thymic nurse cell complexes in increasing opportunities for positive selection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Salomon, D. R. et al. Constitutive activation of integrin alpha 4 beta 1 defines a unique stage of human thymocyte development. J. Exp. Med. 179, 1573–1578 (1994).

    Article  CAS  PubMed  Google Scholar 

  29. Suzuki, G. et al. Loss of SDF-1 receptor expression during positive selection in the thymus. Int. Immunol. 10, 1049–1056 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Gray, D. H. et al. Developmental kinetics turnover and stimulatory capacity of thymic epithelial cells. Blood 108, 3777–3785 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Rossi, S. W. et al. RANK signals from CD4+3− inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J. Exp. Med. 204, 1267–1272 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. White, A. J. et al. Lymphotoxin signals from positively selected thymocytes regulate the terminal differentiation of medullary thymic epithelial cells. J. Immunol. 185, 4769–4776 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Lkhagvasuren, E., Sakata, M., Ohigashi, I. & Takahama, Y. Lymphotoxin β receptor regulates the development of CCL21-expressing subset of postnatal medullary thymic epithelial cells. J. Immunol. 190, 5110–5117 (2013). Offers evidence for developmental heterogeneity within the mTEClow population and shows that this compartment contains functionally mature mTECs.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Anderson, M. S. et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 298, 1395–1401 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  37. McCarthy, N. I. et al. Osteoprotegerin-mediated homeostasis of RANK+ thymic epithelial cells does not limit Foxp3+ regulatory T cell development. J. Immunol. 195, 2675–2682 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hikosaka, Y. et al. The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity 29, 438–450 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Sansom, S. N. et al. 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, 1918–1931 (2014). Reveals, through comprehensive analysis of gene expression patterns at the single-cell level in mTECs, previously unrecognized patterns in promiscuous gene expression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Danan-Gotthold, M., Guyon, C., Giraud, M., Levanon, E. Y. & Abramson, J. Extensive RNA editing and splicing increase immune self-representation diversity in medullary thymic epithelial cells. Genome Biol. 17, 219 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  42. Nagamine, K. et al. Positional cloning of the APECED gene. Nat. Genet. 17, 393–398 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Aaltonen, J. et al. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat. Genet. 17, 399–403 (1997).

    Article  Google Scholar 

  44. Org, T. et al. AIRE activated tissue specific genes have histone modifications associated with inactive chromatin. Hum. Mol. Genet. 18, 4699–4710 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Koh, A. S., Kingston, R. E., Benoist, C. & Mathis, D. Global relevance of Aire binding to hypomethylated lysine-4 of histone-3. Proc. Natl Acad. Sci. USA 107, 13016–13021 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Anderson, M. S. & Su, M. A. AIRE expands: new roles in immune tolerance and beyond. Nat. Rev. Immunol. 16, 247–258 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Debrinski, J. et al. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J. Exp. Med. 202, 33–45 (2005).

    Article  CAS  Google Scholar 

  48. Villaseñor, J., Besse, W., Benoist, C. & Mathis, D. Ectopic expression of peripheral-tissue antigens in the thymic epithelium: probabilistic, monoallelic, misinitiated. Proc. Natl Acad. Sci. USA 105, 15854–15859 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Seach, N. et al. The lymphotoxin pathway regulates Aire-independent expression of ectopic genes and chemokines in thymic stromal cells. J. Immunol. 180, 5384–5392 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Takaba, H. et al. Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. Cell 163, 975–987 (2015). Provides evidence that FEZF2 regulates thymic tolerance via a mechanism involving LT β R-dependent expression of tissue-restricted self-antigens in mTECs.

    Article  CAS  PubMed  Google Scholar 

  51. Akiyama, T. et al. The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 29, 423–437 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Boehm, T., Scheu, S., Pfeffer, K. & Bleul, C. C. Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LTβR. J. Exp. Med. 198, 757–769 (2003). Presents direct evidence that the development and function of the thymus medulla is under control of TNFR superfamily molecules.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Cloosen, S. et al. Expression of tumor-associated differentiation antigens, MUC1 glycoforms and CEA, in human thymic epithelial cells: Implications for self-tolerance and tumor therapy. Cancer Res. 67, 3919–3926 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Pinto, S. et al. Overlapping gene coexpression patterns in human medullary thymic epithelial cells generate self-antigen diversity. Proc. Natl Acad. Sci. USA 110, E3497–E3505 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Brennecke, P. et al. Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells. Nat. Immunol. 16, 933–941 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Meredith, M., Zemmour, D., Mathis, D. & Benoist, C. Aire controls gene expression in the thymic epithelium with ordered stochasticity. Nat. Immunol. 16, 942–949 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  59. Tykocinski, L. O. et al. Epigenetic regulation of promiscuous gene expression in thymic medullary epithelial cells. Proc. Natl Acad. Sci. USA 107, 19426–19431 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Ohigashi, I. et al. Adult thymic medullary epithelium is maintained and regenerated by lineage-restricted cells rather than bipotent progenitors. Cell Rep. 13, 1432–1443 (2015).

    Article  CAS  PubMed  Google Scholar 

  61. Nishikawa, Y. et al. Temporal lineage tracing of Aire-expressing cells reveals a requirement for Aire in their maturation program. J. Immunol. 192, 2585–2592 (2014).

    Article  CAS  PubMed  Google Scholar 

  62. Yano, M. et al. Aire controls the differentiation program of thymic epithelial cells in the medulla for the establishment of self-tolerance. J. Exp. Med. 205, 2827–2838 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Metzger, T. C. et al. Lineage tracing and cell ablation identify a post-Aire-expressing thymic epithelial cell population. Cell Rep. 5, 166–179 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Wang, X. et al. Post-Aire maturation of thymic medullary epithelial cells involves selective expression of keratinocyte-specific autoantigens. Front. Immunol. 3, 19 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Ueno, T. et al. CCR7 signals are essential for cortex-medulla migration of developing thymocytes. J. Exp. Med. 200, 493–505 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kurobe, H. et al. CCR7-dependent cortex-to-medulla migration of positively selected thymocytes is essential for establishing central tolerance. Immunity 24, 165–177 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Cowan, J. E. et al. Differential requirement for CCR4 and CCR7 during the development of innate and adaptive αβ T cells in the adult thymus. J. Immunol. 193, 1204–1212 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hu, Z. et al. CCR4 promotes medullary entry and thymocyte–dendritic cell interactions required for central tolerance. J. Exp. Med. 212, 1947–1965 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Cowan, J. E., McCarthy, N. I. & Anderson, G. CCR7 controls thymus recirculation, but not production and emigration, of Foxp3+ T cells. Cell Rep. 14, 1041–1048 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hubert, F. X. et al. Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance. Blood 118, 2462–2472 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Perry, J. S. A. et al. Distinct contributions of Aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus. Immunity 41, 414–426 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Lei, Y. et al. Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development. J. Exp. Med. 208, 383–394 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Cordier, A. C. & Heremans, J. F. Nude mouse embryos: ectodermal nature of the primordial thymic defect. Scand. J. Immunol. 4, 193–196 (1975).

    Article  CAS  PubMed  Google Scholar 

  75. Cordier, A. C. & Haumont, S. M. Development of thymus, parathyroids, and ultimo-branchial bodies in NMRI and nude mice. Am. J. Anat. 157, 227–263 (1980).

    Article  CAS  PubMed  Google Scholar 

  76. Le Douarin, N. M. & Jotereau, F. V. Tracing cells of the avian thymus through embryonic life in interspecific chimeras. J. Exp. Med. 142, 17–40 (1975).

    Article  CAS  PubMed  Google Scholar 

  77. Gordon, J. et al. Functional evidence for a single endodermal origin for the thymic epithelium. Nat. Immunol. 5, 546–553 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Rossi, S. W., Jenkinson, W. E., Anderson, G. & Jenkinson, E. J. Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature 441, 988–991 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Rodewald, H. R. Thymus organogenesis. Annu. Rev. Immunol. 26, 355–388 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Blackburn, C. C. & Manley, N. R. Developing a new paradigm for thymus organogenesis. Nat. Rev. Immunol. 4, 278–289 (2004).

    Article  CAS  PubMed  Google Scholar 

  81. Vaidya, H. J., Briones Leon, A. & Blackburn, C. C. FOXN1 in thymus organogenesis and development. Eur. J. Immunol. 46, 1826–1837 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Corbeaux, T. et al. Thymopoiesis in mice depends on a Foxn1-positive thymic epithelial cell lineage. Proc. Natl Acad. Sci. USA 107, 16613–16618 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Bleul, C. C. et al. Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature 441, 992–996 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Bleul, C. C. & Boehm, T. Laser capture microdissection-based expression profiling identifies PD1-ligand as a target of the nude locus gene product. Eur. J. Immunol. 31, 2497–2503 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Žuklys, S. et al. Foxn1 regulates key target genes essential for T cell development in postnatal thymic epithelial cells. Nat. Immunol. 17, 1206–1215 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Rode, I. et al. Foxn1 protein expression in the developing, aging, and regenerating thymus. J. Immunol. 195, 5678–5687 (2015).

    Article  CAS  PubMed  Google Scholar 

  87. Jenkinson, W. E., Bacon, A., White, A. J., Anderson, G. & Jenkinson, E. J. An epithelial progenitor pool regulates thymus growth. J. Immunol. 181, 6101–6108 (2008).

    Article  CAS  PubMed  Google Scholar 

  88. Lucas, B. et al. Control of the thymic medulla and its influence on αβ T-cell development. Immunol. Rev. 271, 23–27 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Klug, D. B. et al. Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment. Proc. Natl Acad. Sci. USA 95, 11822–11827 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Klug, D. B., Carter, C., Gimenez-Conti, I. B. & Richie, E. R. Thymocyte-independent and thymocyte-dependent phases of epithelial patterning in the fetal thymus. J. Immunol. 169, 2842–2845 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Baik, S., Jenkinson, E. J., Lane, P. J. L., Anderson, G. & Jenkinson, W. E. Generation of both cortical and Aire+ medullary thymic epithelial compartments from CD205+ progenitors. Eur. J. Immunol. 43, 589–594 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Ohigashi, I. et al. Aire-expressing thymic medullary epithelial cells originate from β5t-expressing progenitor cells. Proc. Natl Acad. Sci. USA 110, 9885–9890 (2013). References 91 and 92 collectively provide direct in vivo evidence that mTECs are derived from TEC progenitors that express the cTEC markers CD205 and β 5t.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Rodewald, H. R., Paul, S., Haller, C., Bluethmann, H. & Blum, C. Thymus medulla consisting of epithelial islets each derived from a single progenitor. Nature 414, 763–768 (2001). Presents the first functional evidence for the existence of lineage-restricted mTEC progenitors.

    Article  CAS  PubMed  Google Scholar 

  94. Alves, N. L. et al. Serial progression of cortical and medullary thymic epithelial microenvironments. Eur. J. Immunol. 44, 16–22 (2014).

    Article  CAS  PubMed  Google Scholar 

  95. Farr, A. G., Hosier, S., Nelson, A., Itohara, S. & Tonegawa, S. Distribution of thymocytes expressing gamma delta receptors in the murine thymus during development. J. Immunol. 144, 492–498 (1990).

    CAS  PubMed  Google Scholar 

  96. Roberts, N. A. et al. Rank signaling links the development of invariant γδ T-cell progenitors and Aire+ medullary epithelium. Immunity 36, 427–437 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Sekai, M., Hamazaki, Y. & Minato, N. Medullary thymic epithelial stem cells maintain a functional thymus to ensure lifelong central T cell tolerance. Immunity 41, 753–761 (2014). Provides the first direct definition of a lineage-restricted mTEC progenitor in the embryonic thymus capable of the long-term generation of mature mTEC compartments.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Nowell, C. S. et al. Foxn1 regulates lineage progression in cortical and medullary thymic epithelial cells but is dispensable for medullary sublineage divergence. PLoS Genet. 7, e1002348 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  102. Blackburn, C. C. et al. The nu gene acts cell-autonomously and is required for differentiation of thymic epithelial progenitors. Proc. Natl Acad. Sci. USA 93, 5742–5746 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Akiyama, N. et al. Identification of embryonic precursor cells that differentiate into thymic epithelial cells expressing autoimmune regulator. J. Exp. Med. 213, 1441–1458 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Mouri, Y. et al. Lymphoyoxin signal promotes thymic organogenesis by eliciting RANK expression in the embryonic thymic stroma. J. Immunol. 186, 5047–5057 (2011).

    Article  CAS  PubMed  Google Scholar 

  105. Rode, I. & Boehm, T. Regenerative capacity of adult cortical thymic epithelial cells. Proc. Natl Acad. Sci. USA 109, 3463–3468 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Ulyanchenko, S. et al. Identification of a bipotent epithelial progenitor population in the adult thymus. Cell Rep. 14, 2819–2832 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Wong, K. et al. Multilineage potential and self renewal define an epithelial progenitor cell population in the adult thymus. Cell Rep. 8, 1198–1209 (2014).

    Article  CAS  PubMed  Google Scholar 

  108. Ucar, A. et al. Adult thymus contains Foxn1− epithelial stem cells that are bipotent for medullary and cortical thymic epithelial lineages. Immunity 41, 257–269 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Ucar, O. et al. A thymic epithelial stem cell pool persists throughout ontogeny and is modulated by TGF-β. Cell Rep. 17, 448–457 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Onder, L. et al. Alternative NF-κB signaling regulates mTEC differentiation from podoplanin-expressing presursors in the cortico-medullary junction. Eur. J. Immunol. 45, 2218–2231 (2015).

    Article  CAS  PubMed  Google Scholar 

  111. Mayer, C. E. et al. Dynamic spatio-temporal contribution of single β5t+ cortical epithelial precursors to the thymus medulla. Eur. J. Immunol. 46, 846–856 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Bredenkamp, N., Nowell, C. S. & Blackburn, C. C. Regeneration of the aged thymus by a single transcription factor. Development 141, 1627–1637 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Bredenkamp, N. et al. An organized and functional thymus generated from FOXN1-reprogrammed fibroblasts. Nat. Cell Biol. 16, 902–908 (2014). Demonstrates success in reprogramming embryonic fibroblasts into functional thymic epithelium by introducing FOXN1, offering potential opportunities for TEC-replacement therapies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Lai, L. & Jin, J. Generation of thymic epithelial cell progenitors by mouse embryonic stem cells. Stem Cells 27, 3012–3020 (2009).

    Article  CAS  PubMed  Google Scholar 

  115. Parent, A. V. et al. Generation of functional thymic epithelium from human embryonic stem cells that supports host T cell development. Cell Stem Cell 13, 219–229 (2013).

    Article  CAS  PubMed  Google Scholar 

  116. Sun, X. et al. Directed differentiation of human embryonic stem cells into thymic epithelial progenitor-like cells reconstitutes the thymic microenvironment in vivo. Cell Stem Cell 13, 230–236 (2013).

    Article  CAS  PubMed  Google Scholar 

  117. Soh, C. W. et al. FOXN1(GFP/w) reporter hESCs enable identification of integrin-α4, HLA-DR, and EpCAM as markers of human PSC-derived FOXN1+ thymic epithelial progenitors. Stem Cell Rep. 2, 925–937 (2014).

    Article  CAS  Google Scholar 

  118. Su, M. et al. Efficient in vitro generation of functional thymic epithelial progenitors from human embryonic stem cells. Sci. Rep. 5, 9882 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Boyd, R. L., Soh, C. L., Boyd, N. R., Stanley, E. G. & Chidgey, A. P. Rewiring immunity: generating a functional thymus from hESCs ... are we there yet? Cell Stem Cell 13, 135–136 (2013).

    Article  CAS  PubMed  Google Scholar 

  120. Chaudhry, M. S., Velardi, E., Dudakov, J. A. & van den Brink, M. R. Thymus: the next (re)generation. Immunol. Rev. 271, 56–71 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The Takahama laboratory is supported by grants from the Ministry of Education, Culture, Sports, Science and Technology–Japan Society for the Promotion of Science (MEXT–JSPS; 24111004 and 16H02630 to Y.T. and 15K19130 to I.O.). The Anderson laboratory is supported by a UK Medical Research Council (MRC) Programme grant and a Cancer Research UK (CRUK) Cancer Immunology grant. The Takahama and Anderson laboratories have received joint support from The Royal Society, The Daiwa Anglo-Japanese Foundation and the MEXT–JSPS (the MEXT Joint Usage Research Center Program and the JSPS Open Partnership Joint Project).

Author information

Authors and Affiliations

  1. Division of Experimental Immunology, Institute of Advanced Medical Sciences, University of Tokushima, 770-8503, Tokushima, Japan

    Yousuke Takahama & Izumi Ohigashi

  2. Institute for Immunology and Immunotherapy, Medical School, University of Birmingham, B15 2TT, Birmingham, UK

    Song Baik & Graham Anderson

Authors
  1. Yousuke Takahama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Izumi Ohigashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Song Baik
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Graham Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yousuke Takahama.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Positive selection

The process by which newly generated double-positive thymocytes that interact at low affinity with self-peptide—MHC complexes presented by cortical thymic epithelial cells are induced to survive and differentiate into single-positive thymocytes.

Hassall's corpuscles

A fraction of medullary thymic epithelial cells that form a concentric epithelial structure, which is apparent in the thymus of several limited species, including humans.

Autoimmune regulator

(AIRE). A nuclear protein that is expressed by a subpopulation of medullary thymic epithelial cells and is essential for the establishment of self-tolerance in T cells.

Promiscuous gene expression

A characteristic unique to medullary thymic epithelial cells, in which virtually all genes, including tissue-restricted self-antigens, are expressed.

nude mouse

A naturally occurring mouse strain in which congenital loss of the transcription factor Forkhead box N1 causes defective hair growth and defective thymic epithelial cell development, resulting in defective T cell production and severe immunodeficiency.

Thymic atrophy

A reduction in the size of the thymus that can be caused by ageing, viral infection, irradiation and many other stresses and is associated with a decline in T cell production.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Takahama, Y., Ohigashi, I., Baik, S. et al. Generation of diversity in thymic epithelial cells. Nat Rev Immunol 17, 295–305 (2017). https://doi.org/10.1038/nri.2017.12

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri.2017.12

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing