The Mechanisms of T Cell Selection in the Thymus

Trends in Immunology

Volumn 38, Issue 11, 2017, Pages 805-816

  Takaba, Hiroyuki ^a   Takayanagi, Hiroshi ^a  

^a UNIVERSITY OF TOKYO   (Japan)

Author keywords

Aire; Fezf2; negative selection; promiscuous gene expression; TRA

Indexed keywords

AUTOANTIGEN; AUTOIMMUNE REGULATOR PROTEIN; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR FEZF2; UNCLASSIFIED DRUG; ZNF312 PROTEIN, HUMAN;

ANTIGEN EXPRESSION; AUTOIMMUNITY; CELL SELECTION; EPIGENETICS; EPITHELIUM CELL; GENE EXPRESSION REGULATION; HUMAN; IMMUNE RESPONSE; IMMUNOLOGICAL TOLERANCE; IMMUNOREGULATION; NONHUMAN; REGULATORY T LYMPHOCYTE; REVIEW; T LYMPHOCYTE; THYMIC CORTEX; THYMIC MEDULLA; THYMUS; TRANSCRIPTION REGULATION; ANIMAL; ANTIBODY SPECIFICITY; ANTIGEN MEDIATED CLONAL SELECTION; CELL DIFFERENTIATION; GENETICS; HEMATOPOIESIS; IMMUNOLOGY; LYMPHOCYTE ACTIVATION; METABOLISM; PHYSIOLOGY;

ANIMALS; AUTOANTIGENS; CELL DIFFERENTIATION; CLONAL SELECTION, ANTIGEN-MEDIATED; GENE EXPRESSION REGULATION; HEMATOPOIESIS; HUMANS; LYMPHOCYTE ACTIVATION; ORGAN SPECIFICITY; SELF TOLERANCE; T-LYMPHOCYTES; THYMUS GLAND; TRANSCRIPTION FACTORS;

EID: 85027722331     PISSN: 14714906     EISSN: 14714981     Source Type: Journal    
DOI: 10.1016/j.it.2017.07.010     Document Type: Review

References (89)

1. Pancer, Z., Cooper, M.D., The evolution of adaptive immunity. Annu. Rev. Immunol. 24 (2006), 497–518.
2. Melchers, F., Checkpoints that control B cell development. J. Clin. Invest. 125 (2015), 2203–2210.
3. Miller, J.F., The golden anniversary of the thymus. Nat. Rev. Immunol. 11 (2011), 489–495.
4. Davis, M.M., et al. Ligand recognition by αβ T cell receptors. Annu. Rev. Immunol. 16 (1998), 523–544.
5. Klein, L., et al. Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat. Rev. Immunol. 14 (2014), 377–391.
6. + natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol. Rev. 212 (2006), 8–27.
7. Takada, K., Takahama, Y., Positive-selection-inducing self-peptides displayed by cortical thymic epithelial cells. Adv. Immunol. 125 (2015), 87–110.
8. Anderson, G., Takahama, Y., Thymic epithelial cells: working class heroes for T cell development and repertoire selection. Trends Immunol. 33 (2012), 256–263.
9. + T cells. Curr. Opin. Immunol. 24 (2012), 92–98.
10. + T cell development by thymus-specific proteasomes. Science 316 (2007), 1349–1353.
11. Förster, R., et al. CCR7 and its ligands: balancing immunity and tolerance. Nat. Rev. Immunol. 8 (2008), 362–371.
12. Derbinski, J., et al. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat. Immunol. 2 (2001), 1032–1039.
13. St-Pierre, C., et al. Differential features of AIRE-induced and AIRE-independent promiscuous gene expression in thymic epithelial cells. J. Immunol. 195 (2015), 498–506.
14. Hubert, F.X., et al. Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance. Blood 118 (2011), 2462–2472.
15. Perry, J.S., Hsieh, C.S., Development of T-cell tolerance utilizes both cell-autonomous and cooperative presentation of self-antigen. Immunol. Rev. 271 (2016), 141–155.
16. Sakaguchi, S., Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101 (2000), 455–458.
17. Li, X., Zheng, Y., Regulatory T cell identity: formation and maintenance. Trends Immunol. 36 (2015), 344–353.
18. Shevach, E.M., Thornton, A.M., tTregs, pTregs, and iTregs: similarities and differences. Immunol. Rev. 259 (2014), 88–102.
19. Yadav, M., et al. Peripherally induced tregs − role in immune homeostasis and autoimmunity. Front. Immunol., 4, 2013, 232.
20. Burzyn, D., et al. A special population of regulatory T cells potentiates muscle repair. Cell 155 (2013), 1282–1295.
21. Malchow, S., et al. Aire-dependent thymic development of tumor-associated regulatory T cells. Science 339 (2013), 1219–1224.
22. Ohigashi, I., et al. Development and developmental potential of cortical thymic epithelial cells. Immunol. Rev. 271 (2016), 10–22.
23. Nehls, M., et al. New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature 372 (1994), 103–107.
24. Žuklys, S., et al. Foxn1 regulates key target genes essential for T cell development in postnatal thymic epithelial cells. Nat. Immunol. 17 (2016), 1206–1215.
25. Nakagawa, Y., et al. Thymic nurse cells provide microenvironment for secondary T cell receptor α rearrangement in cortical thymocytes. Proc. Natl. Acad. Sci. U. S. A. 109 (2012), 20572–20577.
26. Akiyama, T., et al. The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 29 (2008), 423–437.
27. Hikosaka, Y., et al. The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity 29 (2008), 438–450.
28. Akiyama, N., et al. Limitation of immune tolerance-inducing thymic epithelial cell development by Spi-B-mediated negative feedback regulation. J. Exp. Med. 211 (2014), 2425–2438.
29. Satoh, R., et al. Requirement of Stat3 signaling in the postnatal development of thymic medullary epithelial cells. PLoS Genet., 12, 2016, e1005776.
30. Lomada, D., et al. Stat3 Signaling promotes survival and maintenance of medullary thymic epithelial cells. PLoS Genet., 12, 2016, e1005777.
31. Gray, D.H., et al. Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood 108 (2006), 3777–3785.
32. 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 (2014), 1918–1931.
33. DeVoss, J., et al. Spontaneous autoimmunity prevented by thymic expression of a single self-antigen. J. Exp. Med. 203 (2006), 2727–2735.
34. Fan, Y., et al. Thymus-specific deletion of insulin induces autoimmune diabetes. EMBO J. 28 (2009), 2812–2824.
35. Ucar, O., et al. An evolutionarily conserved mutual interdependence between Aire and microRNAs in promiscuous gene expression. Eur. J. Immunol. 43 (2013), 1769–1778.
36. Wu, G., et al. DNA methylation profile of Aire-deficient mouse medullary thymic epithelial cells. BMC Immunol., 13, 2012, 58.
37. Brennecke, P., et al. Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells. Nat. Immunol. 16 (2015), 933–941.
38. Rattay, K., et al. Evolutionary conserved gene co-expression drives generation of self-antigen diversity in medullary thymic epithelial cells. J. Autoimmun. 67 (2016), 65–75.
39. Kyewski, B., Klein, L., A central role for central tolerance. Annu. Rev. Immunol. 24 (2006), 571–606.
40. Anderson, M.S., et al. Projection of an immunological self shadow within the thymus by the Aire protein. Science 298 (2002), 1395–1401.
41. Yamano, T., et al. Thymic B cells are licensed to present self antigens for central t cell tolerance induction. Immunity 42 (2015), 1048–1061.
42. DeVoss, J.J., et al. An autoimmune response to odorant binding protein 1a is associated with dry eye in the Aire-deficient mouse. J. Immunol. 184 (2010), 4236–4246.
43. Hubert, F.X., et al. Aire-deficient C57BL/6 mice mimicking the common human 13-base pair deletion mutation present with only a mild autoimmune phenotype. J. Immunol. 182 (2009), 3902–3918.
44. Consortium, F.-G.A., An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat. Genet. 17 (1997), 399–403.
45. Nagamine, K., et al. Positional cloning of the APECED gene. Nat. Genet. 17 (1997), 393–398.
46. Browne, S.K., Anticytokine autoantibody-associated immunodeficiency. Annu. Rev. Immunol. 32 (2014), 635–657.
47. Capalbo, D., et al. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy: insights into genotype-phenotype correlation. Int. J. Endocrinol, 2012, 2012, 353250.
48. Meyer, S., et al. AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies. Cell 166 (2016), 582–595.
49. Nishikawa, Y., et al. Temporal lineage tracing of Aire-expressing cells reveals a requirement for Aire in their maturation program. J. Immunol. 192 (2014), 2585–2592.
50. 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 (2011), 383–394.
51. + thymocytes. J. Immunol. 183 (2009), 7682–7691.
52. Gardner, J.M., et al. Deletional tolerance mediated by extrathymic Aire-expressing cells. Science 321 (2008), 843–847.
53. + T cells. Immunity 39 (2013), 560–572.
54. Guerau-de-Arellano, M., et al. Neonatal tolerance revisited: a perinatal window for Aire control of autoimmunity. J. Exp. Med. 206 (2009), 1245–1252.
55. Yang, S., et al. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance. Science 348 (2015), 589–594.
56. Carding, S.R., Egan, P.J., γδ T cells: functional plasticity and heterogeneity. Nat. Rev. Immunol. 2 (2002), 336–345.
57. Vantourout, P., Hayday, A., Six-of-the-best: unique contributions of γδ T cells to immunology. Nat. Rev. Immunol. 13 (2013), 88–100.
58. Fujikado, N., et al. Aire inhibits the generation of a perinatal population of interleukin-17A-producing γδ T cells to promote immunologic tolerance. Immunity 45 (2016), 999–1012.
59. Mathis, D., Benoist, C., Aire. Annu. Rev. Immunol. 27 (2009), 287–312.
60. Waterfield, M., et al. The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance. Nat. Immunol. 15 (2014), 258–265.
61. Org, T., et al. The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EMBO Rep. 9 (2008), 370–376.
62. Koh, A.S., et al. Global relevance of Aire binding to hypomethylated lysine-4 of histone-3. Proc. Natl. Acad. Sci. U. S. A. 107 (2010), 13016–13021.
63. Gaetani, M., et al. AIRE-PHD fingers are structural hubs to maintain the integrity of chromatin-associated interactome. Nucleic Acids Res. 40 (2012), 11756–11768.
64. Oven, I., et al. AIRE recruits P-TEFb for transcriptional elongation of target genes in medullary thymic epithelial cells. Mol. Cell. Biol. 27 (2007), 8815–8823.
65. Bansal, K., et al. The transcriptional regulator Aire binds to and activates super-enhancers. Nat. Immunol. 18 (2017), 263–273.
66. Akiyama, T., et al. TNF receptor family signaling in the development and functions of medullary thymic epithelial cells. Front. Immunol., 3, 2012, 278.
67. Haljasorg, U., et al. A highly conserved NF-κB-responsive enhancer is critical for thymic expression of Aire in mice. Eur. J. Immunol. 45 (2015), 3246–3256.
68. LaFlam, T.N., et al. Identification of a novel cis-regulatory element essential for immune tolerance. J. Exp. Med. 212 (2015), 1993–2002.
69. Zhu, M.L., et al. Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator. Nat. Commun., 7, 2016, 11350.
70. Dragin, N., et al. Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases. J. Clin. Invest. 126 (2016), 1525–1537.
71. Derbinski, J., et al. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J. Exp. Med. 202 (2005), 33–45.
72. Takaba, H., et al. Fezf2 orchestrates a thymic program of self-antigen expression for immune tolerance. Cell 163 (2015), 975–987.
73. Shim, S., et al. Cis-regulatory control of corticospinal system development and evolution. Nature 486 (2012), 74–79.
74. Sanders, S.J., et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485 (2012), 237–241.
75. Kwan, K.Y., Transcriptional dysregulation of neocortical circuit assembly in ASD. Int. Rev. Neurobiol. 113 (2013), 167–205.
76. Shu, X.S., et al. FEZF2, a novel 3p14 tumor suppressor gene, represses oncogene EZH2 and MDM2 expression and is frequently methylated in nasopharyngeal carcinoma. Carcinogenesis 34 (2013), 1984–1993.
77. Seach, N., et al. The lymphotoxin pathway regulates Aire-independent expression of ectopic genes and chemokines in thymic stromal cells. J. Immunol. 180 (2008), 5384–5392.
78. Danzl, N.M., et al. Regulation of medullary thymic epithelial cell differentiation and function by the signaling protein Sin. J. Exp. Med. 207 (2010), 999–1013.
79. Demirci, F.Y., et al. Functional polymorphisms of the coagulation factor II gene (F2) and susceptibility to systemic lupus erythematosus. J. Rheumatol. 38 (2011), 652–657.
80. Asciutto, G., et al. Low levels of IgG autoantibodies against the apolipoprotein B antigen p210 increases the risk of cardiovascular death after carotid endarterectomy. Atherosclerosis 239 (2015), 289–294.
81. Roulois, D., et al. MUC1-specific cytotoxic T lymphocytes in cancer therapy: induction and challenge. BioMed Res. Int., 2013, 2013, 871936.
82. Träger, U., et al. The immune response to melanoma is limited by thymic selection of self-antigens. PLoS One, 7, 2012, e35005.
83. Zhu, M.L., et al. Aire deficiency promotes TRP-1-specific immune rejection of melanoma. Cancer Res. 73 (2013), 2104–2116.
84. Khan, I.S., et al. Enhancement of an antitumor immune response by transient blockade of central T cell tolerance. J. Exp. Med. 211 (2014), 761–768.
85. Garchon, H.J., Genetics of autoimmune myasthenia gravis, a model for antibody-mediated autoimmunity in man. J. Autoimmun. 21 (2003), 105–110.
86. Giraud, M., et al. An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature 448 (2007), 934–937.
87. Lodato, S., et al. Gene co-regulation by Fezf2 selects neurotransmitter identity and connectivity of corticospinal neurons. Nat. Neurosci. 17 (2014), 1046–1054.
88. Zhang, S., et al. Fezf2 promotes neuronal differentiation through localised activation of Wnt/β-catenin signalling during forebrain development. Development 141 (2014), 4794–4805.
89. Boehm, T., et al. Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lymphoepithelial cross talk via LTβR. J. Exp. Med. 198 (2003), 757–769.