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Thymic tolerance as a key brake on autoimmunity

Nature Immunology volume 19, pages 659–664 (2018)Cite this article

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Abstract

Although the thymus has long been recognized as a key organ for T cell selection, the intricate details linking these selection events to human autoimmunity have been challenging to decipher. Over the last two decades, there has been rapid progress in understanding the role of thymic tolerance mechanisms in autoimmunity through genetics. Here we review some of the recent progress in understanding key thymic tolerance processes that are critical for preventing autoimmune disease.

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Fig. 1: Properties of mTECs and drivers of TSA expression.
Fig. 2: Model of hypomorphic Zap70 and altered T cell selection.

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References

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

    Article  PubMed  CAS  Google Scholar 

  2. Kisielow, P., Blüthmann, 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  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Finnish-German APECED Consortium. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat. Genet. 17, 399–403 (1997).

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  8. Perheentupa, J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J. Clin. Endocrinol. Metab. 91, 2843–2850 (2006).

    Article  PubMed  CAS  Google Scholar 

  9. Husebye, E. S., Perheentupa, J., Rautemaa, R. & Kämpe, O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J. Intern. Med. 265, 514–529 (2009).

    Article  PubMed  CAS  Google Scholar 

  10. Kisand, K. et al. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J. Exp. Med. 207, 299–308 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Puel, A. et al. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J. Exp. Med. 207, 291–297 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Meloni, A. et al. Autoantibodies against type I interferons as an additional diagnostic criterion for autoimmune polyendocrine syndrome type I. J. Clin. Endocrinol. Metab. 93, 4389–4397 (2008).

    Article  PubMed  CAS  Google Scholar 

  13. Meyer, S. et al. AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies. Cell 166, 582–595 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. 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  PubMed  CAS  Google Scholar 

  15. 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  PubMed  PubMed Central  CAS  Google Scholar 

  16. Gardner, J. M. et al. Deletional tolerance mediated by extrathymic Aire-expressing cells. Science 321, 843–847 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Gardner, J. M. et al. Extrathymic Aire-expressing cells are a distinct bone marrow–derived population that induce functional inactivation of CD4+ T cells. Immunity 39, 560–572 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Yamano, T. et al. Thymic B cells are licensed to present self antigens for central T cell tolerance induction. Immunity 42, 1048–1061 (2015).

    Article  PubMed  CAS  Google Scholar 

  19. Liston, A., Lesage, S., Wilson, J., Peltonen, L. & Goodnow, C. C. Aire regulates negative selection of organ-specific T cells. Nat. Immunol. 4, 350–354 (2003).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  21. Taniguchi, R. T. et al. Detection of an autoreactive T-cell population within the polyclonal repertoire that undergoes distinct autoimmune regulator (Aire)-mediated selection. Proc. Natl. Acad. Sci. USA 109, 7847–7852 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Malchow, S. et al. Aire-dependent thymic development of tumor-associated regulatory T cells. Science 339, 1219–1224 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. 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).This study examines T reg cell–specific TCRs in a limited repertoire system and identifies TCRs that depend on Aire for their selection.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Yang, S., Fujikado, N., Kolodin, D., Benoist, C. & Mathis, D. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance. Science 348, 589–594 (2015).This study invokes another layer of a tolerance defect in the Aire-deficient model where T reg cells are inappropriately selected early in life that then help protect against autoimmune responses in the tissues.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Landegren, N. et al. Proteome-wide survey of the autoimmune target repertoire in autoimmune polyendocrine syndrome type 1. Sci. Rep. 6, 20104 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Alimohammadi, M. et al. Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen. N. Engl. J. Med. 358, 1018–1028 (2008).

    Article  PubMed  CAS  Google Scholar 

  27. Alimohammadi, M. et al. Pulmonary autoimmunity as a feature of autoimmune polyendocrine syndrome type 1 and identification of KCNRG as a bronchial autoantigen. Proc. Natl. Acad. Sci. USA 106, 4396–4401 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Shum, A. K. et al. BPIFB1 is a lung-specific autoantigen associated with interstitial lung disease. Sci. Transl. Med. 5, 206ra139 (2013).

    Article  PubMed  CAS  Google Scholar 

  29. Pöntynen, N. et al. Aire deficient mice do not develop the same profile of tissue-specific autoantibodies as APECED patients. J. Autoimmun. 27, 96–104 (2006).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. 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).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  38. Khan, I. S. et al. Enhancement of an anti-tumor immune response by transient blockade of central T cell tolerance. J. Exp. Med. 211, 761–768 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Kawano, H. et al. Aire expression is inherent to most medullary thymic epithelial cells during their differentiation program. J. Immunol. 195, 5149–5158 (2015).

    Article  PubMed  CAS  Google Scholar 

  40. Bakhru, P. et al. Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity. JCI Insight 2, 2 (2017). This study shows that central tolerance imposes a barrier to robust tumor responses and that combination therapy including RANK ligand blockade and peripheral tolerance blockade can enhance tumor immune responses.

    Article  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  44. Bansal, K., Yoshida, H., Benoist, C. & Mathis, D. The transcriptional regulator Aire binds to and activates super-enhancers. Nat. Immunol. 18, 263–273 (2017). This study demonstrates that Aire appears to target genomic regions enriched for super-enhancers to help drive its activity to promote TSA expression. Furthermore, this study provides biochemical evidence that an interaction with topoisomerase I may be part of this targeting property.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Guha, M. et al. DNA breaks and chromatin structural changes enhance the transcription of autoimmune regulator target genes. J. Biol. Chem. 292, 6542–6554 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  47. Oven, I. et al. AIRE recruits P-TEFb for transcriptional elongation of target genes in medullary thymic epithelial cells. Mol. Cell. Biol. 27, 8815–8823 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Giraud, M. et al. Aire unleashes stalled RNA polymerase to induce ectopic gene expression in thymic epithelial cells. Proc. Natl. Acad. Sci. USA 109, 535–540 (2012).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  51. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Takaba, H. et al. Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. Cell 163, 975–987 (2015). In this study, Fezf2 is identified as an additional transcriptional factor that promotes thymic TSA expression for the induction of immune tolerance.

    Article  PubMed  CAS  Google Scholar 

  53. Guo, C. et al. Fezf2 expression identifies a multipotent progenitor for neocortical projection neurons, astrocytes, and oligodendrocytes. Neuron 80, 1167–1174 (2013).

    Article  PubMed  CAS  Google Scholar 

  54. Cosway, E. J. et al. Redefining thymus medulla specialization for central tolerance. J. Exp. Med. 214, 3183–3195 (2017). This study helps clarify the potential role for lymphotoxin β signaling in thymic medulla specification. Here a more complex role of lymphotoxin receptor β signaling was unraveled, including a role for both mTECs and dendritic cell populations.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. 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).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Leonard, J. D. et al. Identification of natural regulatory T cell epitopes reveals convergence on a dominant autoantigen. Immunity 47, 107–117 (2017).This study identifies the antigen specificity for a T reg cell–specific clone that was originally identified in prostate tumors. Tetramer analysis for Tcaf3-specific CD4 + T cells shows a large skewing to the T reg cell lineage and dependency on Aire.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  58. 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  PubMed  CAS  Google Scholar 

  59. Murata, S. et al. Regulation of CD8+ T cell development by thymus-specific proteasomes. Science 316, 1349–1353 (2007).

    Article  PubMed  CAS  Google Scholar 

  60. Nitta, T. et al. Human thymoproteasome variations influence CD8 T cell selection. Sci. Immunol. 2, 2 (2017). This translational study finds evidence correlating a SNP risk variant for Sjögren’s syndrome with activity of the thymoproteosome for positive selection. These results suggest that this could be part of the mechanism by which autoimmunity is triggered in this disease.

    Article  Google Scholar 

  61. Sakaguchi, N. et al. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 426, 454–460 (2003).

    Article  PubMed  CAS  Google Scholar 

  62. Tanaka, S. et al. Graded attenuation of TCR signaling elicits distinct autoimmune diseases by altering thymic T cell selection and regulatory T cell function. J. Immunol. 185, 2295–2305 (2010).

    Article  PubMed  CAS  Google Scholar 

  63. Hsu, L.-Y., Tan, Y. X., Xiao, Z., Malissen, M. & Weiss, A. A hypomorphic allele of ZAP-70 reveals a distinct thymic threshold for autoimmune disease versus autoimmune reactivity. J. Exp. Med. 206, 2527–2541 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Sakaguchi, S., Benham, H., Cope, A. P. & Thomas, R. T-cell receptor signaling and the pathogenesis of autoimmune arthritis: insights from mouse and man. Immunol. Cell Biol. 90, 277–287 (2012).

    Article  PubMed  CAS  Google Scholar 

  65. Chan, A. Y. et al. A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70. J. Exp. Med. 213, 155–165 (2016).This study identifies a single family with inheritance of an autoimmune syndrome that correlated with the presence of two mutant ZAP70 alleles. This family provides evidence of hypomorphic Zap70 activity in the generation of autoimmunity.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Bruserud, Ø., Oftedal, B. E., Wolff, A. B. & Husebye, E. S. AIRE-mutations and autoimmune disease. Curr. Opin. Immunol. 43, 8–15 (2016).

    Article  PubMed  CAS  Google Scholar 

  67. Marx, A. et al. Thymoma and paraneoplastic myasthenia gravis. Autoimmunity 43, 413–427 (2010).

    Article  PubMed  CAS  Google Scholar 

  68. Marx, A. et al. The autoimmune regulator AIRE in thymoma biology: autoimmunity and beyond. J. Thorac. Oncol. 5(Suppl. 4), S266–S272 (2010).

    Article  PubMed  Google Scholar 

  69. Cheng, M. H. et al. Acquired autoimmune polyglandular syndrome, thymoma, and an AIRE defect. N. Engl. J. Med. 362, 764–766 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Liu, Y. et al. Autoimmune regulator expression in thymomas with or without autoimmune disease. Immunol. Lett. 161, 50–56 (2014).

    Article  PubMed  CAS  Google Scholar 

  71. Meager, A. et al. Anti-cytokine autoantibodies in autoimmunity: preponderance of neutralizing autoantibodies against interferon-α, interferon-ω and interleukin-12 in patients with thymoma and/or myasthenia gravis. Clin. Exp. Immunol. 132, 128–136 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Wolfe, G. I. et al. Randomized trial of thymectomy in myasthenia gravis. N. Engl. J. Med. 375, 511–522 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Vafiadis, P. et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat. Genet. 15, 289–292 (1997).

    Article  PubMed  CAS  Google Scholar 

  74. Giraud, M. et al. An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature 448, 934–937 (2007).

    Article  PubMed  CAS  Google Scholar 

  75. Renton, A. E. et al. A genome-wide association study of myasthenia gravis. JAMA Neurol. 72, 396–404 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

M.S.A. is supported by the US National Institutes of Health, the Helmsley Charitable Trust, the California Institute of Regenerative Medicine and the Larry L. Hillblom Foundation.

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  1. Diabetes Center, University of California, San Francisco, San Francisco, CA, USA

    Mickie Cheng & Mark S. Anderson

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Cheng, M., Anderson, M.S. Thymic tolerance as a key brake on autoimmunity. Nat Immunol 19, 659–664 (2018). https://doi.org/10.1038/s41590-018-0128-9

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