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:

The role of thymic tolerance in CNS autoimmune disease

Nature Reviews Neurology volume 14, pages 723–734 (2018)Cite this article

Subjects

Abstract

The contributions of the peripheral adaptive and innate immune systems to CNS autoimmunity have been extensively studied. However, the role of thymic selection in these conditions is much less well understood. The thymus is the primary lymphoid organ for the generation of T cells; thymic mechanisms ensure that cells with an overt autoreactive specificity are eliminated before they emigrate to the periphery and control the generation of thymic regulatory T cells. Evidence from animal studies demonstrates that thymic T cell selection is important for establishing tolerance to autoantigens. However, there is a considerable knowledge gap regarding the role of thymic selection in autoimmune conditions of the human CNS. In this Review, we critically examine the current body of experimental evidence for the contribution of thymic tolerance to CNS autoimmune diseases. An understanding of why dysfunction of either thymic or peripheral tolerance mechanisms rarely leads to CNS inflammation is currently lacking. We examine the potential of de novo T cell formation and thymic selection as novel therapeutic avenues and highlight areas for future study that are likely to make these targets the focus of future treatments.

Key points

  • The thymus is vital in establishing T cell tolerance that enables the initiation of immune responses to pathogens but avoids autoimmune responses.

  • Evidence from preclinical animal models associates changes in thymic selection with CNS autoimmunity.

  • Studies of human CNS inflammation suggest a role for autoreactive T cells that have escaped thymic negative selection.

  • The relative contributions of thymic and peripheral tolerance to CNS disease are understudied.

  • Thymic selection is underappreciated as a potential therapeutic target in CNS autoimmune disease and should be a focus of future research.

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

Fig. 1: Mechanisms of thymic central tolerance.
Fig. 2: Expression of CNS antigens in the thymus.
Fig. 3: Responses to myelin antigens in mouse models.
Fig. 4: Potential therapeutic options in central tolerance.

Similar content being viewed by others

References

  1. Fineberg, N. A. et al. The size, burden and cost of disorders of the brain in the UK. J. Psychopharmacol. Oxf. Engl. 27, 761–770 (2013).

    Google Scholar 

  2. Compston, A. & Coles, A. Multiple sclerosis. Lancet 372, 1502–1517 (2008).

    CAS  PubMed  Google Scholar 

  3. Weinshenker, B. G. & Wingerchuk, D. M. Neuromyelitis spectrum disorders. Mayo Clin. Proc. 92, 663–679 (2017).

    PubMed  Google Scholar 

  4. Graus, F. et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 15, 391–404 (2016).

    PubMed  PubMed Central  Google Scholar 

  5. Binks, S. N. M., Klein, C. J., Waters, P., Pittock, S. J. & Irani, S. R. LGI1, CASPR2 and related antibodies: a molecular evolution of the phenotypes. J. Neurol. Neurosurg. Psychiatry 89, 526–534 (2018).

    PubMed  Google Scholar 

  6. Balint, B., Vincent, A., Meinck, H.-M., Irani, S. R. & Bhatia, K. P. Movement disorders with neuronal antibodies: syndromic approach, genetic parallels and pathophysiology. Brain 141, 13–36 (2018).

    PubMed  Google Scholar 

  7. Varley, J., Vincent, A. & Irani, S. R. Clinical and experimental studies of potentially pathogenic brain-directed autoantibodies: current knowledge and future directions. J. Neurol. 262, 1081–1095 (2015).

    CAS  PubMed  Google Scholar 

  8. Riedhammer, C. & Weissert, R. Antigen presentation, autoantigens, and immune regulation in multiple sclerosis and other autoimmune diseases. Front. Immunol. 6, 322 (2015).

    PubMed  PubMed Central  Google Scholar 

  9. Meffre, E. The establishment of early B cell tolerance in humans: lessons from primary immunodeficiency diseases. Ann. NY Acad. Sci. 1246, 1–10 (2011).

    CAS  PubMed  Google Scholar 

  10. Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003).

    CAS  PubMed  Google Scholar 

  11. Tiller, T. et al. Autoreactivity in human IgG+ memory B cells. Immunity 26, 205–213 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Jones, A. & Hawiger, D. Peripherally induced regulatory T cells: recruited protectors of the central nervous system against autoimmune neuroinflammation. Front. Immunol. 8, 532 (2017).

    PubMed  PubMed Central  Google Scholar 

  13. Holländer, G. et al. Cellular and molecular events during early thymus development. Immunol. Rev. 209, 28–46 (2006).

    PubMed  Google Scholar 

  14. 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 

  15. Xing, Y. & Hogquist, K. A. T-cell tolerance: central and peripheral. Cold Spring Harb. Perspect. Biol. 4, a006957 (2012).

    PubMed  PubMed Central  Google Scholar 

  16. Bautista, J. L. et al. Intraclonal competition limits the fate determination of regulatory T cells in the thymus. Nat. Immunol. 10, 610–617 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Leung, M. W. L., Shen, S. & Lafaille, J. J. TCR-dependent differentiation of thymic Foxp3+ cells is limited to small clonal sizes. J. Exp. Med. 206, 2121–2130 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 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).

    CAS  PubMed  Google Scholar 

  19. Yu, W. et al. Clonal deletion prunes but does not eliminate self-specific αβ CD8+ T lymphocytes. Immunity 42, 929–941 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Legoux, F. P. et al. CD4+ T cell tolerance to tissue-restricted self antigens is mediated by antigen-specific regulatory T cells rather than deletion. Immunity 43, 896–908 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Malhotra, D. et al. Tolerance is established in polyclonal CD4+ T cells by distinct mechanisms, according to self-peptide expression patterns. Nat. Immunol. 17, 187–195 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 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). A transcriptomic study that identified genes that are regulated by Aire and described the proportion of mTECs that express key autoantigens.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. McNeil, L. K., Starr, T. K. & Hogquist, K. A. A requirement for sustained ERK signaling during thymocyte positive selection in vivo. Proc. Natl Acad. Sci. USA 102, 13574–13579 (2005).

    CAS  PubMed  Google Scholar 

  24. Daniels, M. A. et al. Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature 444, 724–729 (2006).

    CAS  PubMed  Google Scholar 

  25. Pignata, C. et al. Congenital alopecia and nail dystrophy associated with severe functional T cell immunodeficiency in two sibs. Am. J. Med. Genet. 65, 167–170 (1996).

    CAS  PubMed  Google Scholar 

  26. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  28. Akirav, E. M., Xu, Y. & Ruddle, N. H. Resident B cells regulate thymic expression of myelin oligodendrocyte glycoprotein. J. Neuroimmunol. 235, 33–39 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang, L. et al. Epitope-specific tolerance modes differentially specify susceptibility to proteolipid protein-induced experimental autoimmune encephalomyelitis. Front. Immunol. 8, 1511 (2017).

    PubMed  PubMed Central  Google Scholar 

  31. Perchellet, A., Brabb, T. & Goverman, J. M. Crosspresentation by nonhematopoietic and direct presentation by hematopoietic cells induce central tolerance to myelin basic protein. Proc. Natl Acad. Sci. USA 105, 14040–14045 (2008).

    CAS  PubMed  Google Scholar 

  32. Simon, A. K., Hollander, G. A. & McMichael, A. Evolution of the immune system in humans from infancy to old age. Proc. Biol. Sci. 282, 20143085 (2015).

    PubMed  PubMed Central  Google Scholar 

  33. Graus, F. et al. Neuronal surface antigen antibodies in limbic encephalitis: clinical-immunologic associations. Neurology 71, 930–936 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Bauer, J. et al. Innate and adaptive immunity in human epilepsies. Epilepsia 58 (Suppl. 3), 57–68 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Skorstad, G., Hestvik, A. L. K., Vartdal, F. & Holmøy, T. Cerebrospinal fluid T cell responses against glutamic acid decarboxylase 65 in patients with stiff person syndrome. J. Autoimmun. 32, 24–32 (2009).

    CAS  PubMed  Google Scholar 

  36. Burton, A. R. et al. Central nervous system destruction mediated by glutamic acid decarboxylase-specific CD4+ T cells. J. Immunol. 184, 4863–4870 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Wilson, R. et al. Condition-dependent generation of aquaporin-4 antibodies from circulating B cells in neuromyelitis optica. Brain 141, 1063–1074 (2018).

    PubMed  PubMed Central  Google Scholar 

  38. Makuch, M. et al. N-Methyl-D-aspartate receptor antibody production from germinal center reactions: therapeutic implications. Ann. Neurol. 83, 553–561 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Binks, S. et al. Distinct HLA associations of LGI1 and CASPR2-antibody diseases. Brain 141, 2263–2271 (2018).

    PubMed Central  Google Scholar 

  40. Handel, A. E., Lincoln, M. R. & Ramagopalan, S. V. Of mice and men: experimental autoimmune encephalitis and multiple sclerosis. Eur. J. Clin. Invest. 41, 1254–1258 (2011).

    PubMed  Google Scholar 

  41. Aharoni, R. et al. Age dependent course of EAE in Aire −/− mice. J. Neuroimmunol. 262, 27–34 (2013).

    CAS  PubMed  Google Scholar 

  42. Nalawade, S. A. et al. Aire is not essential for regulating neuroinflammatory disease in mice transgenic for human autoimmune-diseases associated MHC class II genes HLA-DR2b and HLA-DR4. Cell. Immunol. 331, 38–48 (2018).

    CAS  PubMed  Google Scholar 

  43. Malchow, S. et al. Aire enforces immune tolerance by directing autoreactive T cells into the regulatory T cell lineage. Immunity 44, 1102–1113 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Cowan, J. E. et al. Aire controls the recirculation of murine Foxp3+ regulatory T cells back to the thymus. Eur. J. Immunol. 48, 844–854 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Mazza, C. et al. Clinical heterogeneity and diagnostic delay of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. Clin. Immunol. 139, 6–11 (2011).

    CAS  PubMed  Google Scholar 

  46. Jiang, W., Anderson, M. S., Bronson, R., Mathis, D. & Benoist, C. Modifier loci condition autoimmunity provoked by Aire deficiency. J. Exp. Med. 202, 805–815 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Pan, J.-B. et al. PaGenBase: a pattern gene database for the global and dynamic understanding of gene function. PLOS ONE 8, e80747 (2013).

    PubMed  PubMed Central  Google Scholar 

  48. Xia, J. et al. Age-related disruption of steady-state thymic medulla provokes autoimmune phenotype via perturbing negative selection. Aging Dis. 3, 248–259 (2012).

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  50. Mair, F. et al. The NFκB-inducing kinase is essential for the developmental programming of skin-resident and IL-17-producing γδT cells. eLife 4, e10087 (2015).

    PubMed  PubMed Central  Google Scholar 

  51. Schirmer, L., Rothhammer, V., Hemmer, B. & Korn, T. Enriched CD161highCCR6+ γδ T cells in the cerebrospinal fluid of patients with multiple sclerosis. JAMA Neurol. 70, 345–351 (2013).

    PubMed  Google Scholar 

  52. Herzig, Y. et al. Transcriptional programs that control expression of the autoimmune regulator gene Aire. Nat. Immunol. 18, 161–172 (2017).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  54. Dengjel, J. et al. Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. Proc. Natl Acad. Sci. USA 102, 7922–7927 (2005).

    CAS  PubMed  Google Scholar 

  55. Aichinger, M., Wu, C., Nedjic, J. & Klein, L. Macroautophagy substrates are loaded onto MHC class II of medullary thymic epithelial cells for central tolerance. J. Exp. Med. 210, 287–300 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Schuster, C. et al. The autoimmunity-associated gene CLEC16A modulates thymic epithelial cell autophagy and alters T cell selection. Immunity 42, 942–952 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Serre, L. et al. Thymic-specific serine protease limits central tolerance and exacerbates experimental autoimmune encephalomyelitis. J. Immunol. 199, 3748–3756 (2017).

    CAS  PubMed  Google Scholar 

  58. Lincoln, M. R. et al. Epistasis among HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci determines multiple sclerosis susceptibility. Proc. Natl Acad. Sci. USA 106, 7542–7547 (2009).

    CAS  PubMed  Google Scholar 

  59. Yoshida, K. et al. The diabetogenic mouse MHC class II molecule I-Ag7 is endowed with a switch that modulates TCR affinity. J. Clin. Invest. 120, 1578–1590 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Schubert, D. A. et al. Self-reactive human CD4 T cell clones form unusual immunological synapses. J. Exp. Med. 209, 335–352 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. International Multiple Sclerosis Genetics Consortium et al. The multiple sclerosis genomic map: role of peripheral immune cells and resident microglia in susceptibility. Preprint at bioRxiv https://doi.org/10.1101/143933 (2017).

    Article  Google Scholar 

  62. Luo, C. T. & Li, M. O. Transcriptional control of regulatory T cell development and function. Trends Immunol. 34, 531–539 (2013).

    CAS  PubMed  Google Scholar 

  63. Verbsky, J. W. & Chatila, T. A. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders: an evolving web of heritable autoimmune diseases. Curr. Opin. Pediatr. 25, 708–714 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Chen, X. et al. Thymic regulation of autoimmune disease by accelerated differentiation of Foxp3+ regulatory T cells through IL-7 signaling pathway. J. Immunol. 183, 6135–6144 (2009).

    CAS  PubMed  Google Scholar 

  65. Dombrowski, Y. et al. Regulatory T cells promote myelin regeneration in the central nervous system. Nat. Neurosci. 20, 674–680 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Bae, K. W. et al. A novel mutation and unusual clinical features in a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Eur. J. Pediatr. 170, 1611–1615 (2011).

    PubMed  Google Scholar 

  67. Kinnunen, T. et al. Specific peripheral B cell tolerance defects in patients with multiple sclerosis. J. Clin. Invest. 123, 2737–2741 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 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 

  69. Volovitz, I. et al. T cell seeding: neonatal transfer of anti-myelin basic protein T cell lines renders Fischer rats susceptible later in life to the active induction of experimental autoimmune encephalitis. Immunology 128, 92–102 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Sagan, S. A. et al. Tolerance checkpoint bypass permits emergence of pathogenic T cells to neuromyelitis optica autoantigen aquaporin-4. Proc. Natl Acad. Sci. USA 113, 14781–14786 (2016). This study showed that T cell transfer from Aqp4- knockout mice could cause EAE, suggesting that thymic tolerance is key in the pathogenesis of NMOSDs.

    CAS  PubMed  Google Scholar 

  71. Bentivoglio, M. & Kristensson, K. Tryps and trips: cell trafficking across the 100-year-old blood–brain barrier. Trends Neurosci. 37, 325–333 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Sixt, M. et al. Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in T cell recruitment across the blood-brain barrier in experimental autoimmune encephalomyelitis. J. Cell Biol. 153, 933–946 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Gerwien, H. et al. Imaging matrix metalloproteinase activity in multiple sclerosis as a specific marker of leukocyte penetration of the blood-brain barrier. Sci. Transl Med. 8, 364ra152 (2016).

    PubMed  Google Scholar 

  74. Engelhardt, B., Vajkoczy, P. & Weller, R. O. The movers and shapers in immune privilege of the CNS. Nat. Immunol. 18, 123–131 (2017).

    CAS  PubMed  Google Scholar 

  75. Römer, C. et al. Blocking stroke-induced immunodeficiency increases CNS antigen-specific autoreactivity but does not worsen functional outcome after experimental stroke. J. Neurosci. 35, 7777–7794 (2015).

    PubMed  Google Scholar 

  76. Kyratsous, N. I. et al. Visualizing context-dependent calcium signaling in encephalitogenic T cells in vivo by two-photon microscopy. Proc. Natl Acad. Sci. USA 114, E6381–E6389 (2017). An imaging study that showed that T cells frequently scan the leptomeningeal space for antigens.

    CAS  PubMed  Google Scholar 

  77. Kipnis, J., Gadani, S. & Derecki, N. C. Pro-cognitive properties of T cells. Nat. Rev. Immunol. 12, 663–669 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Schwartz, M. & Raposo, C. Protective autoimmunity: a unifying model for the immune network involved in CNS repair. Neuroscientist 20, 343–358 (2014).

    PubMed  Google Scholar 

  79. Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337 (2015). A definitive description of the lymphatic vessels within the CNS.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Aspelund, A. et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 212, 991–999 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Absinta, M. et al. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. eLife 6, e29738 (2017). An imaging study that identified lymphatic vessels within the human CNS.

    PubMed  PubMed Central  Google Scholar 

  82. Cserr, H. F., Harling-Berg, C. J. & Knopf, P. M. Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance. Brain Pathol. 2, 269–276 (1992).

    CAS  PubMed  Google Scholar 

  83. Steinman, L. Elaborate interactions between the immune and nervous systems. Nat. Immunol. 5, 575–581 (2004).

    CAS  PubMed  Google Scholar 

  84. Walsh, J. T. et al. Regulatory T cells in central nervous system injury: a double-edged sword. J. Immunol. 193, 5013–5022 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Varrin-Doyer, M. et al. Aquaporin 4-specific T cells in neuromyelitis optica exhibit a Th17 bias and recognize Clostridium ABC transporter. Ann. Neurol. 72, 53–64 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. den Braber, I. et al. Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans. Immunity 36, 288–297 (2012).

    Google Scholar 

  88. Trotter, J. L., Clifford, D. B., Montgomery, E. B. & Ferguson, T. B. Thymectomy in multiple sclerosis: a 3-year follow-up. Neurology 35, 1049–1051 (1985).

    CAS  PubMed  Google Scholar 

  89. Schatz, D. G. & Swanson, P. C. V(D)J recombination: mechanisms of initiation. Annu. Rev. Genet. 45, 167–202 (2011).

    CAS  PubMed  Google Scholar 

  90. Hug, A. et al. Thymic export function and T cell homeostasis in patients with relapsing remitting multiple sclerosis. J. Immunol. 171, 432–437 (2003).

    CAS  PubMed  Google Scholar 

  91. Thewissen, M. et al. Premature immunosenescence in rheumatoid arthritis and multiple sclerosis patients. Ann. NY Acad. Sci. 1051, 255–262 (2005).

    CAS  PubMed  Google Scholar 

  92. Duszczyszyn, D. A. et al. Altered naive CD4 and CD8 T cell homeostasis in patients with relapsing-remitting multiple sclerosis: thymic versus peripheral (non-thymic) mechanisms. Clin. Exp. Immunol. 143, 305–313 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Thewissen, M. et al. Analyses of immunosenescent markers in patients with autoimmune disease. Clin. Immunol. 123, 209–218 (2007).

    CAS  Google Scholar 

  94. Puissant-Lubrano, B. et al. Thymic output and peripheral T lymphocyte subsets in relapsing — remitting multiple sclerosis patients treated or not by IFN-β. J. Neuroimmunol. 193, 188–194 (2008).

    CAS  PubMed  Google Scholar 

  95. Venken, K. et al. Natural naive CD4+CD25+CD127low regulatory T cell (Treg) development and function are disturbed in multiple sclerosis patients: recovery of memory Treg homeostasis during disease progression. J. Immunol. 180, 6411–6420 (2008).

    CAS  PubMed  Google Scholar 

  96. Chiarini, M. et al. Renewal of the T cell compartment in multiple sclerosis patients treated with glatiramer acetate. Mult. Scler. 16, 218–227 (2010).

    CAS  PubMed  Google Scholar 

  97. Duszczyszyn, D. A. et al. Thymic involution and proliferative T cell responses in multiple sclerosis. J. Neuroimmunol. 221, 73–80 (2010).

    CAS  PubMed  Google Scholar 

  98. Haegert, D. G. et al. Reduced thymic output and peripheral naïve CD4 T cell alterations in primary progressive multiple sclerosis (PPMS). J. Neuroimmunol. 233, 233–239 (2011).

    CAS  PubMed  Google Scholar 

  99. Zanotti, C. et al. Opposite effects of interferon-β on new B and T cell release from production sites in multiple sclerosis patients. J. Neuroimmunol. 240–241, 147–150 (2011).

    PubMed  Google Scholar 

  100. Zanotti, C. et al. Peripheral accumulation of newly produced T and B lymphocytes in natalizumab-treated multiple sclerosis patients. Clin. Immunol. 145, 19–26 (2012).

    CAS  PubMed  Google Scholar 

  101. Chiarini, M. et al. Newly produced T and B lymphocytes and T cell receptor repertoire diversity are reduced in peripheral blood of fingolimod-treated multiple sclerosis patients. Mult. Scler. 21, 726–734 (2015).

    CAS  PubMed  Google Scholar 

  102. Hazenberg, M. D., Borghans, J. A. M., de Boer, R. J. & Miedema, F. Thymic output: a bad TREC record. Nat. Immunol. 4, 97–99 (2003).

    CAS  PubMed  Google Scholar 

  103. Balint, B. et al. T cell homeostasis in pediatric multiple sclerosis: old cells in young patients. Neurology 81, 784–792 (2013).

    PubMed  Google Scholar 

  104. Broux, B. et al. Haplotype 4 of the multiple sclerosis-associated interleukin-7 receptor alpha gene influences the frequency of recent thymic emigrants. Genes Immun. 11, 326–333 (2010).

    CAS  PubMed  Google Scholar 

  105. Cao, Y. et al. Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis. Sci. Transl Med. 7, 287ra74 (2015). In this study, myelin-reactive T cells were identified in patients with MS.

    PubMed  PubMed Central  Google Scholar 

  106. Contin-Bordes, C. et al. Expansion of myelin autoreactive CD8+ T lymphocytes in patients with neuropsychiatric systemic lupus erythematosus. Ann. Rheum. Dis. 70, 868–871 (2011).

    CAS  PubMed  Google Scholar 

  107. Salou, M. et al. Expanded CD8 T cell sharing between periphery and CNS in multiple sclerosis. Ann. Clin. Transl Neurol. 2, 609–622 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. de Paula Alves Sousa, A. et al. Intrathecal T cell clonal expansions in patients with multiple sclerosis. Ann. Clin. Transl Neurol. 3, 422–433 (2016).

    PubMed  PubMed Central  Google Scholar 

  109. Held, K. et al. αβ T cell receptors from multiple sclerosis brain lesions show MAIT cell-related features. Neurol. Neuroimmunol. Neuroinflamm. 2, e107 (2015). In this study, TCR sequencing demonstrated the presence of clonally expanded T cell populations in MS brains and showed that these populations linger for at least 18 years.

    PubMed  PubMed Central  Google Scholar 

  110. Munger, K. L., Levin, L. I., Hollis, B. W., Howard, N. S. & Ascherio, A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. J. Am. Med. Assoc. 296, 2832–2838 (2006).

    CAS  Google Scholar 

  111. Handel, A. E. et al. Smoking and multiple sclerosis: an updated meta-analysis. PLOS ONE 6, e16149 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Munger, K. L. et al. Childhood body mass index and multiple sclerosis risk: a long-term cohort study. Mult. Scler. 19, 1323–1329 (2013).

    PubMed  PubMed Central  Google Scholar 

  113. Zoller, A. L. & Kersh, G. J. Estrogen induces thymic atrophy by eliminating early thymic progenitors and inhibiting proliferation of β-selected thymocytes. J. Immunol. 176, 7371–7378 (2006).

    CAS  PubMed  Google Scholar 

  114. Dragin, N. et al. Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases. J. Clin. Invest. 126, 1525–1537 (2016).

    PubMed  PubMed Central  Google Scholar 

  115. Bakhru, P. & Su, M. A. Estrogen turns down ‘the AIRE’. J. Clin. Invest. 126, 1239–1241 (2016).

    PubMed  PubMed Central  Google Scholar 

  116. Zhu, M.-L. et al. Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator. Nat. Commun. 7, 11350 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Gur, E. B. et al. Vitamin D deficiency in pregnancy may affect fetal thymus development. Ginekol. Pol. 87, 378–383 (2016).

    PubMed  Google Scholar 

  118. Mayan, I. et al. Thymus activity, vitamin D, and respiratory infections in adolescent swimmers. Isr. Med. Assoc. J. 17, 571–575 (2015).

    PubMed  Google Scholar 

  119. Brockman-Schneider, R. A., Pickles, R. J. & Gern, J. E. Effects of vitamin D on airway epithelial cell morphology and rhinovirus replication. PLOS ONE 9, e86755 (2014).

    PubMed  PubMed Central  Google Scholar 

  120. Munger, K. L. et al. Vitamin D status during pregnancy and risk of multiple sclerosis in offspring of women in the Finnish maternity cohort. JAMA Neurol. 73, 515–519 (2016).

    PubMed  PubMed Central  Google Scholar 

  121. Disanto, G. et al. Month of birth and thymic output. JAMA Neurol. 70, 527–528 (2013).

    PubMed  Google Scholar 

  122. Crozier, S. R. et al. Maternal vitamin D status in pregnancy is associated with adiposity in the offspring: findings from the Southampton Women’s Survey. Am. J. Clin. Nutr. 96, 57–63 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Kanamori, M. et al. Epstein-Barr virus nuclear antigen leader protein induces expression of thymus- and activation-regulated chemokine in B cells. J. Virol. 78, 3984–3993 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Hanabuchi, S. et al. Thymic stromal lymphopoietin-activated plasmacytoid dendritic cells induce the generation of FOXP3+ regulatory T cells in human thymus. J. Immunol. 184, 2999–3007 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Ruland, C. et al. Chemokine CCL17 is expressed by dendritic cells in the CNS during experimental autoimmune encephalomyelitis and promotes pathogenesis of disease. Brain Behav. Immun. 66, 382–393 (2017).

    CAS  PubMed  Google Scholar 

  126. Cavalcante, P. et al. Inflammation and Epstein-Barr virus infection are common features of myasthenia gravis thymus: possible roles in pathogenesis. Autoimmune Dis. 2011, 213092 (2011).

    PubMed  PubMed Central  Google Scholar 

  127. Meyer, M. et al. Lack of evidence for Epstein-Barr virus infection in myasthenia gravis thymus. Ann. Neurol. 70, 515–518 (2011).

    PubMed  Google Scholar 

  128. Zeyrek, D., Ozturk, E., Ozturk, A. & Cakmak, A. Decreased thymus size in full-term newborn infants of smoking mothers. Med. Sci. Monit. 14, CR423–CR426 (2008).

    PubMed  Google Scholar 

  129. Araki, T. et al. Normal thymus in adults: appearance on CT and associations with age, sex, BMI and smoking. Eur. Radiol. 26, 15–24 (2016).

    PubMed  Google Scholar 

  130. Muraro, P. A. et al. Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients. J. Exp. Med. 201, 805–816 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Darlington, P. J. et al. Diminished Th17 (not Th1) responses underlie multiple sclerosis disease abrogation after hematopoietic stem cell transplantation. Ann. Neurol. 73, 341–354 (2013). This study showed that reconstitution of the T cell compartment after haematopoietic stem cell transplantation for the treatment of MS in adults is associated with the appearance of recent thymic emigrant T cells, suggesting that thymopoiesis can occur in adulthood.

    CAS  PubMed  Google Scholar 

  132. Erkmen, C. P., Fadul, C. E., Dalmau, J. & Erkmen, K. Thymoma-associated paraneoplastic encephalitis (TAPE): diagnosis and treatment of a potentially fatal condition. J. Thorac. Cardiovasc. Surg. 141, e17–e20 (2011).

    PubMed  Google Scholar 

  133. Tanaka, H. et al. Stiff man syndrome with thymoma. Ann. Thorac. Surg. 80, 739–741 (2005).

    PubMed  Google Scholar 

  134. Evoli, A. & Lancaster, E. Paraneoplastic disorders in thymoma patients. J. Thorac. Oncol. 9, S143–S147 (2014).

    PubMed  PubMed Central  Google Scholar 

  135. Bernard, C. et al. Thymoma associated with autoimmune diseases: 85 cases and literature review. Autoimmun. Rev. 15, 82–92 (2016).

    CAS  PubMed  Google Scholar 

  136. Leite, M. I. et al. Myasthenia gravis and neuromyelitis optica spectrum disorder: a multicenter study of 16 patients. Neurology 78, 1601–1607 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  138. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  140. Fan, Y. et al. Bioengineering thymus organoids to restore thymic function and induce donor-specific immune tolerance to allografts. Mol. Ther. 23, 1262–1277 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Seet, C. S. et al. Generation of mature T cells from human hematopoietic stem and progenitor cells in artificial thymic organoids. Nat. Methods 14, 521–530 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Su, M. et al. ESC-derived thymic epithelial cells expressing MOG prevents EAE by central and peripheral tolerance mechanisms. Cell. Immunol. 322, 84–91 (2017). A proof-of-concept study in a mouse model, which showed that the forced expression of myelin oligodendrocyte glycoprotein (MOG) in TECs that were derived from embryonic stem cells could ameliorate EAE through the generation of T reg cells.

    CAS  PubMed  Google Scholar 

  143. Burt, R. K. et al. Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis. JAMA 313, 275–284 (2015).

    PubMed  Google Scholar 

  144. Yang, H. et al. Obesity accelerates thymic aging. Blood 114, 3803–3812 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Wong, C. P., Song, Y., Elias, V. D., Magnusson, K. R. & Ho, E. Zinc supplementation increases zinc status and thymopoiesis in aged mice. J. Nutr. 139, 1393–1397 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Hwang, Y. G. et al. Increased vitamin D is associated with decline of naïve, but accumulation of effector, CD8 T cells during early aging. Adv. Aging Res. 2, 72–80 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Velardi, E. et al. Sex steroid blockade enhances thymopoiesis by modulating Notch signaling. J. Exp. Med. 211, 2341–2349 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Dumont-Lagacé, M., St-Pierre, C. & Perreault, C. Sex hormones have pervasive effects on thymic epithelial cells. Sci. Rep. 5, 12895 (2015).

    PubMed  PubMed Central  Google Scholar 

  149. Clise-Dwyer, K., Huston, G. E., Buck, A. L., Duso, D. K. & Swain, S. L. Environmental and intrinsic factors lead to antigen unresponsiveness in CD4+ recent thymic emigrants from aged mice. J. Immunol. 178, 1321–1331 (2007).

    CAS  PubMed  Google Scholar 

  150. Stubbington, M. J. T. et al. T cell fate and clonality inference from single-cell transcriptomes. Nat. Methods 13, 329–332 (2016). This study demonstrated that paired TCR sequences could be reassembled from single-cell RNA sequencing data and used to identify clonally expanded T cell populations.

    PubMed  PubMed Central  Google Scholar 

  151. Ng, Y.-S., Wardemann, H., Chelnis, J., Cunningham-Rundles, C. & Meffre, E. Bruton’s tyrosine kinase is essential for human B cell tolerance. J. Exp. Med. 200, 927–934 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Ait-Azzouzene, D. et al. An immunoglobulin Cκ-reactive single chain antibody fusion protein induces tolerance through receptor editing in a normal polyclonal immune system. J. Exp. Med. 201, 817–828 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Hervé, M. et al. CD40 ligand and MHC class II expression are essential for human peripheral B cell tolerance. J. Exp. Med. 204, 1583–1593 (2007).

    PubMed  PubMed Central  Google Scholar 

  154. de Jonge, H. J. M. et al. Evidence based selection of housekeeping genes. PLOS ONE 2, e898 (2007).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank members of the Holländer and Irani groups for many helpful and insightful conversations. Particular thanks go to L. Handunnetthi (University of Oxford, UK) and B. Adriaanse (University of Oxford, UK) for their kind, critical reading of this manuscript. A.E.H. was supported by an Academic Clinical Lectureship from the National Institute for Health Research (NIHR).

Author information

Authors and Affiliations

  1. Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

    Adam E. Handel

  2. Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

    Adam E. Handel & Sarosh R. Irani

  3. Paediatric Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland

    Georg A. Holländer

Authors
  1. Adam E. Handel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sarosh R. Irani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Georg A. Holländer
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.E.H. researched data for the article. All authors made substantial contributions to discussion of the content, wrote the article and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Adam E. Handel.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

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

Glossary

Thymic involution

The process by which atrophy of the thymus occurs with increasing age.

γδ T cells

Unconventional T cells that express γδ T cell receptors, which predominantly react to antigens in an MHC-independent manner, the mechanisms of which are still poorly understood.

Homeostatic expansion

The proliferative process of peripheral lymphocytes that ensures an appropriate representation of naive and memory cells for the proper functioning of the adaptive immune system.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Handel, A.E., Irani, S.R. & Holländer, G.A. The role of thymic tolerance in CNS autoimmune disease. Nat Rev Neurol 14, 723–734 (2018). https://doi.org/10.1038/s41582-018-0095-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41582-018-0095-7

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