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.

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

Key Points

  • The cell fate decisions of developing thymocytes are coordinated by interactions with self-peptide–MHC complexes that are displayed by various types of thymic antigen presenting cells (APCs).

  • Different thymic APCs use cell type-specific strategies of self antigen sampling and processing.

  • Cortical thymic epithelial cells (cTECs) use unique proteolytic pathways to generate MHC class I-bound and MHC class II-bound peptides, and these 'private' peptides expressed by cTECs are critical for the positive selection of a fully functional T cell repertoire.

  • Several types of haematopoieteic and non-haematopoietic APCs cooperatively present self antigens for central tolerance induction.

  • Medullary thymic epithelial cells (mTECs) promiscuously express peripheral self antigens and autonomously present these to thymocytes.

  • Different subsets of dendritic cells sample blood-borne and mTEC-derived self antigens within the thymus or transport peripheral self antigens into the thymus.

Abstract

The fate of developing T cells is specified by the interaction of their antigen receptors with self-peptide–MHC complexes that are displayed by thymic antigen-presenting cells (APCs). Various subsets of thymic APCs are strategically positioned in particular thymic microenvironments and they coordinate the selection of a functional and self-tolerant T cell repertoire. In this Review, we discuss the different strategies that these APCs use to sample and process self antigens and to thereby generate partly unique, 'idiosyncratic' peptide–MHC ligandomes. We discuss how the particular composition of the peptide–MHC ligandomes that are presented by specific APC subsets not only shapes the T cell repertoire in the thymus but may also indelibly imprint the behaviour of mature T cells in the periphery.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Stromal cell interactions during T cell development.
Figure 2: Unique proteolytic pathways generate 'private' MHC-bound peptides in cTECs.
Figure 3: Topological aspects of 'promiscuous gene expression' and direct versus indirect presentation of tissue-restricted antigens.
Figure 4: Consequences of positive selection by 'private' versus 'public' peptides: a hypothesis.

References

  1. 1

    Kyewski, B. & Klein, L. A central role for central tolerance. Annu. Rev. Immunol. 24, 571–606 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. 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).

    Article  PubMed  Google Scholar 

  3. 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).

    Article  CAS  Google Scholar 

  4. 4

    Florea, B. I. et al. Activity-based profiling reveals reactivity of the murine thymoproteasome-specific subunit β5t. Chem. Biol. 17, 795–801 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

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

    Article  CAS  PubMed  Google Scholar 

  6. 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).

    Article  CAS  PubMed  Google Scholar 

  7. 7

    Gommeaux, J. et al. Thymus-specific serine protease regulates positive selection of a subset of CD4+ thymocytes. Eur. J. Immunol. 39, 956–964 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. 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).

    Article  CAS  PubMed  Google Scholar 

  9. 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).

    Article  CAS  PubMed  Google Scholar 

  10. 10

    Honey, K., Nakagawa, T., Peters, C. & Rudensky, A. Cathepsin L regulates CD4+ 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Nitta, T. et al. Thymoproteasome shapes immunocompetent repertoire of CD8+ T cells. Immunity 32, 29–40 (2010).

    Article  CAS  PubMed  Google Scholar 

  12. 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).

    Article  PubMed  Google Scholar 

  13. 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).

    Article  CAS  PubMed  Google Scholar 

  14. 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).

    Article  CAS  PubMed  Google Scholar 

  15. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 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).

    Article  CAS  PubMed  Google Scholar 

  17. 17

    Cho, J. H., Kim, H. O., Surh, C. D. & Sprent, J. T cell receptor-dependent regulation of lipid rafts controls naive CD8+ T cell homeostasis. Immunity 32, 214–226 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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). References 18 and 19 show that T cell responsiveness is set in the thymus and maintained in mature T cells in proportion to the avidity of the positively selecting interaction. Reference 18 concludes that T cells with stronger affinity for self dominate in response to infections, whereas reference 19 challenges the generality of such correlations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Persaud, S. P., Parker, C. R., Lo, W. L., Weber, K. S. & Allen, P. M. Intrinsic CD4+ 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).

    Article  CAS  Google Scholar 

  21. 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).

    Article  CAS  PubMed  Google Scholar 

  22. 22

    Daley, S. R., Hu, D. Y. & Goodnow, C. C. Helios marks strongly autoreactive CD4+ 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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). Using different approaches, references 22 and 23 quantify 'early' and 'late' negative selection in the cortex and the medulla, respectively, and conclude that the extent of clonal deletion in the cortex exceeds that in the medulla.

    Article  PubMed  Google Scholar 

  24. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Irla, M., Hollander, G. & Reith, W. Control of central self-tolerance induction by autoreactive CD4+ thymocytes. Trends Immunol. 31, 71–79 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. 27

    Mathis, D. & Benoist, C. Aire. Annu. Rev. Immunol. 27, 287–312 (2009).

    Article  CAS  PubMed  Google Scholar 

  28. 28

    Peterson, P., Org, T. & Rebane, A. Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nature Rev. Immunol. 8, 948–957 (2008).

    Article  CAS  Google Scholar 

  29. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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).

    CAS  PubMed  Google Scholar 

  31. 31

    Hinterberger, M. et al. Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance. Nature Immunol. 11, 512–519 (2010). Through diminution of MHC class II on mTECs, this study documents an autonomous contribution of mTECs to both dominant and recessive mechanisms of CD4+ T cell tolerance and provides experimental support for the affinity model of T Reg cell development versus clonal deletion.

    Article  CAS  Google Scholar 

  32. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Oukka, M. et al. CD4 T cell tolerance to nuclear proteins induced by medullary thymic epithelium. Immunity 4, 545–553 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. 34

    Aschenbrenner, K. et al. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nature Immunol. 8, 351–358 (2007).

    Article  CAS  Google Scholar 

  35. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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).

    Article  CAS  PubMed  Google Scholar 

  37. 37

    Munz, C. Enhancing immunity through autophagy. Annu. Rev. Immunol. 27, 423–449 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Mizushima, N. Autophagy in protein and organelle turnover. Cold Spring Harb. Symp. Quant. Biol. 76, 397–402 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. 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).

    Article  CAS  PubMed  Google Scholar 

  41. 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).

    Article  CAS  PubMed  Google Scholar 

  42. 42

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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).

    Article  CAS  PubMed  Google Scholar 

  44. 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).

    Article  PubMed  Google Scholar 

  45. 45

    Irla, M. et al. Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity. Immunity 29, 451–463 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. 46

    DeVoss, J. et al. Spontaneous autoimmunity prevented by thymic expression of a single self-antigen. J. Exp. Med. 203, 2727–2735 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Fan, Y. et al. Thymus-specific deletion of insulin induces autoimmune diabetes. EMBO J. 28, 2812–2824 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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).

    Article  CAS  PubMed  Google Scholar 

  49. 49

    Le Borgne, M. et al. The impact of negative selection on thymocyte migration in the medulla. Nature Immunol. 10, 823–830 (2009).

    Article  CAS  Google Scholar 

  50. 50

    Ueda, Y. et al. Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus. Nature Commun. 3, 1098 (2012).

    Article  CAS  Google Scholar 

  51. 51

    Klein, L. Dead man walking: how thymocytes scan the medulla. Nature Immunol. 10, 809–811 (2009).

    Article  CAS  Google Scholar 

  52. 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).

    Article  PubMed  Google Scholar 

  53. 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).

    Article  PubMed  Google Scholar 

  54. 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).

    Article  PubMed  Google Scholar 

  55. 55

    Wu, L. & Shortman, K. Heterogeneity of thymic dendritic cells. Semin. Immunol. 17, 304–312 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Joffre, O. P., Segura, E., Savina, A. & Amigorena, S. Cross-presentation by dendritic cells. Nature Rev. Immunol. 12, 557–569 (2012).

    Article  CAS  Google Scholar 

  58. 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).

    Article  CAS  PubMed  Google Scholar 

  59. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 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).

    Article  CAS  PubMed  Google Scholar 

  61. 61

    Atibalentja, D. F., Murphy, K. M. & Unanue, E. R. Functional redundancy between thymic CD8α+ and Sirpα+ conventional dendritic cells in presentation of blood-derived lysozyme by MHC class II proteins. J. Immunol. 186, 1421–1431 (2011).

    Article  CAS  PubMed  Google Scholar 

  62. 62

    Baba, T., Badr Mel, S., Tomaru, U., Ishizu, A. & Mukaida, N. Novel process of intrathymic tumor-immune tolerance through CCR2-mediated recruitment of Sirpα+ dendritic cells: a murine model. PLoS ONE 7, e41154 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 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).

    Article  CAS  Google Scholar 

  64. 64

    Villadangos, J. A. & Young, L. Antigen-presentation properties of plasmacytoid dendritic cells. Immunity 29, 352–361 (2008).

    Article  CAS  PubMed  Google Scholar 

  65. 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).

    Article  PubMed  Google Scholar 

  66. 66

    Hadeiba, H. et al. Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance. Immunity 36, 438–450 (2012). This study shows that endogenous pDCs take up subcutaneously injected antigen and transport it to the thymus in a CCR9-dependent manner. Upon intravenous injection, antigen-loaded pDCs delete specific thymocytes, which indicates that migratory pDCs can support central tolerance.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 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).

    Article  CAS  Google Scholar 

  68. 68

    Bonasio, R. et al. Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nature Immunol. 7, 1092–1100 (2006).

    Article  CAS  Google Scholar 

  69. 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).

    Article  CAS  PubMed  Google Scholar 

  70. 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).

    Article  CAS  PubMed  Google Scholar 

  71. 71

    Mori, S. et al. Presence of B cell progenitors in the thymus. J. Immunol. 158, 4193–4199 (1997).

    CAS  PubMed  Google Scholar 

  72. 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). Using BCR- and TCR-transgenic mice, this study shows that autoreactive thymic B cells are efficient APCs for negative selection. Thymic B cells may capture autoantigens through their BCR and present these to developing thymocytes for clonal deletion.

    Article  CAS  PubMed  Google Scholar 

  73. 73

    Frommer, F. & Waisman, A. B cells participate in thymic negative selection of murine auto-reactive CD4+ T cells. PLoS ONE 5, e15372 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 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).

    CAS  PubMed  Google Scholar 

  75. 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).

    Article  CAS  PubMed  Google Scholar 

  76. 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).

    Article  CAS  Google Scholar 

  77. 77

    Weiss, S. & Bogen, B. MHC class II-restricted presentation of intracellular antigen. Cell 64, 767–776 (1991).

    Article  CAS  PubMed  Google Scholar 

  78. 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).

    Article  CAS  PubMed  Google Scholar 

  79. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 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).

    Article  CAS  Google Scholar 

  81. 81

    Lo, W. L. et al. An endogenous peptide positively selects and augments the activation and survival of peripheral CD4+ T cells. Nature Immunol. 10, 1155–1161 (2009).

    Article  CAS  Google Scholar 

  82. 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).

    Article  CAS  Google Scholar 

  83. 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).

    Article  CAS  Google Scholar 

  84. 84

    Wirnsberger, G., Hinterberger, M. & Klein, L. Regulatory T-cell differentiation versus clonal deletion of autoreactive thymocytes. Immunol. Cell Biol. 89, 45–53 (2011).

    Article  PubMed  Google Scholar 

  85. 85

    Cowan, J. E. et al. The thymic medulla is required for Foxp3+ regulatory but not conventional CD4+ thymocyte development. J. Exp. Med. 210, 675–681 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Klein, L. & Jovanovic, K. Regulatory T cell lineage commitment in the thymus. Semin. Immunol. 23, 401–409 (2011).

    Article  CAS  PubMed  Google Scholar 

  87. 87

    Mathis, D. & Benoist, C. A decade of AIRE. Nature Rev. Immunol. 7, 645–650 (2007).

    Article  CAS  Google Scholar 

  88. 88

    Malchow, S. et al. Aire-dependent thymic development of tumor-associated regulatory T cells. Science 339, 1219–1224 (2013). This study reports that T Reg cells that were consistently found to be enriched in prostate tumours of mice recognized an unknown antigen that was also present in the healthy prostate. These cells were found to differentiate as 'natural' (that is, thymically induced) T Reg cells in an AIRE-dependent manner, which provides evidence for a link between AIRE-mediated expression of peripheral tissue antigens and the development of organ-specific T Reg cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 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).

    Article  CAS  Google Scholar 

  90. 90

    Leung, M. W., 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    St-Pierre, C. et al. Transcriptome sequencing of neonatal thymic epithelial cells. Sci. Rep. 3, 1860 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Gottumukkala, R. V. et al. Myocardial infarction triggers chronic cardiac autoimmunity in type 1 diabetes. Sci. Transl Med. 4, 138ra180 (2012).

    Article  Google Scholar 

  95. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 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).

    Article  CAS  PubMed  Google Scholar 

  98. 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).

    Article  CAS  PubMed  Google Scholar 

  99. 99

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

    Article  CAS  PubMed  Google Scholar 

  100. 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).

    Article  CAS  PubMed  Google Scholar 

  101. 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).

    Article  CAS  PubMed  Google Scholar 

  102. 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).

    Article  CAS  PubMed  Google Scholar 

  103. 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. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    van Lummel, M. et al. Post-translational modification of HLA-DQ binding islet-autoantigens in type 1 diabetes. Diabetes 63, 237–247 (2014).

    Article  CAS  PubMed  Google Scholar 

  106. 106

    Gascoigne, N. R. & Palmer, E. Signaling in thymic selection. Curr. Opin. Immunol. 23, 207–212 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 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).

    Article  PubMed  Google Scholar 

  110. 110

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

    Article  CAS  PubMed  Google Scholar 

  111. 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).

    Article  PubMed  Google Scholar 

  112. 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).

    Article  Google Scholar 

  113. 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).

    Article  CAS  PubMed  Google Scholar 

  114. 114

    Collado, J. A. et al. Composition of the HLA-DR-associated human thymus peptidome. Eur. J. Immunol. 43, 2273–2282 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. 115

    Espinosa, G. et al. Peptides presented by HLA class I molecules in the human thymus. J. Proteomics 94, 23–36 (2013).

    Article  CAS  PubMed  Google Scholar 

  116. 116

    Adamopoulou, E. et al. Exploring the MHC-peptide matrix of central tolerance in the human thymus. Nature Commun. 4, 2039 (2013).

    Article  CAS  Google Scholar 

  117. 117

    Fortier, M. H. et al. The MHC class I peptide repertoire is molded by the transcriptome. J. Exp. Med. 205, 595–610 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. 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).

    Article  CAS  PubMed  Google Scholar 

  119. 119

    Millet, V., Naquet, P. & Guinamard, R. R. Intercellular MHC transfer between thymic epithelial and dendritic cells. Eur. J. Immunol. 38, 1257–1263 (2008).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

L.K. received support from the Deutsche Forschungsgemeinschaft, Germany (Collaborative research centre SFB 1054 and grants KL 1228/4-1 and KL 1228/5-1). B.K. was supported by the German Cancer Research Center (DKFZ), the Deutsche Forschungsgemeinschaft (Collaborative research centre SFB 938) and the European Research Council (ERC-2012-AdG). P.M.A. was supported by the US National Institutes of Health (NIH) grant AI-24157. K.A.H is supported by NIH grants AI088209, AI35296 and AI39560.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Ludger Klein.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Positive selection

The process by which immature double-positive thymocytes that express T cell receptors with intermediate affinity and/or avidity for self-peptide–MHC complexes are induced to differentiate into mature single-positive thymocytes.

Negative selection

(Also known as clonal deletion). The intrathymic elimination of double-positive or single-positive thymocytes that express T cell receptors with high affinity for self antigens.

Death by neglect

A form of programmed cell death that occurs when double-positive thymocytes fail to engage in positively selecting interactions with self-peptide–MHC complexes on cortical thymic epithelial cells within their finite lifespan of 3–4 days.

β-selection

The pre-T cell receptor (pre-TCR)-driven process by which double-negative thymocytes that carry a productively rearranged TCR β-chain undergo proliferative expansion and developmental progression.

Peptide–MHC ligandome

(pMHC ligandome). The repertoire of peptides that are bound by MHC molecules.

Proteasome

The standard proteasome is composed of 14α-subunits and 14β-subunits. Three of the β-subunits (β1, β2 and β5) are involved in peptide-bond cleavage. Interferon-γ induces the expression of the immunosubunits β1i, β2i and β5i that can replace the catalytic subunits of the standard proteasome to generate the immunoproteasome, which has distinct cleavage-site preferences.

Macroautophagy

The generally nonspecific sequestration of cytoplasm into a double- or multiple-membrane-delimited compartment (autophagosome) of non-lysosomal origin. Certain proteins, organelles and pathogens may be selectively degraded by this process.

BCL-2-interacting mediator of cell death

(BIM). A pro-apoptotic molecule that is crucial for negative selection.

MHC anchor residues

Amino acid residues of an antigenic peptide that bind in pockets in the peptide-binding groove of a major histocompatibility molecule and account for much of the binding energy and specificity of binding.

CD5

A membrane protein that associates with the T cell receptor (TCR) complex. It modulates the TCR signal transduction cascade through interactions with various kinases and phosphatases.

NR4A1

NR4A1 encodes an orphan nuclear receptor that is upregulated by T cell receptor signalling in thymocytes and mature T cells.

HY TCR

An MHC class I-restricted transgenic T cell receptor (TCR) that recognizes a self antigen that is encoded by the Y chromosome.

OT-I TCR

An MHC class I-restricted transgenic T cell receptor (TCR) that recognizes a peptide epitope from ovalbumin.

Tonic TCR stimulation

Continuous 'subthreshold' recognition of self-peptide–MHC complexes by mature T cells, which results in a basal activation state that enables T cells to rapidly respond to foreign antigen.

Tissue-restricted antigens

(TRAs). Self constituents encoded by genes that are expressed by only one or a few tissue-specific cell lineages as opposed to housekeeping genes. The term TRA is an operational definition based on available expression catalogues, according to which TRAs are expressed in less than 5 of the 60 tested tissues.

Thymic crosstalk

The mutual developmental dependence of the T cell and the stromal cell (that is, non-T cell) compartments of the thymus, which is specified by complex receptor–ligand interactions.

C2TAkd mice

A mouse strain that expresses a designer microRNA that targets the MHC class 2 trans activator (C2TA) specifically in medullary thymic epithelial cells (mTECs). This leads to a reduction of MHC class II expression to approximately 10% of its physiological levels, while preserving intact mTEC differentiation and tissue-restricted antigen expression.

CCR9

CC-chemokine receptor 9; a G protein-coupled receptor that recognizes the chemokine CCL25 (also known as TECK and thymus expressed chemokine).

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Klein, L., Kyewski, B., Allen, P. et al. Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat Rev Immunol 14, 377–391 (2014). https://doi.org/10.1038/nri3667

Download citation

Further reading

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