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:

Thymic epithelial cell heterogeneity: TEC by TEC

Nature Reviews Immunology volume 20, pages 239–253 (2020)Cite this article

Subjects

Abstract

The generation of a functional T cell repertoire in the thymus is mainly orchestrated by thymic epithelial cells (TECs), which provide developing T cells with cues for their navigation, proliferation, differentiation and survival. The TEC compartment has been segregated historically into two major populations of medullary TECs and cortical TECs, which differ in their anatomical localization, molecular characteristics and functional roles. However, recent studies have shown that TECs are highly heterogeneous and comprise multiple subpopulations with distinct molecular and functional characteristics, including tuft cell-like or corneocyte-like phenotypes. Here, we review the most recent advances in our understanding of TEC heterogeneity from a molecular, functional and developmental perspective. In particular, we highlight the key insights that were recently provided by single-cell genomic technologies and in vivo fate mapping and discuss them in the context of previously published data.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: Thymic epithelial cell heterogeneity and development.
Fig. 2: Function and diversity of cortical thymic epithelial cells.
Fig. 3: Model for the differentiation of medullary thymic epithelial cells.
Fig. 4: The heterogeneity of mature medullary thymic epithelial cells stems from differential expression of tissue-restricted antigens.
Fig. 5: Corneocyte-like medullary thymic epithelial cells and Hassal’s corpuscles.
Fig. 6: Thymic tuft cells.

Similar content being viewed by others

References

  1. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Aschenbrenner, K. et al. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat. Immunol. 8, 351–358 (2007). This paper presents one of the first key pieces of evidence to show that AIRE + mTECs are not only involved in clonal deletion but also have a key role in the induction of FOXP3 + T reg cells specific for tissue-restricted antigens.

    CAS  PubMed  Google Scholar 

  3. Cowan, J. E. et al. The thymic medulla is required for Foxp3+ regulatory but not conventional CD4+ thymocyte development. J. Exp. Med. 210, 675–681 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Takahama, Y., Ohigashi, I., Baik, S. & Anderson, G. Generation of diversity in thymic epithelial cells. Nat. Rev. Immunol. 17, 295–305 (2017).

    CAS  PubMed  Google Scholar 

  5. Bornstein, C. et al. Single-cell mapping of the thymic stroma identifies IL-25-producing tuft epithelial cells. Nature 559, 622–626 (2018). This study provides the first comprehensive cell atlas for the thymic stroma (based on scRNA-seq analysis) and identifies thymic tuft cells as a highly divergent subset of mTECs.

    CAS  PubMed  Google Scholar 

  6. 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).

    CAS  PubMed  Google Scholar 

  7. Kozai, M. et al. Essential role of CCL21 in establishment of central self-tolerance in T cells. J. Exp. Med. 214, 1925–1935 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  9. Miragaia, R. J. et al. Single-cell RNA-sequencing resolves self-antigen expression during mTEC development. Sci. Rep. 8, 685 (2018).

    PubMed  PubMed Central  Google Scholar 

  10. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 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). Together with Yano et al. (2008), this study is the first to show that AIRE + mTECs are not terminally differentiated cells but rather give rise to phenotypically distinct subsets characterized by high levels of KRT10 expression.

    CAS  PubMed  Google Scholar 

  12. 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 

  13. Miller, C. N. et al. Thymic tuft cells promote an IL-4-enriched medulla and shape thymocyte development. Nature 559, 627–631 (2018). This study reports the identification and characterization of thymic tuft cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Panneck, A. R. et al. Cholinergic epithelial cell with chemosensory traits in murine thymic medulla. Cell Tissue Res. 358, 737–748 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Soultanova, A. et al. Cholinergic chemosensory cells of the thymic medulla express the bitter receptor Tas2r131. Int. Immunopharmacol. 29, 143–147 (2015).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 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).

    CAS  PubMed  Google Scholar 

  18. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Lepletier, A. et al. Interplay between follistatin, activin A, and BMP4 signaling regulates postnatal thymic epithelial progenitor cell differentiation during aging. Cell Rep. 27, 3887–3901 (2019).

    CAS  PubMed  Google Scholar 

  20. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 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).

    CAS  PubMed  Google Scholar 

  22. 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).

    CAS  PubMed  Google Scholar 

  23. Bleul, C. C. et al. Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature 441, 992–996 (2006). Together with Rossi et al. (2006), this paper provides the first evidence to support the existence of bipotent TEPCs in the embryonic and neonatal thymus.

    CAS  PubMed  Google Scholar 

  24. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Bennett, A. R. et al. Identification and characterization of thymic epithelial progenitor cells. Immunity 16, 803–814 (2002).

    CAS  PubMed  Google Scholar 

  26. Gill, J., Malin, M., Hollander, G. A. & Boyd, R. Generation of a complete thymic microenvironment by MTS24+ thymic epithelial cells. Nat. Immunol. 3, 635–642 (2002).

    CAS  PubMed  Google Scholar 

  27. Rossi, S. W. et al. Redefining epithelial progenitor potential in the developing thymus. Eur. J. Immunol. 37, 2411–2418 (2007).

    CAS  PubMed  Google Scholar 

  28. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  30. Dumont-Lagacé, M. et al. Detection of quiescent radioresistant epithelial progenitors in the adult thymus. Front. Immunol. 8, 1717 (2017).

    PubMed  PubMed Central  Google Scholar 

  31. Sheridan, J. M. et al. Thymospheres are formed by mesenchymal cells with the potential to generate adipocytes, but not epithelial cells. Cell Rep. 21, 934–942 (2017).

    CAS  PubMed  Google Scholar 

  32. Barsanti, M. et al. A novel Foxn1eGFP/+ mouse model identifies Bmp4-induced maintenance of Foxn1 expression and thymic epithelial progenitor populations. Eur. J. Immunol. 47, 291–304 (2017).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  34. Plotkin, J., Prockop, S. E., Lepique, A. & Petrie, H. T. Critical role for CXCR4 signaling in progenitor localization and T cell differentiation in the postnatal thymus. J. Immunol. 171, 4521–4527 (2003).

    CAS  PubMed  Google Scholar 

  35. Jenkinson, W. E. et al. Chemokine receptor expression defines heterogeneity in the earliest thymic migrants. Eur. J. Immunol. 37, 2090–2096 (2007).

    CAS  PubMed  Google Scholar 

  36. Gossens, K. et al. Thymic progenitor homing and lymphocyte homeostasis are linked via S1P-controlled expression of thymic P-selectin/CCL25. J. Exp. Med. 206, 761–778 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Bleul, C. C. & Boehm, T. Chemokines define distinct microenvironments in the developing thymus. Eur. J. Immunol. 30, 3371–3379 (2000).

    CAS  PubMed  Google Scholar 

  38. Hozumi, K. et al. Delta-like 4 is indispensable in thymic environment specific for T cell development. J. Exp. Med. 205, 2507–2513 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  42. Fujimoto, Y. et al. CD83 expression influences CD4+ T cell development in the thymus. Cell 108, 755–767 (2002).

    CAS  PubMed  Google Scholar 

  43. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 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).

    Google Scholar 

  45. Yang, S. J. et al. The quantitative assessment of MHC II on thymic epithelium: implications in cortical thymocyte development. Int. Immunol. 18, 729–739 (2006).

    CAS  PubMed  Google Scholar 

  46. Fiorini, E. et al. Cutting edge: thymic crosstalk regulates delta-like 4 expression on cortical epithelial cells. J. Immunol. 181, 8199–8203 (2008).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  48. Nakagawa, Y. et al. Thymic nurse cells provide microenvironment for secondary T cell receptor α rearrangement in cortical thymocytes. Proc. Natl Acad. Sci. USA 109, 20572–20577 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Guyden, J. C. & Pezzano, M. Thymic nurse cells: a microenvironment for thymocyte development and selection. Int. Rev. Cytol. 223, 1–37 (2003).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Akiyama, T., Shinzawa, M. & Akiyama, N. TNF receptor family signaling in the development and functions of medullary thymic epithelial cells. Front. Immunol. 3, 278 (2012).

    PubMed  PubMed Central  Google Scholar 

  52. Hamazaki, Y. et al. Medullary thymic epithelial cells expressing Aire represent a unique lineage derived from cells expressing claudin. Nat. Immunol. 8, 304–311 (2007).

    CAS  PubMed  Google Scholar 

  53. 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).

    CAS  PubMed  Google Scholar 

  54. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 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).

    CAS  PubMed  Google Scholar 

  56. Akiyama, T. et al. Dependence of self-tolerance on TRAF6-directed development of thymic stroma. Science 308, 248–251 (2005).

    CAS  PubMed  Google Scholar 

  57. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Bonito, A. J. et al. Medullary thymic epithelial cell depletion leads to autoimmune hepatitis. J Clin. Invest. 123, 3510–3524 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Burkly, L. et al. Expression of RelB is required for the development of thymic medulla and dendritic cells. Nature 373, 531–536 (1995).

    CAS  PubMed  Google Scholar 

  60. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. White, A. J. et al. Sequential phases in the development of Aire-expressing medullary thymic epithelial cells involve distinct cellular input. Eur. J. Immunol. 38, 942–947 (2008).

    CAS  PubMed  Google Scholar 

  62. Irla, M. et al. Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity. Immunity 29, 451–463 (2008).

    CAS  PubMed  Google Scholar 

  63. 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).

    CAS  PubMed  Google Scholar 

  64. Venanzi, E. S., Gray, D. H. D., Benoist, C. & Mathis, D. Lymphotoxin pathway and Aire influences on thymic medullary epithelial cells are unconnected. J. Immunol. 179, 5693–5700 (2007).

    CAS  PubMed  Google Scholar 

  65. Martins, V. C., Boehm, T. & Bleul, C. C. Ltβr signaling does not regulate Aire-dependent transcripts in medullary thymic epithelial cells. J. Immunol. 181, 400–407 (2008).

    CAS  PubMed  Google Scholar 

  66. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Michel, C. et al. Revisiting the road map of medullary thymic epithelial cell differentiation. J. Immunol. 199, 3488–3503 (2017).

    CAS  PubMed  Google Scholar 

  68. 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).

    CAS  PubMed  Google Scholar 

  69. 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).

    CAS  PubMed  Google Scholar 

  70. Zhang, S. L. & Bhandoola, A. Trafficking to the thymus. Curr. Top. Microbiol. Immunol. 373, 87–111 (2013).

    Google Scholar 

  71. Cosway, E. J. et al. Formation of the intrathymic dendritic cell pool requires CCL21-mediated recruitment of CCR7+ progenitors to the thymus. J. Immunol. 201, 516–523 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  73. Klein, L., Klugmann, M., Nave, K.-A., Tuohy, V. K. & Kyewski, B. Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells. Nat. Med. 6, 56–61 (2000).

    CAS  PubMed  Google Scholar 

  74. Anderson, M. S. et al. Projection of an immunological self shadow within the thymus by the aire protein. Science. 298, 1395–1401 (2002). This study is the first to uncover the functional role of AIRE in promiscuous gene expression and central tolerance induction.

    CAS  PubMed  Google Scholar 

  75. DeVoss, J. et al. Spontaneous autoimmunity prevented by thymic expression of a single self-antigen. J. Exp. Med. 203, 2727–2735 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Fan, Y. et al. Thymus-specific deletion of insulin induces autoimmune diabetes. EMBO J. 28, 2812–2824 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Gavanescu, I., Kessler, B., Ploegh, H., Benoist, C. & Mathis, D. Loss of Aire-dependent thymic expression of a peripheral tissue antigen renders it a target of autoimmunity. Proc. Natl Acad. Sci.USA 104, 4583–4587 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Lv, H. et al. Impaired thymic tolerance to α-myosin directs autoimmunity to the heart in mice and humans. J. Clin. Invest. 121, 1561–1573 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 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).

    PubMed  PubMed Central  Google Scholar 

  82. 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). This comprehensive study is the first to identify the phenomenon of promiscuous gene expression as an integral functional property of mTECs.

    CAS  PubMed  Google Scholar 

  83. 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).

    PubMed  Google Scholar 

  84. Sousa Cardoso, R. et al. Onset of promiscuous gene expression in murine fetal thymus organ culture. Immunology 119, 369–375 (2006).

    PubMed  PubMed Central  Google Scholar 

  85. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Kernfeld, E. M. et al. A single-cell transcriptomic atlas of thymus organogenesis resolves cell types and developmental maturation. Immunity 48, 1258–1270 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  88. Avichezer, D. et al. An immunologically privileged retinal antigen elicits tolerance: major role for central selection mechanisms. J. Exp. Med. 198, 1665–1676 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Gillard, G. O. & Farr, A. G. Features of medullary thymic epithelium implicate postnatal development in maintaining epithelial heterogeneity and tissue-restricted antigen expression. J. Immunol. 176, 5815–5824 (2006).

    CAS  PubMed  Google Scholar 

  90. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Villasenor, 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 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).

    CAS  PubMed  Google Scholar 

  93. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 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). Together with Sansom et al. (2014) and Meredith et al. (2015), this study is the first to use scRNA-seq analysis to address the complexity of promiscuous gene expression in mTECs at a single-cell level.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Takase, H. et al. Thymic expression of peripheral tissue antigens in humans: a remarkable variability among individuals. Int. Immunol. 17, 1131–1140 (2005).

    CAS  PubMed  Google Scholar 

  96. Takaba, H. et al. Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. Cell 163, 975–987 (2015).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  98. 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).

    Google Scholar 

  99. Perniola, R. Twenty years of AIRE. Front. Immunol. 9, 98 (2018).

    PubMed  PubMed Central  Google Scholar 

  100. Nishikawa, Y. et al. Biphasic Aire expression in early embryos and in medullary thymic epithelial cells before end-stage terminal differentiation. J. Exp. Med. 207, 963–971 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Nuber, U. A., Schäfer, S., Stehr, S., Rackwitz, H. R. & Franke, W. W. Patterns of desmocollin synthesis in human epithelia: immunolocalization of desmocollins 1 and 3 in special epithelia and in cultured cells. Eur. J. Cell Biol. 71, 1–13 (1996).

    CAS  PubMed  Google Scholar 

  102. Hale, L. P. & Markert, M. L. Corticosteroids regulate epithelial cell differentiation and Hassall body formation in the human thymus. J. Immunol. 172, 617–624 (2004).

    CAS  PubMed  Google Scholar 

  103. Farr, A. G. & Anderson, S. K. Epithelial heterogeneity in the murine thymus: fucose-specific lectins bind medullary epithelial cells. J. Immunol. 134, 2971–2977 (1985).

    CAS  PubMed  Google Scholar 

  104. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 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). Together with Perry et al. (2014), this pioneering study provides key mechanistic insights into the complementary roles of mTECs and DCs in antigen presentation in the thymus.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Leventhal, D. S. et al. Dendritic cells coordinate the development and homeostasis of organ-specific regulatory T cells. Immunity 44, 847–859 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Watanabe, N. et al. Hassall’s corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature 436, 1181–1185 (2005).

    CAS  PubMed  Google Scholar 

  108. Odaka, C. et al. TGF-β type II receptor expression in thymic epithelial cells inhibits the development of Hassall’s corpuscles in mice. Int. Immunol. 25, 633–642 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Mikušová, R., Mešťanová, V., Polák, Š. & Varga, I. What do we know about the structure of human thymic Hassall’s corpuscles? A histochemical, immunohistochemical, and electron microscopic study. Ann. Anat. 211, 140–148 (2017).

    PubMed  Google Scholar 

  110. Banerjee, A., McKinley, E. T., von Moltke, J., Coffey, R. J. & Lau, K. S. Interpreting heterogeneity in intestinal tuft cell structure and function. J. Clin. Invest. 128, 1711–1719 (2018).

    PubMed  PubMed Central  Google Scholar 

  111. Gerbe, F., Legraverend, C. & Jay, P. The intestinal epithelium tuft cells: specification and function. Cell. Mol. Life Sci. 69, 2907–2917 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Farr, A. G. & Rudensky, A. Medullary thymic epithelium: a mosaic of epithelial ‘self’? J. Exp. Med. 188, 1–4 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Van Ewijk, W. Cell surface topography of thymic microenvironments. Lab. Invest. 59, 579–590 (1988).

    PubMed  Google Scholar 

  114. Gerbe, F. et al. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 529, 226–230 (2016).

    CAS  PubMed  Google Scholar 

  115. Yamaguchi, T. et al. Skn-1a/Pou2f3 is required for the generation of Trpm5-expressing microvillous cells in the mouse main olfactory epithelium. BMC Neurosci. 15, 13 (2014).

    PubMed  PubMed Central  Google Scholar 

  116. Ohmoto, M. et al. Pou2f3/Skn-1a is necessary for the generation or differentiation of solitary chemosensory cells in the anterior nasal cavity. Biosci. Biotechnol. Biochem. 77, 2154–2156 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Saqui-Salces, M. et al. Gastric tuft cells express DCLK1 and are expanded in hyperplasia. Histochem. Cell Biol. 136, 191–204 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Gerbe, F. et al. Distinct ATOH1 and Neurog3 requirements define tuft cells as a new secretory cell type in the intestinal epithelium. J. Cell Biol. 192, 767–780 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Bjerknes, M. et al. Origin of the brush cell lineage in the mouse intestinal epithelium. Dev. Biol. 362, 194–218 (2012).

    CAS  PubMed  Google Scholar 

  120. Sato, A., Hamano, M. & Miyoshi, S. Increasing frequency of occurrence of tuft cells in the main excretory duct during postnatal development of the rat submandibular gland. Anat. Rec. 252, 276–280 (1998).

    CAS  PubMed  Google Scholar 

  121. Höfer, D. & Drenckhahn, D. Cytoskeletal markers allowing discrimination between brush cells and other epithelial cells of the gut including enteroendocrine cells. Histochem. Cell Biol. 105, 405–412 (1996).

    PubMed  Google Scholar 

  122. Kasper, M. et al. Colocalization of cytokeratin 18 and villin in type III alveolar cells (brush cells) of the rat lung. Histochemistry 101, 57–62 (1994).

    CAS  PubMed  Google Scholar 

  123. O’Leary, C. E., Schneider, C. & Locksley, R. M. Tuft cells — systemically dispersed sensory epithelia integrating immune and neural circuitry. Annu. Rev. Immunol. 37, 47–72 (2019).

    PubMed  Google Scholar 

  124. Nadjsombati, M. S. et al. Detection of succinate by intestinal tuft cells triggers a type 2 innate immune circuit. Immunity 49, 33–41 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Von Moltke, J., Ji, M., Liang, H. E. & Locksley, R. M. Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature 529, 221–225 (2016).

    Google Scholar 

  126. Howitt, M. R. et al. Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 351, 1329–1333 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Lei, W. et al. Activation of intestinal tuft cell-expressed Sucnr1 triggers type 2 immunity in the mouse small intestine. Proc. Natl Acad. Sci. USA 115, 5552–5557 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Schneider, C. et al. A metabolite-triggered tuft cell-ILC2 circuit drives small intestinal remodeling. Cell 174, 271–284 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Research in the Abramson laboratory is kindly supported by the European Research Council (ERC-2016-CoG-724821), Israel Science Foundation (1796/16), Chan Zuckerberg Initiative, Sy Syms Foundation, Wohl Biology Endowment Fund, Erica Drake Fund, Slomo and Cindy Silvian Foundation, The Enoch Foundation, Ruth and Samuel David Gameroff Family Foundation and Lilly Fulop Fund for Multiple Sclerosis Research.

Author information

Authors and Affiliations

  1. Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

    Noam Kadouri, Shir Nevo, Yael Goldfarb & Jakub Abramson

Authors
  1. Noam Kadouri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shir Nevo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yael Goldfarb
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jakub Abramson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Jakub Abramson.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Immunology thanks A. Chidgey, Y. Takahama and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Thymic epithelial cells

(TECs). Specialized stromal cells found in the thymus that have the ability to present antigens on MHC class I and class II molecules to developing T cells (thymocytes). Their main known functions include the induction of T cell lineage commitment, positive selection of functional T cell clones and negative selection of self-reactive T cell clones.

Positive selection

A crucial checkpoint in αβ T cell development, exclusively facilitated by cortical thymic epithelial cells, that ensures only functionally competent T cell clones capable of recognizing peptide–MHC complexes with adequately high affinity continue in the developmental process. T cell clones that do not recognize peptide–MHC complexes with sufficient affinity die by neglect.

Negative selection

A selection process mediated by thymus-resident antigen-presenting cells (for example, medullary thymic epithelial cells, dendritic cells and B cells) that ensures T cell clones that recognize self-peptide–MHC complexes with very high affinity are eliminated from the repertoire. This process occurs mainly in the thymic medulla, although there is some evidence that negative selection can also occur in the cortex.

Agonist selection

A selection process that ensures CD4+ T cell clones that recognize self-peptide–MHC class II complexes with medium to high affinity differentiate into CD4+CD25+FOXP3+ regulatory T cells. It has been suggested that this process is mediated by medulla-resident antigen-presenting cells (such as medullary thymic epithelial cells, dendritic cells and B cells).

Autoimmune regulator

(AIRE). A transcriptional regulator, expressed almost exclusively in mature MHCIIhi medullary thymic epithelial cells. It induces the expression of most tissue-restricted antigen genes in the thymus, a step that is necessary for purging of self-reactive T cells and induction of central tolerance.

Thymoproteasome

A specialized form of the proteasome that is found exclusively in cortical thymic epithelial cells and that is essential for the generation of a unique peptide repertoire to support positive selection of T cell clones. The thymoproteasome uniquely incorporates the β5t subunit (encoded by Psmb11).

Reaggregate thymic organ cultures

(RTOC). An experimental method that enables the ex vivo generation of three-dimensional thymic organoids from purified fetal thymic epithelial cells and other thymic cell subsets. The resulting organoids can also be used in transplantation studies for a longer period of time.

Thymic nurse cells

(TNCs). Large cortical thymic epithelial structures that internalize developing thymocytes through extensions of the plasma membrane. Thymic nurse cells can internalize up to 200 double-positive thymocytes and have been shown to be crucial for secondary T cell receptor α-chain rearrangement.

Nude mice

A mouse strain having a naturally occurring loss-of-function mutation in the Forkhead box N1 (Foxn1) gene, which encodes a transcription factor that is crucial for the development of hair follicles, mammary glands and thymic epithelial cells. As a result, nude mice develop no hair and have a dysfunctional thymic rudiment, which is unable to support normal T cell development, resulting in severe immunodeficiency.

Csn2 Cre+Rosa26 tdTomato reporter mice

Csn2Cre+ mice are a transgenic mouse model in which the coding sequence for Cre recombinase is inserted downstream of the Csn2 gene promoter. Rosa26tdTomato mice are a transgenic mouse model in which the tdTomato reporter gene, together with a stop cassette flanked by loxP sites, is inserted into the Rosa26 locus. As Csn2 is specifically expressed in most MHCIIhiCD80hi (mTEChi) cells, the Csn2Cre+Rosa26tdTomato reporter mice enable lineage tracing of mTEChi-derived cells.

CCL21Ser-deficient mice

A transgenic mouse model in which the tdTomato reporter gene is inserted at the translation initiation site of the Ccl21a gene promoter, without affecting the expression of Ccl21b or Ccl21c genes. Mice homozygous for the insertion are therefore specifically deficient for CCL21Ser, but not for CCL21Leu, which is encoded by Ccl21b and/or Ccl21c.

Tissue-restricted antigens

(TRAs). Proteins that are expressed, processed and presented by thymic epithelial cells to developing thymocytes for the purpose of selection that are otherwise specifically expressed only in five or fewer peripheral tissues.

AIRE-dependent gene

A gene that requires autoimmune regulator (AIRE) for its expression.

AIRE-enhanced genes

Genes that have low levels of expression in the absence of autoimmune regulator (AIRE) but expression of which is significantly increased by AIRE.

Ordered stochasticity

The autoimmune regulator (AIRE) protein is said to operate with ordered stochasticity, such that the genes it activates in individual medullary thymic epithelial cells are stochastically selected, but the process is not completely random as co-expression groups of genes within cells are found.

Autoimmune polyendocrine syndrome type 1

(APS1). A genetic disorder, caused by mutations in the AIRE gene, that leads to a devastating multi-organ autoimmune syndrome. It is diagnosed when patients present with at least two out of three of the classical symptoms, which include chronic mucocutaneous candidiasis, hypoparathyroidism and adrenocortical insufficiency.

Hassall’s corpuscles

Islet-like structures found in the medullary region of the thymus that are composed of squamous epithelial cells expressing high levels of various keratins (for example, KRT10) and involucrin.

Type 2 immune response

An immune response characterized by an increased production of various cytokines (such as IL-4, IL-5 and IL-13) and concomitant activation of distinct immune cell populations, including T helper 2 cells, eosinophils, basophils, mast cells, group 2 innate lymphoid cells and type 2 natural killer T cells. The type 2 immune response has an important role in host defence against parasites, but when dysregulated may underlie the development of diverse allergic disorders.

Group 2 innate lymphoid cells

(ILC2s). A population of lymphoid-derived cells that are defined by the absence of key lymphoid, myeloid and dendritic cell markers and by expression of the transcription factor GATA3 and various type 2 cytokines, such as IL-4, IL-5, IL-9 and IL-13. They have been identified in many tissues, including the skin, intestinal tract and respiratory tract, and they have been suggested to have a role in immune responses against parasites, as well as in allergy and asthma.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kadouri, N., Nevo, S., Goldfarb, Y. et al. Thymic epithelial cell heterogeneity: TEC by TEC. Nat Rev Immunol 20, 239–253 (2020). https://doi.org/10.1038/s41577-019-0238-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41577-019-0238-0

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