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:

Self-representation in the thymus: an extended view

Nature Reviews Immunology volume 4, pages 688–698 (2004)Cite this article

Key Points

  • Self-tolerance of T cells is commonly divided into central (thymic) and peripheral tolerance according to its site of induction. Self-tolerance to most peripheral parenchymal organs has been ascribed to peripheral tolerance. The finding that many tissue-specific genes are expressed by medullary thymic epithelial cells (mTECs) — known as promiscuous gene expression — has changed this view.

  • Tissue-specific self-antigens expressed by mTECs are functionally and structurally highly diverse and encompass essentially all organs. This allows self-antigens, which are expressed in a spatially or temporally restricted manner (such as pregnancy- or puberty-associated self-antigens) to become continuously accessible to developing T cells.

  • mTECs express self-antigens of both large and small organs at similar frequencies, therefore equating possible differences in the tolerogenic potential of organs of varying size.

  • Both genetic and epigenetic mechanisms seem to account for this unorthodox mode of gene expression.

  • Deficiencies in promiscuous gene expression can lead to organ-specific or multi-organ autoimmune syndromes.

  • Promiscuous gene expression might have co-evolved with adaptive immunity in the wake of antigen-receptor diversity early during vertebrate development.

Abstract

The thymus has been viewed as the main site of tolerance induction to self-antigens that are specifically expressed by thymic cells and abundant blood-borne self-antigens, whereas tolerance to tissue-restricted self-antigens has been ascribed to extrathymic (peripheral) tolerance mechanisms. However, the phenomenon of promiscuous expression of tissue-restricted self-antigens by medullary thymic epithelial cells has led to a reassessment of the role of central T-cell tolerance in preventing organ-specific autoimmunity. Recent evidence indicates that both genetic and epigenetic mechanisms account for this unorthodox mode of gene expression. As we discuss here, these new insights have implications for our understanding of self-tolerance in humans, its breakdown in autoimmune diseases and the significance of this tolerance mode in vertebrate evolution.

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 tissues are represented by promiscuous gene expression in medullary thymic epithelial cells (mTECs).
Figure 2: The multiclonal model of promiscuous gene expression.
Figure 3: The differentiation model of promiscuous gene expression in thymic epithelial cells.
Figure 4: Central tolerance to tissue-restricted self-antigens by recessive and dominant mechanisms.
Figure 5: Bystander suppression might compensate for incomplete self-representation in the thymus.

Similar content being viewed by others

References

  1. Ehrlich, P. & Morgenroth, J. II. Ueber Hämolysine. Berl. Klin. Wochenschr. 28, 251–257 (1901).

    Google Scholar 

  2. Hood, L. E., Weissman, I. L., Wood, W. B. & Wilson, J. H. Immunology. 2nd edn. (The Benjamin/Cummings Publishing Company, Inc., Palo Alto, 1978).

    Google Scholar 

  3. Klein, J. Immunology: The Science of Self-Nonself Discrimination. (John Wiley, New York, 1982).

    Google Scholar 

  4. Schwartz, R. H. & Mueller, D. L. in Fundamental Immunology 5th edn (ed. Paul, W. E.) 901–934 (Lippincott Williams & Wilkins, Philadelphia, 2003).

    Google Scholar 

  5. Medzhitov, R. & Janeway, C. A. Jr. Innate immunity, the virtues of a nonclonal system of recognition. Cell 91, 295–298 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Klein, L. & Kyewski, B. Self-antigen presentation by thymic stromal cells: a subtle division of labor. Curr. Opin. Immunol. 12, 179–186 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Alferink, J., Aigner, S., Reibke, R., Hämmerling, G. J. & Arnold, B. Peripheral T cell tolerance: the contribution of permissive T cell migration into parenchymal tissues of the neonate. Immunol. Rev. 169, 255–261 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Walker, L. S. & Abbas, A. K. The enemy within: keeping self-reactive T cells at bay in the periphery. Nature Rev. Immunol. 2, 11–19 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Gotter, J., Brors, B., Hergenhahn, M. & Kyewski, B. Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes co-localized in chromosomal clusters. J. Exp. Med. 199, 155–166 (2004). References 9 and 10 define and describe the phenomenon of promiscuous gene expression by purified mouse and human TEC subsets, addressing the expression pattern, scope and co-localization in chromosomal clusters of promiscuously expressed genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sospedra, M. et al. Transcription of a broad range of self-antigens in human thymus suggests a role for central mechanisms in tolerance toward peripheral antigens. J. Immunol. 161, 5918–5929 (1998).

    CAS  PubMed  Google Scholar 

  12. Bruno, R. et al. Multiple sclerosis candidate autoantigens except myelin oligodendrocyte glycoprotein are transcribed in human thymus. Eur. J. Immunol. 32, 2737–2747 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Bruno, R. et al. Different patterns of nicotinic acetylcholine receptor subunit transcription in human thymus. J. Neuroimmunol. 149, 147–159 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Kyewski, B., Derbinski, J., Gotter, J. & Klein, L. Promiscuous gene expression and central T-cell tolerance: more than meets the eye. Trends Immunol. 23, 364–371 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Mathis, D. & Benoist, C. Back to central tolerance. Immunity 20, 509–516 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Heid, H. W., Moll, I. & Franke, W. W. Patterns of expression of trychocytic and epithelial cytokeratins in mammalian tissue. II. Concomitant and mutually exclusive synthesis of trychocytic and epithelial cytokeratins in diverse human and bovine tissues (hair follicle, nail bed, and matrix, lingua papilla, thymic reticulum). Differentiation 37, 215–230 (1988).

    Article  CAS  PubMed  Google Scholar 

  17. Kirchner, T. et al. Pathogenesis of myasthenia gravis. Acetylcholine receptor-related antigenic determinants in tumor-free thymuses and thymic epithelial tumors. Am. J. Pathol. 130, 268–280 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Jolicoeur, C., Hanahan, D. & Smith, K. M. T-cell tolerance toward a transgenic β-cell antigen and transcription of endogenous pancreatic genes in thymus. Proc. Natl Acad. Sci. USA 91, 6707–6711 (1994). This paper shows transcription of several self-antigens of the exocrine and endocrine pancreas in the mouse thymus and for the first time promotes the notion that ectopic expression of tissue-restricted antigens is a physiological property of thymic stromal cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pribyl, T. M., Campagnoni, C., Kampf, K., Handley, V. W. & Campagnoni, A. T. The major myelin protein genes are expressed in the human thymus. J. Neurosci. Res. 45, 812–819 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Geenen, V. & Lefebre, P. J. The intrathymic expression of insulin-related genes: implications for pathophysiology and prevention of type 1 diabetes. Diabetes Metab. Rev. 14, 95–110 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. van Herrath, M. G., Dockter, D. & Oldstone, M. B. How virus induces a rapid or slow onset insulin-dependant diabetes mellitus in a transgenic model. Immunity 1, 231–242 (1994).

    Article  Google Scholar 

  22. 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).

    Article  CAS  PubMed  Google Scholar 

  23. Salmon, A. M., Bruand, C., Cardona, A., Changeux, J. P. & Berrih-Aknin, S. An acetylcholine receptor α subunit promoter confers intrathymic expression in transgenic mice. Implications for tolerance of a transgenic self-antigen and for autoreactivity in myasthenia gravis. J. Clin. Invest. 101, 2340–2350 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Antonia, S. J., Geiger, T., Miller, J. & Flavell, R. A. Mechanisms of immune tolerance induction through the thymic expression of a peripheral tissue-specific protein. Int. Immunol. 7, 715–725 (1995).

    Article  CAS  PubMed  Google Scholar 

  25. Klein, L., Klein, T., Ruether, U. & Kyewski, B. CD4+ T cell tolerance to human C-reactive protein, an inducible serum protein, is mediated by medullary thymic epithelium. J. Exp. Med. 188, 5–16 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Visan, L. et al. Tolerance induction by intrathymic expressin of P0. J. Immunol. 172, 1364–1370 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Ham, D. I. et al. Central immunotolerance in transgenic mice expressing a foreign antigen under control of the rhodopsin promotor. Invest. Ophthalmol. Vis. Sci. 45, 857–862 (2004).

    Article  PubMed  Google Scholar 

  28. Matzinger, P. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045 (1994).

    Article  CAS  PubMed  Google Scholar 

  29. Volkmann, A., Zal, T. & Stockinger, B. Antigen-presenting cells in the thymus that can negatively select MHC class II-restricted T cells recognizing a circulating self antigen. J. Immunol. 158, 693–706 (1997).

    CAS  PubMed  Google Scholar 

  30. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Alonso, L. & Fuchs, E. Stem cells of the skin epithelium. Proc. Natl Acad. Sci. USA 100, 11830–11835 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Booth, C. & Potten, C. S. Gut instincts: thoughts on intestinal epithelial stem cells. J. Clin. Invest. 105, 1493–1499 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kamath, A. T., Henri, S., Battye, F., Tough, D. F. & Shortman, K. Developmental kinetics and lifespan of dendritic cells in mouse lymphoid organs. Blood 100, 1734–1741 (2002).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Farr, A. G., Dooley, J. L. & Erickson, M. Organization of thymic medullary epithelial heterogeneity: implications for mechanisms of epithelial differentiation. Immunol. Rev. 189, 20–27 (2002). A discussion of two competing models possibly underlying promiscuous gene expression, the differentiation model and the mosaic model. The presence of 'islands' of lung epithelium and thyroid follicles in the mouse thymic medulla are interpreted as evidence for the mosaic model.

    Article  CAS  PubMed  Google Scholar 

  36. Chin, R. K. et al. Lymphotoxin pathway directs thymic Aire expression. Nature Immunol. 4, 1121–1127 (2003). This report shows that triggering of LTβR upregulates Aire gene expression by TECs in vivo and in vitro , thereby identifying Aire as a downstream target of this signalling pathway and providing a first clue to its molecular regulation.

    Article  CAS  Google Scholar 

  37. Chentoufi, A. A. & Polychronakos, C. Insulin expression levels in the thymus modulate insulin-specific autoreactive T-cell tolerance: the mechanism by which the IDDM2 locus may predispose to diabetes. Diabetes 51, 1383–1390 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Langbein, L. et al. Tight junction-related structures in the absence of a lumen: occluding, claudins and tight junction plaque proteins in densely packed cell formations of stratified epithelia and squamous cell carcinomas. Eur. J. Cell Biol. 82, 385–400 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Chentoufi, A. A., Palumbo, M. & Polychronakos, C. Proinsulin expression by Hassall's corpuscles in the mouse thymus. Diabetes 53, 354–359 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Pitkanen, J. & Peterson, P. Autoimmune regulator: from loss of function to autoimmunity. Genes Immun. 4, 12–21 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Anderson, M. S. et al. Projection of an immunological self-shadow within the thymus by the aire protein. Science 298, 1395–1401 (2002). This paper shows that the transcriptional regulator AIRE directs the expression of many promiscuously expressed genes and that its deletion leads to a multi-organ autoimmune syndrome similar to APS-1 in humans.

    Article  CAS  PubMed  Google Scholar 

  42. Liston, A., Lesage, S., Wilson, J., Peltonen, L. & Goodnow, C. C. Aire regulates negative selection of organ-specific T cells. Nature Immunol. 4, 350–354 (2003). These authors show that AIRE directs the expression of a neo-self antigen under the control of the rat insulin promoter in a transgenic model and that in the absence of AIRE, deletion of antigen-specific T cells is abolished.

    Article  CAS  Google Scholar 

  43. Kumar, P. G. et al. The autoimmune regulator (Aire) is a DNA-binding protein. J. Biol. Chem. 276, 41357–41364 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Kajiura, F. et al. NF-κB-inducing kinase establishes self-tolerance in a thymic stroma-dependent manner. J. Immunol. 172, 2067–2075 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Watanabe, N. et al. Human thymic stromal lymphopoietin promotes dendritic cell-mediated CD4+ T cell homeostatic expansion. Nature Immunol. 5, 426–434 (2004).

    Article  CAS  Google Scholar 

  46. Pugliese, A. et al. The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nature Genet. 15, 293–297 (1997).

    Article  CAS  PubMed  Google Scholar 

  47. Vafiadis, P. et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nature Genet. 15, 289–292 (1997). References 46 and 47 describe a correlation between allelic forms of a genomic region upstream of the insulin promoter (the VNTR- IDDM2 locus), expression levels of insulin in the human thymus and susceptibility to type 1 diabetes mellitus, thereby establishing a link between intrathymic expression levels of a tissue-restricted antigen and susceptibility to organ-specific autoimmunity.

    Article  CAS  PubMed  Google Scholar 

  48. Venanzi, E., Anderson, M. S., Johnnidis, J., Benoist, C. & Mathis, D. Aire influences peripheral antigen expression and the development of autoimmunity. (Keystone Symposia, T Cell Development, 10–15 February 2004) Abstract 334 (Banff, Alberta, Canada).

  49. Schonrich, G., Momburg, F., Hammerling, G. J. & Arnold, B. Anergy induced by thymic medullary epithelium. Eur. J. Immunol. 22, 1687–1691 (1992).

    Article  CAS  PubMed  Google Scholar 

  50. Bonomo, A. & Matzinger, P. Thymus epithelium induces tissue-specific tolerance. J. Exp. Med. 177, 1153–1164 (1993).

    Article  CAS  PubMed  Google Scholar 

  51. Hoffmann, M. W., Allison, J. & Miller, J. F. Tolerance induction by thymic epithelium. Proc. Natl Acad. Sci. USA 89, 2526–2530 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sprent, J., Kosaka, H., Gao, E. K., Surh, C. D. & Webb, S. R. Intrathymic and extrathymic tolerance in bone marrow chimeras. Immunol. Rev. 133, 151–176 (1993).

    Article  CAS  PubMed  Google Scholar 

  53. Hoffmann, M. W., Heath, W. R., Ruschmeyer, D. & Miller, J. F. Deletion of high-avidity T cells by thymic epithelium. Proc. Natl Acad. Sci. USA 92, 9851–9855 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Klein, L., Roettinger, B. & Kyewski, B. Sampling of complementing self-antigen pools by thymic stromal cells maximizes the scope of central T cell tolerance. Eur. J. Immunol. 31, 2476–2486 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Scollay, R. & Godfrey, D. I. Thymic emigration: conveyor belts or lucky dips? Immunol. Today 16, 268–273 (1995).

    Article  CAS  PubMed  Google Scholar 

  57. Bousso, P. & Robey, E. Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes. Nature Immunol. 4, 579–585 (2003).

    Article  CAS  Google Scholar 

  58. Witt, C. M. & Robey, E. Characterizing thymocyte migration in an intact thymus using two-photon laser-scanning microscopy. (Keystone Symposia, T Cell Development, 10–15 February 2004) Late abstract (Banff, Alberta, Canada).

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

    Article  CAS  PubMed  Google Scholar 

  60. Annunziato, F., Romagnani, P., Cosmi, L., Lazzeri, E. & Romagnani, S. Chemokines and lymphopoiesis in human thymus. Trends Immunol. 22, 277–281 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Kwan, J. & Killeen, N. CCR7 directs the migration of thymocytes into the thymic medulla. J. Immunol. 172, 3999–4007 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Bajenoff, M., Granjeaud, S. & Guerder, S. The strategy of T cell antigen-presenting cell encounter in antigen-draining lymph nodes revealed by imaging of initial T cell activation. J. Exp. Med. 198, 715–724 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhang, M. et al. T cell tolerance to a neo-self antigen expressed by thymic epithelial cells: the soluble form is more effective than the membrane-bound form. J. Immunol. 170, 3954–3962 (2003). This report supports the concept of 'antigen-spreading' from mTECs to DCs by showing that a soluble form of a neo-self antigen produced by mTECs is more effective in deleting autoreactive thymocytes than a membrane-bound form.

    Article  CAS  PubMed  Google Scholar 

  64. Gallegos, A. & Bevan, M. Requirements for antigen presentation in central tolerance to tissue-specific antigens. (Keystone Symposia, T Cell Development, 10–15 February 2004) Abstract 211 (Banff, Alberta, Canada).

  65. Muller, V. & Bonhoeffer, S. Quantitative constraints on the scope of negative selection. Trends Immunol. 24, 132–135 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. Anderson, A. C. & Kuchroo, V. K. Expression of self-antigen in the thymus: a little goes a long way. J. Exp. Med. 198, 1627–1629 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Le Douarin, N. et al. Evidence for a thymus-dependent form of tolerance that is not based on elimination or anergy of reactive T cells. Immunol. Rev. 149, 35–53 (1996). This review summarizes pioneering studies in the chicken/quail model and in mice by showing that TECs confer transferable tolerance to various non-haematopoietic tissues.

    Article  CAS  PubMed  Google Scholar 

  68. Modigliani, Y., Bandeira, A. & Coutinho, A. A model for developmentally acquired thymus-dependent tolerance to central and peripheral antigens. Immunol. Rev. 149, 155–174 (1996).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  70. Bensinger, S. J., Bandeira, A., Jordan, M. S., Caton, A. J. & Laufer, T. M. Major histocompatibility complex class II-positive cortical epithelium mediates the selection of CD4+CD25+ immunoregulatory T cells. J. Exp. Med. 194, 427–438 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Jordan, M. S. et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nature Immunol. 2, 301–306 (2001).

    Article  CAS  Google Scholar 

  72. Apostolou, I., Sarukhan, A., Klein, L. & von Boehmer, H. Origin of regulatory T cells with known specificity for antigen. Nature Immunol. 3, 756–763 (2002). Both studies 71 and 72 show that ectopic expression of neo-self-antigens by mTECs results in efficient intrathymic selection of antigen-specific CD4+CD25+ T Reg cells.

    Article  CAS  Google Scholar 

  73. Ramsey, C. et al. Aire deficient mice develop multiple features of APECED phenotype and show altered immune response. Hum. Mol. Genet. 11, 397–409 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Khattri, R., Cox, T., Yasayko, S. A. & Ramsdell, F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nature Immunol. 4, 337–342 (2003).

    Article  CAS  Google Scholar 

  75. Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunol. 4, 330–336 (2003).

    Article  CAS  Google Scholar 

  76. Schluesener, H. J. & Wekerle, H. Autoaggressive T lymphocyte lines recognizing the encephalitogenic region of myelin basic protein: in vitro selection from unprimed rat T lymphocyte populations. J. Immunol. 135, 3128–3133 (1985).

    CAS  PubMed  Google Scholar 

  77. Fowell, D. & Mason, D. Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential. J. Exp. Med. 177, 627–636 (1993).

    Article  CAS  PubMed  Google Scholar 

  78. Wucherpfennig, K. W. et al. Clonal expansion and persistence of human T cells specific for an immunodominant myelin basic protein peptide. J. Immunol. 152, 5581–5592 (1994).

    CAS  PubMed  Google Scholar 

  79. Waldmann, H. & Cobbold, S. Regulating the immune response to transplants. A role for CD4+ regulatory cells? Immunity 14, 399–406 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Vogel, A., Strassburg, C. P., Obermayer-Straub, P., Brabant, G. & Manns, M. P. The genetic background of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy and its autoimmune disease components. J. Mol. Med. 80, 201–211 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Soderbergh, A. et al. Prevalence and clinical associations of 10 defined autoantibodies in autoimmune polyendocrine syndrome type I. J. Clin. Endocrinol. Metab. 89, 557–562 (2004).

    Article  PubMed  CAS  Google Scholar 

  82. Viglietta, V., Kent, S. C., Orban, T. & Hafler, D. A. GAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes. J. Clin. Invest. 109, 895–903 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lernmark, A. Controlling the controls: GAD65 autoreactive T cells in type 1 diabetes. J. Clin. Invest. 109, 869–870 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Baekkeskov, S., Knaani, J., Jaume, J. C. & Kash, S. Does GAD have a unique role in triggering IDDM? J. Autoimmun. 15, 279–286 (2000).

    Article  CAS  PubMed  Google Scholar 

  85. Egwuagu, C. E., Charukamnoetkanok, P. & Gery, I. Thymic expression of autoantigens correlates with resistance to autoimmune disease. J. Immunol. 159, 3109–3112 (1997). One of the first reports to show clearly in different species an inverse relationship between intrathymic expression levels of tissue-restricted self-antigens and susceptibility to experimental organ-specific autoimmune diseases.

    CAS  PubMed  Google Scholar 

  86. Liu, H. et al. Mice resistant to experimental autoimmune encephalomyelitis have increased thymic expression of myelin basic protein and increased MBP specific T cell tolerance. J. Neuroimmunol. 115, 118–126 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Miyamoto, K., Miyake, S., Schachner, M. & Yamamura, T. Heterozygous null mutation of myelin P0 protein enhances susceptibility to autoimmune neuritis targeting P0 peptide. Eur. J. Immunol. 33, 656–665 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Thebault-Baumont, K. et al. Acceleration of type 1 diabetes mellitus in proinsulin 2-deficient NOD mice. J. Clin. Invest. 111, 851–857 (2003). References 87 and 88 show that a reduction in the expression level of promiscuously expressed self-antigens tilts the balance towards autoimmunity under experimental conditions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 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. Nature Med. 6, 56–61 (2000).

    Article  CAS  PubMed  Google Scholar 

  90. Anderson, A. C. et al. High frequency of autoreactive myelin proteolipid protein-specific T cells in the periphery of naive mice: mechanisms of selection of the self-reactive repertoire. J. Exp. Med. 191, 761–770 (2000). Both references 89 and 90 show that self-tolerance to PLP is limited to the shorter splice variant of PLP (DM20) due to its predominant expression by TECs. This finding illustrates an inherent pitfall in central tolerance by promiscuous gene expression as a consequence of differential mRNA splicing between TECs and tissue cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Tuohy, V. K. et al. The epitope spreading cascade during progression of experimental autoimmune encephalomyelitis and multiple sclerosis. Immunol. Rev. 164, 93–100 (1998).

    Article  CAS  PubMed  Google Scholar 

  92. Talib, S., Okarma, T. B. & Lebkowski, J. S. Differential expression of human nicotinic acetycholine receptor α subunit variants in muscle and non-muscle tissues. Nucleic Acids Res. 21, 233–237 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Diez, J. et al. Differential splicing of the IA-2 mRNA in pancreas and lymphoid organs as a permissive genetic mechanism for autoimmunity against the IA-2 type 1 diabetes autoantigen. Diabetes 50, 895–900 (2001).

    Article  CAS  PubMed  Google Scholar 

  94. Backlund, J. et al. Glycosylation of type II collagen is of major importance for T cell tolerance and pathology in collagen-induced arthritis. Eur. J. Immunol. 32, 3776–3784 (2002).

    Article  CAS  PubMed  Google Scholar 

  95. Boon, T. & Old, L. J. Cancer tumor antigens. Curr. Opin. Immunol. 9, 681–683 (1997).

    Article  CAS  PubMed  Google Scholar 

  96. Coulie, P. G. Cancer immunotherapy with MAGE antigens. Suppl. Tumori. 1, S63–S65 (2002).

    PubMed  Google Scholar 

  97. Renkvist, N., Castelli, C., Robbins, P. F. & Parmiani, G. A listing of human tumor antigens recognized by T cells. Cancer Immunol. Immunother. 50, 3–15 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Diekman, A. B. et al. Anti-sperm antibodies from infertile patients and their cognate sperm antigens: a review. Identity between SAGA-1, the H6-3C4 antigen, and CD52. Am. J. Reprod. Immunol. 43, 134–143 (2000).

    Article  CAS  PubMed  Google Scholar 

  99. Bellgrau, D. & Duke, R. C. Apoptosis and CD95 ligand in immune privileged sites. Int. Rev. Immunol. 18, 547–562 (1999).

    Article  CAS  PubMed  Google Scholar 

  100. Rijnkels, M., Wheeler, D. A., de Boer, H. A. & Pieper, F. R. Structure and expression of the mouse casein locus. Mamm. Genome 8, 9–15 (1997).

    Article  CAS  PubMed  Google Scholar 

  101. Bonney, E. A. & Matzinger, P. The maternal immune system's interaction with circulating fetal cells. J. Immunol. 158, 40–47 (1997).

    CAS  PubMed  Google Scholar 

  102. von Boehmer, H. et al. Thymic selection revisited: how essential is it? Immunol. Rev. 191, 62–78 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Gauwerky, C. E. & Croce, C. M. Chromosomal translocations in leukaemia. Semin. Cancer Biol. 4, 333–340 (1993).

    CAS  PubMed  Google Scholar 

  104. Mills, K. D., Ferguson, D. O. & Alt, F. W. The role of DNA breaks in genomic instability and tumorigenesis. Immunol. Rev. 194, 77–95 (2003).

    Article  CAS  PubMed  Google Scholar 

  105. Muller-Hermelink, H. K. & Marx, A. Thymoma. Curr. Opin. Oncol. 12, 426–433 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. Jackson-Grusby, L. et al. Loss of genomic methylation causes p53-dependent apoptosis and epigenetic deregulation. Nature Genet. 27, 31–39 (2001).

    Article  CAS  PubMed  Google Scholar 

  107. Petrie, H. T. Cell migration and the control of post-natal T-cell lymphopoiesis in the thymus. Nature Rev. Immunol. 3, 859–866 (2003).

    Article  CAS  Google Scholar 

  108. Nelson, A. J., Hosier, S., Brady, W., Linsley, P. S. & Farr, A. G. Medullary thymic epithelium expresses a ligand for CTLA4 in situ and in vitro. J. Immunol. 151, 2453–2461 (1993).

    CAS  PubMed  Google Scholar 

  109. Surh, C. D. et al. Two subsets of epithelial cells in the thymic medulla. J. Exp. Med. 176, 495–505 (1992).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  111. Humblet, C., Rudensky, A. & Kyewski, B. Presentation and intercellular transfer of self-antigen within the thymic microenvironment: expression of the Eα peptide-I-Ab complex by isolated thymic stromal cells. Int. Immunol. 6, 1949–1958 (1994).

    Article  CAS  PubMed  Google Scholar 

  112. Scheinecker, C., McHugh, R., Shevach, E. M. & Germain, R. N. Constitutive presentation of a natural tissue autoantigen exclusively by dendritic cells in the draining lymph node. J. Exp. Med. 196, 1013–1016 (2002).

    Article  CAS  Google Scholar 

  113. Ten, S., New, M. & Maclaren, N. Clinical review 130: Addison's disease 2001. J. Clin. Endocrinol. Metab. 86, 2909–2922 (2001).

    CAS  PubMed  Google Scholar 

  114. Bergman, M. P. et al. Characterization of H+/K+-ATPase T-cell epitopes in human autoimmune gastritis. Eur. J. Immunol. 33, 539–545 (2003).

    Article  CAS  PubMed  Google Scholar 

  115. Gery, L., Nussenblatt, R. B., Chan, C. C. & Caspi, R. R. in The Molecular Pathology of Autoimmune Diseases. 2nd edn (eds Theofilopoulos, A. N. & Bona, C. A.) 978 (Taylor & Francis, New York, 2002).

    Google Scholar 

  116. Vaidya, B., Kendall-Taylor, P. & Pearce, S. H. S. The Genetics of autoimmune thyroid disease. J. Clin. Endocrinol. Metab. 87, 5385–5397 (2002).

    Article  CAS  PubMed  Google Scholar 

  117. Steinman, L. Multiple sclerosis: a coordinated immunological attack against myelin in the central nervous system. Cell 85, 299–302 (1996).

    Article  CAS  PubMed  Google Scholar 

  118. Vincent, A. Unravelling the pathogenesis of myasthenia gravis. Nature Rev. Immunol. 2, 797–804 (2002).

    Article  CAS  Google Scholar 

  119. Amagai, M., Klaus-Kovtun, V. & Stanley, J. R. Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell 67, 869–877 (1991).

    Article  CAS  PubMed  Google Scholar 

  120. Backlund, J. et al. Predominant selection of T cells specific for the glycosylated collagen type II epitope (263–270) in humanized transgenic mice and in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 99, 9960–9965 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Tisch, R. & McDevitt, H. Insulin-dependent diabetes mellitus. Cell 85, 291–297 (1996).

    Article  CAS  PubMed  Google Scholar 

  122. Palermo, B. et al. Specific cytotoxic lymphocyte responses against MelanA/MART1, tyrosinase and gp100 in vitiligo by the use of major histocompatibility complex–peptide tetramers: the role of cellular immunity in the etiopathogenesis of vitiligo. J. Invest. Dermatol. 117, 326–332 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Mandelcorn-Monson, R. L. et al. Cytotoxic T lymphocyte reactivity to gp100, MelanA/Mart-1, and tyrosinase, in HLA-A2-positive vitiligo patients. J. Invest. Dermatol. 121, 550–556 (2003).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank J. Gotter and B. Arnold for constructive criticism. The studies by the authors have been supported by the DKFZ, the Deutsche Forschungsgemeinschaft (J.D.) and the Mildred-Scheel Foundation.

Author information

Authors and Affiliations

  1. Division of Developmental Immunology, Tumour Immunology Programme, German Cancer Research Centre, Im Neuenheimer Feld 280, Heidelberg, D-69120, Germany

    Bruno Kyewski & Jens Derbinski

Authors
  1. Bruno Kyewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jens Derbinski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bruno Kyewski.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez Gene

AIRE

GAD65

GAD67

IRBP

MART1

NIK

OMIM

APS-1

multiple sclerosis

type 1 diabetes mellitus

FURTHER INFORMATION

GNF Gene Expression Atlas

Swissprot

Bruno Kyewski's homepage

Glossary

GENE ARRAYS

Tools to assess in parallel the expression profile of thousands of coding and non-coding RNAs (or even the transcriptome of whole genomes) by hybridizing labelled RNA or cDNA from cells or tissues to microarrays that contain the known antisense target sequences.

THYMIC INVOLUTION

The thymus reaches its maximal relative weight at birth, the absolute weight and the rate of T-cell production increases until puberty. Then, under the influence of sex hormones, involution begins and the thymus becomes atrophic. The total size is reduced and the stromal compartment is replaced by fibrous and fat tissue. In parallel, thymic T-cell output is proportionally reduced but maintained at low levels.

PARENCHYMAL ORGANS

Organs in which a specialized cell type carries out the physiological function, for example, hepatocytes in the liver, whereas the stromal tissue provides a supporting scaffold. By contrast, in lymphoid organs the stromal network has an indispensable functional role.

HASSALL'S CORPUSCLES

Small clusters or concentric whorls of stratified keratinizing epithelium in the thymic medulla. They probably represent end-stage differentiated epithelial cells either participating in negative selection of thymocytes and/or undergoing apoptosis themselves.

BI-ALLELIC EXPRESSION

Imprinted genes are preferentially expressed from only one allele, depending on their parental origin. Imprinting marks are established during pre-implantation development. However, in rare instances, expression from both alleles is observed in adult tissues.

SPLIT TOLERANCE

Refers to the frequent experimental observations that an allogeneic tissue graft is accepted (tolerated) in vivo, yet peripheral T cells of the host react against allo-antigens of graft type in vitro.

DOMINANT TOLERANCE

Refers to the suppression of an autoimmune response, in vitro or in vivo by suppressor cells including regulatory T cells. By contrast, deletion or anergy induction are referred to as recessive tolerance mechanisms. Dominant tolerance is transferable to naive recipients, whereas recessive tolerance is not.

SCURFY MICE

A mouse strain with a spontaneous mutation in the forkhead box transcription factor P3 (also known as Scurfin), which leads to a rapidly fatal lymphoproliferative disease, causing death by about 4 weeks of age. Scurfin-deficient mice lack regulatory T cells.

BYSTANDER SUPPRESSION

Inhibition of effector T-cell function by suppressor T cells of different antigen specificity, which presumably occurs in T-cell–antigen-presenting cell (APC) clusters, requiring the co-presentation of both antigen specificities by the same APC.

AUTOIMMUNE POLYGLANDULAR SYNDROME TYPE 1

(APS-1). A rare autosomal recessive, autoimmune disorder in humans that is characterized by hypo-parathyroidism, mucocutaneous candidiasis and adrenocortical failure, and is associated with mutations in autoimmune regulator (AIRE). AIRE-deficient mice develop a similar autoimmune phenomena characterized by multi-organ lymphocytic infiltration and circulating autoantibodies.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kyewski, B., Derbinski, J. Self-representation in the thymus: an extended view. Nat Rev Immunol 4, 688–698 (2004). https://doi.org/10.1038/nri1436

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1436

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