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:

Central tolerance: learning self-control in the thymus

Nature Reviews Immunology volume 5, pages 772–782 (2005)Cite this article

Key Points

  • Various experimental approaches have been used to model antigen-specific clonal deletion. Many of these are fraught with non-physiological aspects. A consensus is emerging that clonal deletion occurs as cells transition from the double-positive stage to the single-positive stage.

  • The thymic medulla is a specialized microenvironment for central tolerance. Most thymic dendritic cells reside in this compartment, and medullary thymic epithelial cells (mTECs) can synthesize antigens that are otherwise highly tissue specific.

  • The autoimmune regulator (AIRE) protein has an important part in driving the transcription of genes encoding tissue-specific antigens in mTECs, and AIRE deficiency results in a defect in clonal deletion.

  • The proper functioning of mTECs requires several intracellular-signalling proteins: REL-B, NIK (nuclear-factor-κB-inducing kinase) and TRAF6 (tumour-necrosis-factor-receptor-associated factor 6). In the absence of these molecules, mice have a disorganized thymic architecture, impaired clonal deletion, impaired generation of CD4+CD25+ regulatory T cells and natural killer T cells, and autoimmune disease.

  • One factor in the development of diabetes in the non-obese-diabetic mouse strain is that clonal deletion of self-reactive progenitors in the thymus is impaired.

  • How the T-cell receptor interprets low-affinity and high-affinity ligation to result in positive selection and negative selection, respectively, remains an important unanswered question in the field.

Abstract

In the past few years, there has been a flurry of discoveries and advancements in our understanding of how the thymus prepares T cells to exist at peace in normal healthy tissue: that is, to be self-tolerant. In the thymus, one of the main mechanisms of T-cell central tolerance is clonal deletion, although the selection of regulatory T cells is also important and is gaining enormous interest. In this Review, we discuss the emerging consensus about which models of clonal deletion are most physiological, and we review recent data that define the molecular mechanisms of central tolerance.

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: Central-tolerance mechanisms.
Figure 2: TCR-transgenic mice express a cell-surface TCR earlier in development than do normal mice.
Figure 3: Models of how differences in affinity affect whether differentiation or apoptosis occurs during development.
Figure 4: Aspects of the thymic medulla that are involved in central tolerance.

Similar content being viewed by others

References

  1. Palmer, E. Negative selection — clearing out the bad apples from the T-cell repertoire. Nature Rev. Immunol. 3, 383–391 (2003).

    Article  CAS  Google Scholar 

  2. Hammerling, G. J. et al. Non-deletional mechanisms of peripheral and central tolerance: studies with transgenic mice with tissue-specific expression of a foreign MHC class I antigen. Immunol. Rev. 122, 47–67 (1991).

    Article  CAS  PubMed  Google Scholar 

  3. Wang, F., Huang, C. Y. & Kanagawa, O. Rapid deletion of rearranged T cell antigen receptor (TCR) Vα–Jα segment by secondary rearrangement in the thymus: role of continuous rearrangement of TCR α chain gene and positive selection in the T cell repertoire formation. Proc. Natl Acad. Sci. USA 95, 11834–11839 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. McGargill, M. A., Derbinski, J. M. & Hogquist, K. A. Receptor editing in developing T cells. Nature Immunol. 1, 336–341 (2000).

    Article  CAS  Google Scholar 

  5. Fontenot, J. D. & Rudensky, A. Y. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nature Immunol. 6, 331–337 (2005).

    Article  CAS  Google Scholar 

  6. Sakaguchi, S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nature Immunol. 6, 345–352 (2005).

    Article  CAS  Google Scholar 

  7. Cheroutre, H. Starting at the beginning: new perspectives on the biology of mucosal T cells. Annu. Rev. Immunol. 22, 217–246 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Franki, A. S. et al. Lymphotoxin α1β2: a critical mediator in Vα14i NKT cell differentiation. Mol. Immunol. 42, 413–417 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Baldwin, T. A., Hogquist, K. A. & Jameson, S. C. The fourth way? Harnessing aggressive tendencies in the thymus. J. Immunol. 173, 6515–6520 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Villasenor, J., Benoist, C. & Mathis, D. AIRE and APECED: molecular insights into an autoimmune disease. Immunol. Rev. 204, 156–164 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Brewer, J. A., Kanagawa, O., Sleckman, B. P. & Muglia, L. J. Thymocyte apoptosis induced by T cell activation is mediated by glucocorticoids in vivo. J. Immunol. 169, 1837–1843 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Martin, S. & Bevan, M. J. Antigen-specific and nonspecific deletion of immature cortical thymocytes caused by antigen injection. Eur. J. Immunol. 27, 2726–2736 (1997).

    Article  CAS  PubMed  Google Scholar 

  13. Kisielow, P., Bluthmann, H., Staerz, U. D., Steinmetz, M. & von Boehmer, H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature 333, 742–746 (1988).

    Article  CAS  PubMed  Google Scholar 

  14. Sant'Angelo, D. B. & Janeway, C. A. Jr. Negative selection of thymocytes expressing the D10 TCR. Proc. Natl Acad. Sci. USA 99, 6931–6936 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Baldwin, T. A., Sandau, M. M., Jameson, S. C. & Hogquist, K. A. The timing of TCRα expression critically influences T cell development and selection. J. Exp. Med. 202, 111–121 (2005). In this study, the authors developed a TCR-transgenic model system in which the TCR α-chain was expressed at the appropriate developmental stage. In this model, H-Y-specific clonal deletion occurs at the late (SP) stage of development, which is in contrast to conventional models, in which it occurs early. This indicates that early deletion is a non-physiological aspect of TCR-transgenic models.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhan, Y. et al. Without peripheral interference, thymic deletion is mediated in a cohort of double-positive cells without classical activation. Proc. Natl Acad. Sci. USA 100, 1197–1202 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Surh, C. D. & Sprent, J. T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature 372, 100–103 (1994).

    Article  CAS  PubMed  Google Scholar 

  18. Cho, H. J. et al. Identification of the targets of clonal deletion in an unmanipulated thymus. J. Immunol. 170, 10–13 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Kappler, J. W., Roehm, N. & Marrack, P. T cell tolerance by clonal elimination in the thymus. Cell 49, 273–280 (1987).

    Article  CAS  PubMed  Google Scholar 

  20. Hoffmann, R., Bruno, L., Seidl, T., Rolink, A. & Melchers, F. Rules for gene usage inferred from a comparison of large-scale gene expression profiles of T and B lymphocyte development. J. Immunol. 170, 1339–1353 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Mick, V. E., Starr, T. K., McCaughtry, T. M., McNeil, L. K. & Hogquist, K. A. The regulated expression of a diverse set of genes during thymocyte positive selection in vivo. J. Immunol. 173, 5434–5444 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Huang, Y. H., Li, D., Winoto, A. & Robey, E. A. Distinct transcriptional programs in thymocytes responding to T cell receptor, Notch, and positive selection signals. Proc. Natl Acad. Sci. USA 101, 4936–4941 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tabrizifard, S. et al. Analysis of transcription factor expression during discrete stages of postnatal thymocyte differentiation. J. Immunol. 173, 1094–1102 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Bousso, P., Bhakta, N. R., Lewis, R. S. & Robey, E. Dynamics of thymocyte–stromal cell interactions visualized by two-photon microscopy. Science 296, 1876–1880 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. 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 

  26. 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 

  27. Weih, F. et al. Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-κB/Rel family. Cell 80, 331–340 (1995).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  29. 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 

  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. Chin, R. K. et al. Lymphotoxin pathway directs thymic Aire expression. Nature Immunol. 4, 1121–1127 (2003).

    Article  CAS  Google Scholar 

  32. Akiyama, T. et al. Dependence of self-tolerance on TRAF6-directed development of thymic stroma. Science 308, 248–251 (2005). This study showed that TRAF6 is required for normal differentiation of mTECs and for the development of T Reg cells. T-cell-depleted thymic grafts were used to prove that these defects, and the resultant autoimmunity, were intrinsic to thymic stroma.

    Article  CAS  PubMed  Google Scholar 

  33. Laufer, T. M., DeKoning, J., Markowitz, J. S., Lo, D. & Glimcher, L. H. Unopposed positive selection and autoreactivity in mice expressing class II MHC only on thymic cortex. Nature 383, 81–85 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. DeKoning, J. et al. Thymic cortical epithelium is sufficient for the development of mature T cells in relB-deficient mice. J. Immunol. 158, 2558–2566 (1997).

    CAS  PubMed  Google Scholar 

  35. Elewaut, D. et al. NIK-dependent RelB activation defines a unique signaling pathway for the development of Vα14i NKT cells. J. Exp. Med. 197, 1623–1633 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kobayashi, T. et al. TRAF6 is a critical factor for dendritic cell maturation and development. Immunity 19, 353–363 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Fu, Y. X. & Chaplin, D. D. Development and maturation of secondary lymphoid tissues. Annu. Rev. Immunol. 17, 399–433 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Kumanogoh, A. et al. Increased T cell autoreactivity in the absence of CD40–CD40 ligand interactions: a role of CD40 in regulatory T cell development. J. Immunol. 166, 353–360 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. 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 

  40. Forestier, C. et al. T cell development in mice expressing CD1d directed by a classical MHC class II promoter. J. Immunol. 171, 4096–4104 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. 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+25+ immunoregulatory T cells. J. Exp. Med. 194, 427–438 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Heath, W. R. & Carbone, F. R. Cross-presentation in viral immunity and self-tolerance. Nature Rev. Immunol. 1, 126–134 (2001).

    Article  CAS  Google Scholar 

  43. Gallegos, A. M. & Bevan, M. J. Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J. Exp. Med. 200, 1039–1049 (2004). In this paper, the authors showed that thymic DCs can cross-present self-antigens that are synthesized by mTECs, resulting in clonal deletion of antigen-specific CD4+ or CD8+ T cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Buhlmann, J. E., Elkin, S. K. & Sharpe, A. H. A Role for the B7-1/B7-2:CD28/CTLA-4 pathway during negative selection. J. Immunol. 170, 5421–5428 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Gao, J. X. et al. Perinatal blockade of B7-1 and B7-2 inhibits clonal deletion of highly pathogenic autoreactive T cells. J. Exp. Med. 195, 959–971 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Foy, T. M. et al. An essential role for gp39, the ligand for CD40, in thymic selection. J. Exp. Med. 182, 1377–1388 (1995).

    Article  CAS  PubMed  Google Scholar 

  47. Salomon, B. et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12, 431–440 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Serra, P. et al. CD40 ligation releases immature dendritic cells from the control of regulatory CD4+CD25+ T cells. Immunity 19, 877–889 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Kyewski, B. & Derbinski, J. Self-representation in the thymus: an extended view. Nature Rev. Immunol. 4, 688–698 (2004).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  52. 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). This was the first study to show that deficiency in the transcriptional regulator AIRE impairs clonal deletion of T cells that recognize tissue-specific antigens, in this case a model self-antigen that is expressed under the control of the RIP.

    Article  CAS  Google Scholar 

  53. Liston, A. et al. Gene dosage — limiting role of Aire in thymic expression, clonal deletion, and organ-specific autoimmunity. J. Exp. Med. 200, 1015–1026 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Su, M. A. & Anderson, M. S. Aire: an update. Curr. Opin. Immunol. 16, 746–752 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Pitkanen, J., Vahamurto, P., Krohn, K. & Peterson, P. Subcellular localization of the autoimmune regulator protein. Characterization of nuclear targeting and transcriptional activation domain. J. Biol. Chem. 276, 19597–19602 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Pitkanen, J. et al. The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein. J. Biol. Chem. 275, 16802–16809 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. Gillard, G. O. & Farr, A. G. Contrasting models of promiscuous gene expression by thymic epithelium. J. Exp. Med. 202, 15–19 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Gotter, J., Brors, B., Hergenhahn, M. & Kyewski, B. Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes colocalized in chromosomal clusters. J. Exp. Med. 199, 155–166 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Johnnidis, J. B. et al. Chromosomal clustering of genes controlled by the aire transcription factor. Proc. Natl Acad. Sci. USA 102, 7233–7238 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Uchida, D. et al. AIRE functions as an E3 ubiquitin ligase. J. Exp. Med. 199, 167–172 (2004). In this study, the PHD1 domain of AIRE was shown to mediate ubiquitylation of substrates in vitro , indicating that AIRE might regulate the stability of proteins in the cell.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bottomley, M. J. et al. NMR structure of the first PHD finger of autoimmune regulator protein (AIRE1). Insights into autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) disease. J. Biol. Chem. 280, 11505–11512 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Gil, D., Schamel, W. W., Montoya, M., Sanchez-Madrid, F. & Alarcon, B. Recruitment of Nck by CD3ɛ reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. Cell 109, 901–912 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Gil, D., Schrum, A. G., Alarcon, B. & Palmer, E. T cell receptor engagement by peptide–MHC ligands induces a conformational change in the CD3 complex of thymocytes. J. Exp. Med. 201, 517–522 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Sommers, C. L. et al. A LAT mutation that inhibits T cell development yet induces lymphoproliferation. Science 296, 2040–2043 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Aguado, E. et al. Induction of T helper type 2 immunity by a point mutation in the LAT adaptor. Science 296, 2036–2040 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Sommers, C. L. et al. Mutation of the phospholipase C-γ1-binding site of LAT affects both positive and negative thymocyte selection. J. Exp. Med. 201, 1125–1134 (2005). This study provided a striking example of how attenuation of the TCR signal (in this case, by mutation of a tyrosine phosphorylation site in the adaptor protein LAT) can convert a negatively selecting signal to a positively selecting signal.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Werlen, G., Hausmann, B. & Palmer, E. A motif in the αβ T-cell receptor controls positive selection by modulating ERK activity. Nature 406, 422–426 (2000).

    Article  CAS  PubMed  Google Scholar 

  69. McCarty, N. et al. Signaling by the kinase MINK is essential in the negative selection of autoreactive thymocytes. Nature Immunol. 6, 65–72 (2005). The authors of this study used RNA interference to show that the kinase MINK is required for clonal deletion in several models.

    Article  CAS  Google Scholar 

  70. Szymczak, A. L. et al. The CD3ε proline-rich sequence, and its interaction with Nck, is not required for T cell development and function. J. Immunol. 175, 270–275 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Woronicz, J. D., Calnan, B., Ngo, V. & Winoto, A. Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas. Nature 367, 277–281 (1994).

    Article  CAS  PubMed  Google Scholar 

  72. Cheng, L. E., Chan, F. K., Cado, D. & Winoto, A. Functional redundancy of the Nur77 and Nor-1 orphan steroid receptors in T-cell apoptosis. EMBO J. 16, 1865–1875 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Calnan, B. J., Szychowski, S., Chan, F. K., Cado, D. & Winoto, A. A role for the orphan steroid receptor Nur77 in apoptosis accompanying antigen-induced negative selection. Immunity 3, 273–282 (1995).

    Article  CAS  PubMed  Google Scholar 

  74. Fiorini, E. et al. Peptide-induced negative selection of thymocytes activates transcription of an NF-κB inhibitor. Mol. Cell 9, 637–648 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Zucchelli, S. et al. Defective central tolerance induction in NOD mice: genomics and genetics. Immunity 22, 385–396 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Liston, A. et al. Generalized resistance to thymic deletion in the NOD mouse; a polygenic trait characterized by defective induction of Bim. Immunity 21, 817–830 (2004). References 75 and 76 compared the gene-expression profiles of thymocytes undergoing deletion in TCR-transgenic NOD mice and control mice, and these papers described a general reduction in the level of gene expression that was induced by self-antigen. These studies also used a genetic-backcross approach to identify potentially relevant loci that regulate this process.

    CAS  PubMed  Google Scholar 

  77. Kishimoto, H. & Sprent, J. A defect in central tolerance in NOD mice. Nature Immunol. 2, 1025–1031 (2001).

    Article  CAS  Google Scholar 

  78. Bergman, M. L. et al. CTLA-4−/− mice display T cell-apoptosis resistance resembling that ascribed to autoimmune-prone non-obese diabetic (NOD) mice. J. Autoimmun. 16, 105–113 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Strasser, A. & Bouillet, P. The control of apoptosis in lymphocyte selection. Immunol. Rev. 193, 82–92 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Strasser, A., Harris, A. W., von Boehmer, H. & Cory, S. Positive and negative selection of T cells in T-cell receptor transgenic mice expressing a bcl-2 transgene. Proc. Natl Acad. Sci. USA 91, 1376–1380 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Bouillet, P. et al. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415, 922–926 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Rathmell, J. C., Lindsten, T., Zong, W. X., Cinalli, R. M. & Thompson, C. B. Deficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis. Nature Immunol. 3, 932–939 (2002).

    Article  CAS  Google Scholar 

  83. Harada, H., Quearry, B., Ruiz-Vela, A. & Korsmeyer, S. J. Survival factor-induced extracellular signal-regulated kinase phosphorylates BIM, inhibiting its association with BAX and proapoptotic activity. Proc. Natl Acad. Sci. USA 101, 15313–15317 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Zuklys, S. et al. Normal thymic architecture and negative selection are associated with Aire expression, the gene defective in the autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). J. Immunol. 165, 1976–1983 (2000).

    Article  CAS  PubMed  Google Scholar 

  85. Heino, M. et al. RNA and protein expression of the murine autoimmune regulator gene (Aire) in normal, RelB-deficient and in NOD mouse. Eur. J. Immunol. 30, 1884–1893 (2000).

    Article  CAS  PubMed  Google Scholar 

  86. Wu, L. et al. RelB is essential for the development of myeloid-related CD8α− dendritic cells but not of lymphoid-related CD8α+ dendritic cells. Immunity 9, 839–847 (1998).

    Article  CAS  PubMed  Google Scholar 

  87. Nakagawa, K. et al. Generation of NK1.1+ T cell antigen receptor α/β+ thymocytes associated with intact thymic structure. Proc. Natl Acad. Sci. USA 94, 2472–2477 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Sivakumar, V., Hammond, K. J., Howells, N., Pfeffer, K. & Weih, F. Differential requirement for Rel/nuclear factor κB family members in natural killer T cell development. J. Exp. Med. 197, 1613–1621 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Anderson, M. S. et al. The cellular mechanism of Aire control of T cell tolerance. Immunity 23, 227–239 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Kuroda, N. et al. Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice. J. Immunol. 174, 1862–1870 (2005).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Institutes of Health (United States) (to K.A.H.), and the Canadian Institutes of Health Research and the Alberta Heritage Foundation for Medical Research (Canada) (to T.A.B.).

Author information

Authors and Affiliations

  1. Department of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota, 312 Church Street South East, Minneapolis, 55455, Minnesota, USA

    Kristin A. Hogquist, Troy A. Baldwin & Stephen C. Jameson

Authors
  1. Kristin A. Hogquist
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Troy A. Baldwin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephen C. Jameson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kristin A. Hogquist.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez Gene

Entrez Gene

AIRE

LT-βR

Nik

REL-B

TRAF6

OMIM

OMIM

APECED

IPEX

FURTHER INFORMATION

Kristin Hogquist's and Stephen Jameson's laboratories

Models of negative selection

Glossary

ANERGY

A state of non-responsiveness to antigen. Anergic T or B cells cannot respond to their cognate antigens under optimal conditions of stimulation.

RECEPTOR EDITING

A tolerance mechanism in which the binding of self-antigen during development promotes secondary antigen-receptor gene rearrangement. In the T-cell receptor α-chain or immunoglobulin light chain locus, this results in replacement of the autoreactive receptor with a benign one. This is thought to be one of the main tolerance mechanisms in B-cell development, but it is less well-described for T cells.

CD4+CD25+ REGULATORY T CELL

(TReg cell). A CD4+ T cell that expresses high levels of CD25 (also known as the α-chain of the interleukin-2 receptor), is naturally anergic and requires stimulation through the T-cell receptor for induction of its cell-mediated suppressive function. The role of this subset of T cells is to maintain self-tolerance.

CD8αα+ INTESTINAL EPITHELIAL LYMPHOCYTE

A type of T cell that is found in the intestinal epithelium. The CD8 molecule that they express is a homodimer of CD8α, rather than the CD8αβ heterodimer that is expressed by conventional CD8+ T cells in the lymph nodes. It has been proposed that these cells are self-reactive T cells that have regulatory properties.

NATURAL KILLER T CELL

(NKT cell). A T cell that expresses both natural killer (NK)-cell receptors and an αβ-T-cell receptor (αβ-TCR). In mice, these cells were first identified by their expression of the alloantigen NK1.1 (also known as NKR-P1C). Some mouse NKT cells express an invariant TCR that uses the Vα14 variable region of the TCR α-chain and recognizes CD1d-associated antigen. NKT cells are characterized by cytolytic activity and rapid production of cytokines, including interferon-γ and interleukin-4, and they might regulate the function of other T cells.

CRE–LOXP TECHNOLOGY

A site-specific recombination system. Two short DNA sequences (loxP sites) are engineered to flank the target DNA. Expression of the recombinase Cre leads to excision of the intervening sequence. Depending on the type of promoter that controls Cre expression, Cre can be expressed at specific times during development or by specific subsets of cells.

LCK–CRE MOUSE

A mouse that expresses the recombinase Cre under the control of the Lck proximal promoter. Cre expression is initiated early during thymic development, at the double-negative-2 stage or earlier.

ENDOGENOUS SUPERANTIGEN

A defective mammary tumour-virus sequence that is stably integrated in the genome of certain mouse strains. This sequence encodes an MHC-class-II-binding protein that causes stimulation of T cells that use specific variable regions in the T-cell receptor β-chain.

CROSS-PRESENTATION

The ability of certain antigen-presenting cells to load peptides that are derived from exogenous antigens onto MHC class I molecules. This property is atypical, because most cells exclusively present peptides from their endogenous proteins on MHC class I molecules. Cross-presentation is essential for the initiation of immune responses to viruses that do not infect antigen-presenting cells.

PLANT HOMEODOMAIN

(PHD). A motif that is found in numerous eukaryotic proteins, many of which regulate transcription. This domain encodes a zinc-binding site and is probably involved in protein–protein interactions.

PROTEOMICS APPROACH

The large-scale analysis of the proteins that are expressed by a particular cell or tissue. This is usually used to compare cell populations, states of differentiation or responses to stimuli. Proteomics not only includes the identification and quantification of proteins but also includes the study of the post-translational modifications and interactions of proteins.

SMALL INTERFERING RNA

(siRNA). Synthetic double-stranded RNA molecules of 19–23 nucleotides, which are used to 'knockdown' (silence the expression of) a specific gene. This is known as RNA interference and is mediated by the sequence-specific degradation of mRNA.

NON-OBESE DIABETIC MOUSE STRAIN

(NOD mouse strain). An inbred mouse strain that spontaneously develops T-cell-mediated autoimmune diabetes.

MIMETOPE

When a natural T-cell epitope is not known, it is possible to screen peptides and define a peptide that mimics the stimulatory activity of a natural epitope. This is known as a mimetope.

INSULIN-DEPENDENT DIABETES SUSCEPTIBILITY LOCI

(Idd loci). Regions of genomic DNA that are associated with susceptibility or resistance to diabetes in non-obese diabetic (NOD) mice. They were identified by correlating DNA polymorphism with disease in genetic crosses between NOD mice and non-diabetic mouse strains. Because diabetes is a polygenic autoimmune disease, several susceptibility loci have been defined. The Idd5 region includes the genes that encode CD28, cytotoxic T-lymphocyte antigen 4 (CTLA4) and the natural resistance-associated macrophage proteins (NRAMPs).

BCL-2 FAMILY

(B-cell-lymphoma-2 family). Mitochondrial proteins that increase or decrease the susceptibility of a cell to apoptosis. When the levels of either of the family members BCL-2 or BCL-XL are increased, a cell is more resistant to cell death.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hogquist, K., Baldwin, T. & Jameson, S. Central tolerance: learning self-control in the thymus. Nat Rev Immunol 5, 772–782 (2005). https://doi.org/10.1038/nri1707

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1707

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