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The Role of Dendritic Cells in Central Tolerance

  • Oh, Jaehak (Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California San Francisco) ;
  • Shin, Jeoung-Sook (Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California San Francisco)
  • Received : 2015.03.31
  • Accepted : 2015.06.02
  • Published : 2015.06.30

Abstract

Dendritic cells (DCs) play a significant role in establishing self-tolerance through their ability to present self-antigens to developing T cells in the thymus. DCs are predominantly localized in the medullary region of thymus and present a broad range of self-antigens, which include tissue-restricted antigens expressed and transferred from medullary thymic epithelial cells, circulating antigens directly captured by thymic DCs through coticomedullary junction blood vessels, and peripheral tissue antigens captured and transported by peripheral tissue DCs homing to the thymus. When antigen-presenting DCs make a high affinity interaction with antigen-specific thymocytes, this interaction drives the interacting thymocytes to death, a process often referred to as negative selection, which fundamentally blocks the self-reactive thymocytes from differentiating into mature T cells. Alternatively, the interacting thymocytes differentiate into the regulatory T (Treg) cells, a distinct T cell subset with potent immune suppressive activities. The specific mechanisms by which thymic DCs differentiate Treg cells have been proposed by several laboratories. Here, we review the literatures that elucidate the contribution of thymic DCs to negative selection and Treg cell differentiation, and discusses its potential mechanisms and future directions.

Keywords

References

  1. Banchereau, J., and R. M. Steinman. 1998. Dendritic cells and the control of immunity. Nature 392: 245-252. https://doi.org/10.1038/32588
  2. Mellman, I., and R. M. Steinman. 2001. Dendritic cells: specialized and regulated antigen processing machines. Cell 106 : 255-258. https://doi.org/10.1016/S0092-8674(01)00449-4
  3. Klein, L., M. Hinterberger, G. Wirnsberger, and B. Kyewski. 2009. Antigen presentation in the thymus for positive selection and central tolerance induction. Nat. Rev. Immunol. 9: 833-844. https://doi.org/10.1038/nri2669
  4. Mathis, D., and C. Benoist. 2004. Back to central tolerance. Immunity 20: 509-516. https://doi.org/10.1016/S1074-7613(04)00111-6
  5. Hsieh, C. S., H. M. Lee, and C. W. Lio. 2012. Selection of regulatory T cells in the thymus. Nat. Rev. Immunol. 12: 157-167. https://doi.org/10.1038/nri3155
  6. Goldman, K. P., C. S. Park, M. Kim, P. Matzinger, and C. C. Anderson. 2005. Thymic cortical epithelium induces self tolerance. Eur. J. Immunol. 35: 709-717. https://doi.org/10.1002/eji.200425675
  7. Ahn, S., G. Lee, S. J. Yang, D. Lee, S. Lee, H. S. Shin, M. C. Kim, K. N. Lee, D. C. Palmer, M. R. Theoret, E. J. Jenkinson, G. Anderson, N. P. Restifo, and M. G. Kim. 2008. $TSCOT^+$ thymic epithelial cell-mediated sensitive CD4 tolerance by direct presentation. PLoS Biol. 6: e191. https://doi.org/10.1371/journal.pbio.0060191
  8. Liston, A., K. M. Nutsch, A. G. Farr, J. M. Lund, J. P. Rasmussen, P. A. Koni, and A. Y. Rudensky. 2008. Differentiation of regulatory $Foxp3^+$ T cells in the thymic cortex. Proc. Natl. Acad. Sci. U. S. A. 105: 11903-11908. https://doi.org/10.1073/pnas.0801506105
  9. Cheng, M. H., A. K. Shum, and M. S. Anderson. 2007. What's new in the Aire? Trends Immunol. 28: 321-327. https://doi.org/10.1016/j.it.2007.05.004
  10. Malchow, S., D. S. Leventhal, S. Nishi, B. I. Fischer, L. Shen, G. P. Paner, A. S. Amit, C. Kang, J. E. Geddes, J. P. Allison, N. D. Socci, and P. A. Savage. 2013. Aire-dependent thymic development of tumor-associated regulatory T cells. Science 339: 1219-1224. https://doi.org/10.1126/science.1233913
  11. Mathis, D., and C. Benoist. 2007. A decade of AIRE. Nat. Rev. Immunol. 7: 645-650. https://doi.org/10.1038/nri2136
  12. Wirnsberger, G., M. Hinterberger, and L. Klein. 2011. Regulatory T-cell differentiation versus clonal deletion of autoreactive thymocytes. Immunol. Cell Biol. 89: 45-53. https://doi.org/10.1038/icb.2010.123
  13. Lv, H., E. Havari, S. Pinto, R. V. Gottumukkala, L. Cornivelli, K. Raddassi, T. Matsui, A. Rosenzweig, R. T. Bronson, R. Smith, A. L. Fletcher, S. J. Turley, K. Wucherpfennig, B. Kyewski, and M. A. Lipes. 2011. Impaired thymic tolerance to alpha-myosin directs autoimmunity to the heart in mice and humans. J. Clin. Invest. 121: 1561-1573. https://doi.org/10.1172/JCI44583
  14. Koble, C., and B. Kyewski. 2009. The thymic medulla: a unique microenvironment for intercellular self-antigen transfer. J. Exp. Med. 206: 1505-1513. https://doi.org/10.1084/jem.20082449
  15. Wu, L., and K. Shortman. 2005. Heterogeneity of thymic dendritic cells. Semin. Immunol. 17: 304-312. https://doi.org/10.1016/j.smim.2005.05.001
  16. Ardavin, C., L. Wu, C. L. Li, and K. Shortman. 1993. Thymic dendritic cells and T cells develop simultaneously in the thymus from a common precursor population. Nature 362: 761-763. https://doi.org/10.1038/362761a0
  17. Wu, L., C. L. Li, and K. Shortman. 1996. Thymic dendritic cell precursors: relationship to the T lymphocyte lineage and phenotype of the dendritic cell progeny. J. Exp. Med. 184: 903-911. https://doi.org/10.1084/jem.184.3.903
  18. Res, P. C., F. Couwenberg, F. A. Vyth-Dreese, and H. Spits. 1999. Expression of pTalpha mRNA in a committed dendritic cell precursor in the human thymus. Blood 94: 2647-2657.
  19. Schlenner, S. M., V. Madan, K. Busch, A. Tietz, C. Laufle, C. Costa, C. Blum, H. J. Fehling, and H. R. Rodewald. 2010. Fate mapping reveals separate origins of T cells and myeloid lineages in the thymus. Immunity 32: 426-436. https://doi.org/10.1016/j.immuni.2010.03.005
  20. Luche, H., L. Ardouin, P. Teo, P. See, S. Henri, M. Merad, F. Ginhoux, and B. Malissen. 2011. The earliest intrathymic precursors of CD8alpha(+) thymic dendritic cells correspond to myeloid- type double-negative 1c cells. Eur. J. Immunol. 41: 2165-2175. https://doi.org/10.1002/eji.201141728
  21. Lyszkiewicz, M., N. Zietara, L. Fohse, J. Puchalka, J. Diestelhorst, K. Witzlau, I. Prinz, A. Schambach, and A. Krueger. 2015. Limited niche availability suppresses murine intrathymic dendritic-cell development from noncommitted progenitors. Blood 125: 457-464. https://doi.org/10.1182/blood-2014-07-592667
  22. Li, J., J. Park, D. Foss, and I. Goldschneider. 2009. 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. https://doi.org/10.1084/jem.20082232
  23. Proietto, A. I., D. S. van, P. Zhou, A. Rizzitelli, A. D'Amico, R. J. Steptoe, S. H. Naik, M. H. Lahoud, Y. Liu, P. Zheng, K. Shortman, and L. Wu. 2008. Dendritic cells in the thymus contribute to T-regulatory cell induction. Proc. Natl. Acad. Sci. U. S. A. 105: 19869-19874. https://doi.org/10.1073/pnas.0810268105
  24. Donskoy, E., and I. Goldschneider. 2003. Two developmentally distinct populations of dendritic cells inhabit the adult mouse thymus: demonstration by differential importation of hematogenous precursors under steady state conditions. J. Immunol. 170: 3514-3521. https://doi.org/10.4049/jimmunol.170.7.3514
  25. Baba, T., M. S. Badr, U. Tomaru, A. Ishizu, and N. Mukaida. 2012. Novel process of intrathymic tumor-immune tolerance through CCR2-mediated recruitment of Sirp$alpha^+$ dendritic cells: a murine model. PLoS One 7: e41154. https://doi.org/10.1371/journal.pone.0041154
  26. Baba, T., Y. Nakamoto, and N. Mukaida. 2009. Crucial contribution of thymic Sirp $alpha^+$ conventional dendritic cells to central tolerance against blood-borne antigens in a CCR2-dependent manner. J. Immunol. 183: 3053-3063. https://doi.org/10.4049/jimmunol.0900438
  27. Bonasio, R., M. L. Scimone, P. Schaerli, N. Grabie, A. H. Lichtman, and U. H. von Andrian. 2006. Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nat. Immunol. 7: 1092-1100. https://doi.org/10.1038/ni1385
  28. Hadeiba, H., K. Lahl, A. Edalati, C. Oderup, A. Habtezion, R. Pachynski, L. Nguyen, A. Ghodsi, S. Adler, and E. C. Butcher. 2012. Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance. Immunity 36: 438-450. https://doi.org/10.1016/j.immuni.2012.01.017
  29. Aschenbrenner, K., L. M. D'Cruz, E. H. Vollmann, M. Hinterberger, J. Emmerich, L. K. Swee, A. Rolink, and L. Klein. 2007. Selection of $Foxp3^+$ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat. Immunol. 8: 351-358. https://doi.org/10.1038/ni1444
  30. Aichinger, M., C. Wu, J. Nedjic, and L. Klein. 2013. Macroautophagy substrates are loaded onto MHC class II of medullary thymic epithelial cells for central tolerance. J. Exp. Med. 210: 287-300. https://doi.org/10.1084/jem.20122149
  31. Atibalentja, D. F., K. M. Murphy, and E. R. Unanue. 2011. Functional redundancy between thymic CD8$alpha^+$ and Sirp$alpha^+$ conventional dendritic cells in presentation of blood-derived lysozyme by MHC class II proteins. J. Immunol. 186: 1421-1431. https://doi.org/10.4049/jimmunol.1002587
  32. Oh, J., N. Wu, G. Baravalle, B. Cohn, J. Ma, B. Lo, I. Mellman, S. Ishido, M. Anderson, and J. S. Shin. 2013. MARCH1-mediated MHCII ubiquitination promotes dendritic cell selection of natural regulatory T cells. J. Exp. Med. 210: 1069-1077. https://doi.org/10.1084/jem.20122695
  33. Atibalentja, D. F., C. A. Byersdorfer, and E. R. Unanue. 2009. Thymus-blood protein interactions are highly effective in negative selection and regulatory T cell induction. J. Immunol. 183: 7909-7918. https://doi.org/10.4049/jimmunol.0902632
  34. van Meerwijk, J. P., S. Marguerat, R. K. Lees, R. N. Germain, B. J. Fowlkes, and H. R. MacDonald. 1997. Quantitative impact of thymic clonal deletion on the T cell repertoire. J. Exp. Med. 185: 377-383. https://doi.org/10.1084/jem.185.3.377
  35. Hinterberger, M., M. Aichinger, C. O. Prazeres da, D. Voehringer, R. Hoffmann, and L. Klein. 2010. Autonomous role of medullary thymic epithelial cells in central CD4(+) T cell tolerance. Nat. Immunol. 11: 512-519. https://doi.org/10.1038/ni.1874
  36. Ohnmacht, C., A. Pullner, S. B. King, I. Drexler, S. Meier, T. Brocker, and D. Voehringer. 2009. Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J. Exp. Med. 206: 549-559. https://doi.org/10.1084/jem.20082394
  37. Brocker, T. 1999. The role of dendritic cells in T cell selection and survival. J. Leukoc. Biol. 66: 331-335. https://doi.org/10.1002/jlb.66.2.331
  38. Hubert, F. X., S. A. Kinkel, G. M. Davey, B. Phipson, S. N. Mueller, A. Liston, A. I. Proietto, P. Z. Cannon, S. Forehan, G. K. Smyth, L. Wu, C. C. Goodnow, F. R. Carbone, H. S. Scott, and W. R. Heath. 2011. Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance. Blood 118: 2462-2472. https://doi.org/10.1182/blood-2010-06-286393
  39. Gallegos, A. M., and M. J. Bevan. 2004. Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J. Exp. Med. 200: 1039-1049. https://doi.org/10.1084/jem.20041457
  40. Drrasse-Jeze, G., S. Deroubaix, H. Mouquet, G. D. Victora, T. Eisenreich, K. H. Yao, R. F. Masilamani, M. L. Dustin, A. Rudensky, K. Liu, and M. C. Nussenzweig. 2009. Feedback control of regulatory T cell homeostasis by dendritic cells in vivo. J. Exp. Med. 206: 1853-1862. https://doi.org/10.1084/jem.20090746
  41. Perry, J. S., C. W. Lio, A. L. Kau, K. Nutsch, Z. Yang, J. I. Gordon, K. M. Murphy, and C. S. Hsieh. 2014. Distinct contributions of Aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus. Immunity 41: 414-426. https://doi.org/10.1016/j.immuni.2014.08.007
  42. Jordan, M. S., A. Boesteanu, A. J. Reed, A. L. Petrone, A. E. Holenbeck, M. A. Lerman, A. Naji, and A. J. Caton. 2001. Thymic selection of $CD4^+CD25^+$ regulatory T cells induced by an agonist self-peptide. Nat. Immunol. 2: 301-306. https://doi.org/10.1038/86302
  43. Salomon, B., D. J. Lenschow, L. Rhee, N. Ashourian, B. Singh, A. Sharpe, and J. A. Bluestone. 2000. B7/CD28 costimulation is essential for the homeostasis of the $CD4^+CD25^+$ immunoregulatory T cells that control autoimmune diabetes. Immunity 12: 431-440. https://doi.org/10.1016/S1074-7613(00)80195-8
  44. Mahmud, S. A., L. S. Manlove, H. M. Schmitz, Y. Xing, Y. Wang, D. L. Owen, J. M. Schenkel, J. S. Boomer, J. M. Green, H. Yagita, H. Chi, K. A. Hogquist, and M. A. Farrar. 2014. Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat. Immunol. 15: 473-481. https://doi.org/10.1038/ni.2849
  45. Fontenot, J. D., J. P. Rasmussen, M. A. Gavin, and A. Y. Rudensky. 2005. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6: 1142-1151. https://doi.org/10.1038/ni1263
  46. Lio, C. W., and C. S. Hsieh. 2008. A two-step process for thymic regulatory T cell development. Immunity 28: 100-111. https://doi.org/10.1016/j.immuni.2007.11.021
  47. Watanabe, N., Y. H. Wang, H. K. Lee, T. Ito, Y. H. Wang, W. Cao, and Y. J. Liu. 2005. Hassall's corpuscles instruct dendritic cells to induce $CD4^+CD25^+$ regulatory T cells in human thymus. Nature 436: 1181-1185. https://doi.org/10.1038/nature03886
  48. Hanabuchi, S., T. Ito, W. R. Park, N. Watanabe, J. L. Shaw, E. Roman, K. Arima, Y. H. Wang, K. S. Voo, W. Cao, and Y. J. Liu. 2010. Thymic stromal lymphopoietin-activated plasmacytoid dendritic cells induce the generation of $FOXP3^+$ regulatory T cells in human thymus. J. Immunol. 184: 2999-3007. https://doi.org/10.4049/jimmunol.0804106
  49. Mazzucchelli, R., J. A. Hixon, R. Spolski, X. Chen, W. Q. Li, V. L. Hall, J. Willette-Brown, A. A. Hurwitz, W. J. Leonard, and S. K. Durum. 2008. Development of regulatory T cells requires IL-7Ralpha stimulation by IL-7 or TSLP. Blood 112: 3283-3292. https://doi.org/10.1182/blood-2008-02-137414
  50. Coquet, J. M., J. C. Ribot, N. Babala, S. Middendorp, H. G. van der, Y. Xiao, J. F. Neves, D. Fonseca-Pereira, H. Jacobs, D. J. Pennington, B. Silva-Santos, and J. Borst. 2013. Epithelial and dendritic cells in the thymic medulla promote $CD4^+$$Foxp3^+$ regulatory T cell development via the CD27-CD70 pathway. J. Exp. Med. 210: 715-728. https://doi.org/10.1084/jem.20112061
  51. Matsuki, Y., M. Ohmura-Hoshino, E. Goto, M. Aoki, M. Mito-Yoshida, M. Uematsu, T. Hasegawa, H. Koseki, O. Ohara, M. Nakayama, K. Toyooka, K. Matsuoka, H. Hotta, A. Yamamoto, and S. Ishido. 2007. Novel regulation of MHC class II function in B cells. EMBO J. 26: 846-854. https://doi.org/10.1038/sj.emboj.7601556
  52. Shin, J. S., M. Ebersold, M. Pypaert, L. Delamarre, A. Hartley, and I. Mellman. 2006. Surface expression of MHC class II in dendritic cells is controlled by regulated ubiquitination. Nature 444: 115-118. https://doi.org/10.1038/nature05261
  53. Baravalle, G., H. Park, M. McSweeney, M. Ohmura-Hoshino, Y. Matsuki, S. Ishido, and J. S. Shin. 2011. Ubiquitination of CD86 is a key mechanism in regulating antigen presentation by dendritic cells. J. Immunol. 187: 2966-2973. https://doi.org/10.4049/jimmunol.1101643
  54. van, N. G., R. Wubbolts, B. T. Ten, S. I. Buschow, F. A. Ossendorp, C. J. Melief, G. Raposo, B. W. van Balkom, and W. Stoorvogel. 2006. Dendritic cells regulate exposure of MHC class II at their plasma membrane by oligoubiquitination. Immunity 25: 885-894. https://doi.org/10.1016/j.immuni.2006.11.001
  55. De, G. A., V. Camosseto, J. Thibodeau, M. Ceppi, N. Catalan, P. Pierre, and E. Gatti. 2008. MHC class II stabilization at the surface of human dendritic cells is the result of maturation-dependent MARCH I down-regulation. Proc. Natl. Acad. Sci. U. S. A. 105: 3491-3496. https://doi.org/10.1073/pnas.0708874105
  56. Derbinski, J., J. Gabler, B. Brors, S. Tierling, S. Jonnakuty, M. Hergenhahn, L. Peltonen, J. Walter, and B. Kyewski. 2005. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J. Exp. Med. 202: 33-45.
  57. Skogberg, G., V. Lundberg, M. Berglund, J. Gudmundsdottir, E. Telemo, S. Lindgren, and O. Ekwall. 2015. Human thymic epithelial primary cells produce exosomes carrying tissue-restricted antigens. Immunol. Cell Biol. doi: 10.1038/icb.2015.33.
  58. Liiv, I., U. Haljasorg, K. Kisand, J. Maslovskaja, M. Laan, and P. Peterson. 2012. AIRE-induced apoptosis is associated with nuclear translocation of stress sensor protein GAPDH. Biochem. Biophys. Res. Commun. 423: 32-37. https://doi.org/10.1016/j.bbrc.2012.05.057
  59. Mazzini, E., L. Massimiliano, G. Penna, and M. Rescigno. 2014. Oral tolerance can be established via gap junction transfer of fed antigens from CX3CR1(+) macrophages to CD103(+) dendritic cells. Immunity 40: 248-261. https://doi.org/10.1016/j.immuni.2013.12.012
  60. Zaccard, C. R., S. C. Watkins, P. Kalinski, R. J. Fecek, A. L. Yates, R. D. Salter, V. Ayyavoo, C. R. Rinaldo, and R. B. Mailliard. 2015. CD40L induces functional tunneling nanotube networks exclusively in dendritic cells programmed by mediators of type 1 immunity. J. Immunol. 194: 1047-1056. https://doi.org/10.4049/jimmunol.1401832
  61. Finnish-German APECED Consortium. 1997. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat. Genet. 17: 399-403. https://doi.org/10.1038/ng1297-399
  62. Anderson, M. S., E. S. Venanzi, L. Klein, Z. Chen, S. P. Berzins, S. J. Turley, B. H. von, R. Bronson, A. Dierich, C. Benoist, and D. Mathis. 2002. Projection of an immunological self shadow within the thymus by the aire protein. Science 298: 1395-1401. https://doi.org/10.1126/science.1075958

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