Positive and negative selection of the T cell repertoire: What thymocytes see (and don't see)

Nature Reviews Immunology

Volumn 14, Issue 6, 2014, Pages 377-391

  Klein, Ludger ^a   Kyewski, Bruno ^b   Allen, Paul M ^c   Hogquist, Kristin A ^d  

^a UNIVERSITY OF MUNICH   (Germany)

^b GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

^c WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^d UNIVERSITY OF MINNESOTA MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; PEPTIDE;

ANTIGEN PRESENTATION; ANTIGEN PRESENTING CELL; AUTOIMMUNITY; B LYMPHOCYTE; BRAIN CORTEX; CELL DIFFERENTIATION; CELL FUNCTION; CELL MIGRATION; CELL SELECTION; CORTICAL THYMIC EPITHELIAL CELL; EPITHELIUM CELL; HOMEOSTASIS; HUMAN; IMMUNOLOGICAL TOLERANCE; MAJOR HISTOCOMPATIBILITY COMPLEX; MEDULLA OBLONGATA; MEDULLARY THYMIC EPITHELIAL CELL; NONHUMAN; PATHOGENESIS; PLASMACYTOID DENDRITIC CELL; PRIORITY JOURNAL; PROTEIN ANALYSIS; REGULATORY T LYMPHOCYTE; REVIEW; T LYMPHOCYTE; THYMIC DENDRITIC CELL; THYMOCYTE; THYMUS;

ANIMALS; AUTOANTIGENS; B-LYMPHOCYTES; CELLULAR MICROENVIRONMENT; DENDRITIC CELLS; HUMANS; IMMUNE TOLERANCE; LYMPHOPOIESIS; MICE; RECEPTORS, ANTIGEN, T-CELL; T-LYMPHOCYTES, REGULATORY; THYMOCYTES; THYMUS GLAND;

EID: 84901487911     PISSN: 14741733     EISSN: 14741741     Source Type: Journal    
DOI: 10.1038/nri3667     Document Type: Review

References (119)

1. Kyewski, B. & Klein, L. A central role for central tolerance. Annu. Rev. Immunol. 24, 571-606 (2006).
2. Nakagawa, Y. et al. Thymic nurse cells provide microenvironment for secondary T cell receptor-α rearrangement in cortical thymocytes. Proc. Natl Acad. Sci. USA 109, 20572-20577 (2012).
3. Klein, L., Hinterberger, M., Wirnsberger, G. & Kyewski, B. Antigen presentation in the thymus for positive selection and central tolerance induction. Nature Rev. Immunol. 9, 833-844 (2009).
4. Florea, B. I. et al. Activity-based profiling reveals reactivity of the murine thymoproteasome-specific subunit β5t. Chem. Biol. 17, 795-801 (2010).
5. + T cell development by thymus-specific proteasomes. Science 316, 1349-1353 (2007). (Pubitemid 46871657)
6. Nakagawa, T. et al. Cathepsin L: critical role in Ii degradation and CD4 T cell selection in the thymus. Science 280, 450-453 (1998). (Pubitemid 28208170)
7. + thymocytes. Eur. J. Immunol. 39, 956-964 (2009).
8. Nedjic, J., Aichinger, M., Mizushima, N. & Klein, L. Macroautophagy, endogenous MHC II loading and T cell selection: the benefits of breaking the rules. Curr. Opin. Immunol. 21, 92-97 (2009).
9. Nedjic, J., Aichinger, M., Emmerich, J., Mizushima, N. & Klein, L. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature 455, 396-400 (2008).
10. + T cell selection independently of its effect on invariant chain: a role in the generation of positively selecting peptide ligands. J. Exp. Med. 195, 1349-1358 (2002). (Pubitemid 34564336)
11. + T cells. Immunity 32, 29-40 (2010).
12. Xing, Y., Jameson, S. C. & Hogquist, K. A. Thymoproteasome subunit-β5T generates peptide-MHC complexes specialized for positive selection. Proc. Natl Acad. Sci. USA 110, 6979-6984 (2013).
13. Ziegler, A., Muller, C. A., Bockmann, R. A. & Uchanska-Ziegler, B. Low-affinity peptides and T-cell selection. Trends Immunol. 30, 53-60 (2009).
14. Ryan, K. R., McNeil, L. K., Dao, C., Jensen, P. E. & Evavold, B. D. Modification of peptide interaction with MHC creates TCR partial agonists. Cell. Immunol. 227, 70-78 (2004). (Pubitemid 38393730)
15. Azzam, H. S. et al. CD5 expression is developmentally regulated by T cell receptor (TCR) signals and TCR avidity. J. Exp. Med. 188, 2301-2311 (1998). (Pubitemid 29028502)
16. Stefanova, I., Dorfman, J. R. & Germain, R. N. Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes. Nature 420, 429-434 (2002). (Pubitemid 35415655)
17. + T cell homeostasis. Immunity 32, 214-226 (2010).
18. Palmer, M. J., Mahajan, V. S., Chen, J., Irvine, D. J. & Lauffenburger, D. A. Signaling thresholds govern heterogeneity in IL-7-receptor-mediated responses of naive CD8+ T cells. Immunol. Cell Biol. 89, 581-594 (2011).
19. Mandl, J. N., Monteiro, J. P., Vrisekoop, N. & Germain, R. N. T cell-positive selection uses self-ligand binding strength to optimize repertoire recognition of foreign antigens. Immunity 38, 263-274 (2013).
20. + T cell sensitivity and response to a pathogen are set and sustained by avidity for thymic and peripheral complexes of self peptide and MHC. Nature Immunol. 15, 266-274 (2014).
21. Surh, C. D. & Sprent, J. T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature 372, 100-103 (1994). (Pubitemid 24339491)
22. + T cells in two major waves of thymic deletion distinguished by induction of PD-1 or NF-κB. J. Exp. Med. 210, 269-285 (2013).
23. Stritesky, G. L. et al. Murine thymic selection quantified using a unique method to capture deleted T cells. Proc. Natl Acad. Sci. USA 110, 4679-4684 (2013).
24. McCaughtry, T. M., Baldwin, T. A., Wilken, M. S. & Hogquist, K. A. Clonal deletion of thymocytes can occur in the cortex with no involvement of the medulla. J. Exp. Med. 205, 2575-2584 (2008).
25. Melichar, H. J., Ross, J. O., Herzmark, P., Hogquist, K. A. & Robey, E. A. Distinct temporal patterns of T cell receptor signaling during positive versus negative selection in situ. Sci. Signal. 6, ra92 (2013).
26. + thymocytes. Trends Immunol. 31, 71-79 (2010).
27. Mathis, D. & Benoist, C. Aire. Annu. Rev. Immunol. 27, 287-312 (2009).
28. Peterson, P., Org, T. & Rebane, A. Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nature Rev. Immunol. 8, 948-957 (2008).
29. 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). (Pubitemid 39431128)
30. Oukka, M., Cohen-Tannoudji, M., Tanaka, Y., Babinet, C. & Kosmatopoulos, K. Medullary thymic epithelial cells induce tolerance to intracellular proteins. J. Immunol. 156, 968-975 (1996). (Pubitemid 26048089)
31. + T cell tolerance. Nature Immunol. 11, 512-519 (2010).
32. Klein, L., Klein, T., Ruther, U. & Kyewski, B. CD4 T cell tolerance to human C-reactive protein, an inducible serum protein, is mediated by medullary thymic epithelium. J. Exp. Med. 188, 5-16 (1998). (Pubitemid 28328601)
33. Oukka, M. et al. CD4 T cell tolerance to nuclear proteins induced by medullary thymic epithelium. Immunity 4, 545-553 (1996). (Pubitemid 26233308)
34. + medullary thymic epithelial cells. Nature Immunol. 8, 351-358 (2007). (Pubitemid 46745410)
35. Atibalentja, D. F., Byersdorfer, C. A. & Unanue, E. R. Thymus-blood protein interactions are highly effective in negative selection and regulatory T cell induction. J. Immunol. 183, 7909-7918 (2009).
36. Klein, L., Roettinger, B. & Kyewski, B. Sampling of complementing self-antigen pools by thymic stromal cells maximizes the scope of central T cell tolerance. Eur. J. Immunol. 31, 2476-2486 (2001). (Pubitemid 32785367)
37. Munz, C. Enhancing immunity through autophagy. Annu. Rev. Immunol. 27, 423-449 (2009).
38. 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).
39. Mizushima, N. Autophagy in protein and organelle turnover. Cold Spring Harb. Symp. Quant. Biol. 76, 397-402 (2011).
40. Dongre, A. R. et al. In vivo MHC class II presentation of cytosolic proteins revealed by rapid automated tandem mass spectrometry and functional analyses. Eur. J. Immunol. 31, 1485-1494 (2001). (Pubitemid 32454696)
41. Klein, L., Hinterberger, M., von Rohrscheidt, J. & Aichinger, M. Autonomous versus dendritic cell-dependent contributions of medullary thymic epithelial cells to central tolerance. Trends Immunol. 32, 188-193 (2011).
42. Koble, C. & Kyewski, B. The thymic medulla: a unique microenvironment for intercellular self-antigen transfer. J. Exp. Med. 206, 1505-1513 (2009).
43. Hubert, F. X. et al. Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance. Blood 118, 2462-2472 (2011).
44. 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).
45. + thymocytes control mature medullary thymic epithelial cell cellularity. Immunity 29, 451-463 (2008).
46. DeVoss, J. et al. Spontaneous autoimmunity prevented by thymic expression of a single self-antigen. J. Exp. Med. 203, 2727-2735 (2006).
47. Fan, Y. et al. Thymus-specific deletion of insulin induces autoimmune diabetes. EMBO J. 28, 2812-2824 (2009).
48. Ehrlich, L. I., Oh, D. Y., Weissman, I. L. & Lewis, R. S. Differential contribution of chemotaxis and substrate restriction to segregation of immature and mature thymocytes. Immunity 31, 986-998 (2009).
49. Le Borgne, M. et al. The impact of negative selection on thymocyte migration in the medulla. Nature Immunol. 10, 823-830 (2009).
50. Ueda, Y. et al. Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus. Nature Commun. 3, 1098 (2012).
51. Klein, L. Dead man walking: how thymocytes scan the medulla. Nature Immunol. 10, 809-811 (2009).
52. Derbinski, J., Pinto, S., Rosch, S., Hexel, K. & Kyewski, B. Promiscuous gene expression patterns in single medullary thymic epithelial cells argue for a stochastic mechanism. Proc. Natl Acad. Sci. USA 105, 657-662 (2008). (Pubitemid 351171764)
53. Pinto, S. et al. Overlapping gene coexpression patterns in human medullary thymic epithelial cells generate self-antigen diversity. Proc. Natl Acad. Sci. USA 110, E3497-3505 (2013).
54. Villasenor, J., Besse, W., Benoist, C. & Mathis, D. Ectopic expression of peripheral-tissue antigens in the thymic epithelium: probabilistic, monoallelic, misinitiated. Proc. Natl Acad. Sci. USA 105, 15854-15859 (2008).
55. Wu, L. & Shortman, K. Heterogeneity of thymic dendritic cells. Semin. Immunol. 17, 304-312 (2005). (Pubitemid 40981935)
56. Li, J., Park, J., Foss, D. & Goldschneider, I. Thymus-homing peripheral dendritic cells constitute two of the three major subsets of dendritic cells in the steady-state thymus. J. Exp. Med. 206, 607-622 (2009).
57. Joffre, O. P., Segura, E., Savina, A. & Amigorena, S. Cross-presentation by dendritic cells. Nature Rev. Immunol. 12, 557-569 (2012).
58. Proietto, A. I., Lahoud, M. H. & Wu, L. Distinct functional capacities of mouse thymic and splenic dendritic cell populations. Immunol. Cell Biol. 86, 700-708 (2008).
59. 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).
60. Baba, T., Nakamoto, Y. & Mukaida, N. Crucial contribution of thymic Sirpα+ conventional dendritic cells to central tolerance against blood-borne antigens in a CCR2-dependent manner. J. Immunol. 183, 3053-3063 (2009).
61. + and Sirpα+ conventional dendritic cells in presentation of blood-derived lysozyme by MHC class II proteins. J. Immunol. 186, 1421-1431 (2011).
62. + dendritic cells: a murine model. PLoS ONE 7, e41154 (2012).
63. Reizis, B., Colonna, M., Trinchieri, G., Barrat, F. & Gilliet, M. Plasmacytoid dendritic cells: one-trick ponies or workhorses of the immune system? Nature Rev. Immunol. 11, 558-565 (2011).
64. Villadangos, J. A. & Young, L. Antigen-presentation properties of plasmacytoid dendritic cells. Immunity 29, 352-361 (2008).
65. Wirnsberger, G., Mair, F. & Klein, L. Regulatory T cell differentiation of thymocytes does not require a dedicated antigen-presenting cell but is under T cell-intrinsic developmental control. Proc. Natl Acad. Sci. USA 106, 10278-10283 (2009).
66. Hadeiba, H. et al. Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance. Immunity 36, 438-450 (2012).
67. Hadeiba, H. et al. CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease. Nature Immunol. 9, 1253-1260 (2008).
68. Bonasio, R. et al. Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nature Immunol. 7, 1092-1100 (2006). (Pubitemid 44420654)
69. Akashi, K., Richie, L. I., Miyamoto, T., Carr, W. H. & Weissman, I. L. B lymphopoiesis in the thymus. J. Immunol. 164, 5221-5226 (2000). (Pubitemid 30305199)
70. Feyerabend, T. B. et al. Deletion of Notch1 converts pro-T cells to dendritic cells and promotes thymic B cells by cell-extrinsic and cell-intrinsic mechanisms. Immunity 30, 67-79 (2009).
71. Mori, S. et al. Presence of B cell progenitors in the thymus. J. Immunol. 158, 4193-4199 (1997). (Pubitemid 127483919)
72. Perera, J., Meng, L., Meng, F. & Huang, H. Autoreactive thymic B cells are efficient antigen-presenting cells of cognate self-antigens for T cell negative selection. Proc. Natl Acad. Sci. USA 110, 17011-17016 (2013).
73. + T cells. PLoS ONE 5, e15372 (2010).
74. Kleindienst, P., Chretien, I., Winkler, T. & Brocker, T. Functional comparison of thymic B cells and dendritic cells in vivo. Blood 95, 2610-2616 (2000). (Pubitemid 30210540)
75. Guerri, L. et al. Analysis of APC types involved in CD4 tolerance and regulatory T cell generation using reaggregated thymic organ cultures. J. Immunol. 190, 2102-2110 (2013).
76. Yuseff, M. I., Pierobon, P., Reversat, A. & Lennon-Dumenil, A. M. How B cells capture, process and present antigens: a crucial role for cell polarity. Nature Rev. Immunol. 13, 475-486 (2013).
77. Weiss, S. & Bogen, B. MHC class II-restricted presentation of intracellular antigen. Cell 64, 767-776 (1991). (Pubitemid 121001164)
78. Munthe, L. A., Corthay, A., Os, A., Zangani, M. & Bogen, B. Systemic autoimmune disease caused by autoreactive B cells that receive chronic help from Ig V region-specific T cells. J. Immunol. 175, 2391-2400 (2005). (Pubitemid 41113849)
79. Detanico, T., Heiser, R. A., Aviszus, K., Bonorino, C. & Wysocki, L. J. Self-tolerance checkpoints in CD4 T cells specific for a peptide derived from the B cell antigen receptor. J. Immunol. 187, 82-91 (2011).
80. Ebert, P. J., Jiang, S., Xie, J., Li, Q. J. & Davis, M. M. An endogenous positively selecting peptide enhances mature T cell responses and becomes an autoantigen in the absence of microRNA miR-181a. Nature Immunol. 10, 1162-1169 (2009).
81. + T cells. Nature Immunol. 10, 1155-1161 (2009).
82. Martin, B. et al. Highly self-reactive naive CD4 T cells are prone to differentiate into regulatory T cells. Nature Commun. 4, 2209 (2013).
83. Hsieh, C. S., Lee, H. M. & Lio, C. W. Selection of regulatory T cells in the thymus. Nature Rev. Immunol. 12, 157-167 (2012).
84. Wirnsberger, G., Hinterberger, M. & Klein, L. Regulatory T-cell differentiation versus clonal deletion of autoreactive thymocytes. Immunol. Cell Biol. 89, 45-53 (2011).
85. + thymocyte development. J. Exp. Med. 210, 675-681 (2013).
86. Klein, L. & Jovanovic, K. Regulatory T cell lineage commitment in the thymus. Semin. Immunol. 23, 401-409 (2011).
87. Mathis, D. & Benoist, C. A decade of AIRE. Nature Rev. Immunol. 7, 645-650 (2007). (Pubitemid 47123552)
88. Malchow, S. et al. Aire-dependent thymic development of tumor-associated regulatory T cells. Science 339, 1219-1224 (2013).
89. Bautista, J. L. et al. Intraclonal competition limits the fate determination of regulatory T cells in the thymus. Nature Immunol. 10, 610-617 (2009).
90. + cells is limited to small clonal sizes. J. Exp. Med. 206, 2121-2130 (2009).
91. Moran, A. E. et al. T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J. Exp. Med. 208, 1279-1289 (2011).
92. St-Pierre, C. et al. Transcriptome sequencing of neonatal thymic epithelial cells. Sci. Rep. 3, 1860 (2013).
93. Lv, H. et al. Impaired thymic tolerance to α-myosin directs autoimmunity to the heart in mice and humans. J. Clin. Invest. 121, 1561-1573 (2011).
94. Gottumukkala, R. V. et al. Myocardial infarction triggers chronic cardiac autoimmunity in type 1 diabetes. Sci. Transl Med. 4, 138ra180 (2012).
95. 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). (Pubitemid 38139246)
96. Durinovic-Bello, I. et al. Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin. Genes Immun. 11, 188-193 (2010).
97. Pugliese, A. et al. The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nature Genet. 15, 293-297 (1997). (Pubitemid 27098726)
98. Vafiadis, P. et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nature Genet. 15, 289-292 (1997). (Pubitemid 27098725)
99. Giraud, M. et al. An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature 448, 934-937 (2007). (Pubitemid 47312776)
100. Colobran, R. et al. Association of an SNP with intrathymic transcription of TSHR and Graves' disease: a role for defective thymic tolerance. Hum. Mol. Genet. 20, 3415-3423 (2011).
101. Klein, L., Klugmann, M., Nave, K. A., Tuohy, V. K. & Kyewski, B. Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells. Nature Med. 6, 56-61 (2000). (Pubitemid 30048526)
102. de Jong, V. M. et al. Alternative splicing and differential expression of the islet autoantigen IGRP between pancreas and thymus contributes to immunogenicity of pancreatic islets but not diabetogenicity in humans. Diabetologia 56, 2651-2658 (2013).
103. Pinto, S. et al. Mis-initiation of intrathymic MART-1 transcription and biased TCR usage explain the high frequency of MART-1-specific T cells. Eur. J. Immunol. (in the press).
104. Scally, S. W. et al. A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J. Exp. Med. 210, 2569-2582 (2013).
105. van Lummel, M. et al. Post-translational modification of HLA-DQ binding islet-autoantigens in type 1 diabetes. Diabetes 63, 237-247 (2014).
106. Gascoigne, N. R. & Palmer, E. Signaling in thymic selection. Curr. Opin. Immunol. 23, 207-212 (2011).
107. Bains, I., van Santen, H. M., Seddon, B. & Yates, A. J. Models of self-peptide sampling by developing T cells identify candidate mechanisms of thymic selection. PLoS Comput. Biol. 9, e1003102 (2013).
108. Org, T. et al. The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EMBO Rep. 9, 370-376 (2008).
109. Koh, A. S. et al. Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity. Proc. Natl Acad. Sci. USA 105, 15878-15883 (2008).
110. Abramson, J., Giraud, M., Benoist, C. & Mathis, D. Aire's partners in the molecular control of immunological tolerance. Cell 140, 123-135 (2010).
111. 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).
112. Danso-Abeam, D., Humblet-Baron, S., Dooley, J. & Liston, A. Models of aire-dependent gene regulation for thymic negative selection. Frontiers Immunol. 2, 14 (2011).
113. Marrack, P., Ignatowicz, L., Kappler, J. W., Boymel, J. & Freed, J. H. Comparison of peptides bound to spleen and thymus class II. J. Exp. Med. 178, 2173-2183 (1993). (Pubitemid 23344875)
114. Collado, J. A. et al. Composition of the HLA-DR-associated human thymus peptidome. Eur. J. Immunol. 43, 2273-2282 (2013).
115. Espinosa, G. et al. Peptides presented by HLA class I molecules in the human thymus. J. Proteomics 94, 23-36 (2013).
116. Adamopoulou, E. et al. Exploring the MHC-peptide matrix of central tolerance in the human thymus. Nature Commun. 4, 2039 (2013).
117. Fortier, M. H. et al. The MHC class I peptide repertoire is molded by the transcriptome. J. Exp. Med. 205, 595-610 (2008).
118. Mester, G., Hoffmann, V. & Stevanovic, S. Insights into MHC class I antigen processing gained from large-scale analysis of class I ligands. Cell. Mol. Life Sci. 68, 1521-1532 (2011).
119. Millet, V., Naquet, P. & Guinamard, R. R. Intercellular MHC transfer between thymic epithelial and dendritic cells. Eur. J. Immunol. 38, 1257-1263 (2008).