Browse > Article
http://dx.doi.org/10.4110/in.2015.15.3.111

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)
Publication Information
IMMUNE NETWORK / v.15, no.3, 2015 , pp. 111-120 More about this Journal
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
Dendritic cell; Central tolerance; Thymus; Clonal deletion; Negative selection; Regulatory T cell;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Banchereau, J., and R. M. Steinman. 1998. Dendritic cells and the control of immunity. Nature 392: 245-252.   DOI
2 Mellman, I., and R. M. Steinman. 2001. Dendritic cells: specialized and regulated antigen processing machines. Cell 106 : 255-258.   DOI
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.   DOI
4 Mathis, D., and C. Benoist. 2004. Back to central tolerance. Immunity 20: 509-516.   DOI
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.   DOI
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.   DOI
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.   DOI
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.   DOI
9 Cheng, M. H., A. K. Shum, and M. S. Anderson. 2007. What's new in the Aire? Trends Immunol. 28: 321-327.   DOI
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.   DOI
11 Mathis, D., and C. Benoist. 2007. A decade of AIRE. Nat. Rev. Immunol. 7: 645-650.   DOI
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.   DOI
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.   DOI
14 Koble, C., and B. Kyewski. 2009. The thymic medulla: a unique microenvironment for intercellular self-antigen transfer. J. Exp. Med. 206: 1505-1513.   DOI
15 Wu, L., and K. Shortman. 2005. Heterogeneity of thymic dendritic cells. Semin. Immunol. 17: 304-312.   DOI
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.   DOI
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.   DOI
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 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.   DOI
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.   DOI
21 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.   DOI
22 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.   DOI
23 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.   DOI
24 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.   DOI
25 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.   DOI
26 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.   DOI
27 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.   DOI
28 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.   DOI
29 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.   DOI
30 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.   DOI
31 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.   DOI
32 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.   DOI
33 Brocker, T. 1999. The role of dendritic cells in T cell selection and survival. J. Leukoc. Biol. 66: 331-335.   DOI
34 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.   DOI
35 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.   DOI
36 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.   DOI
37 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.   DOI
38 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.   DOI
39 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.   DOI
40 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.   DOI
41 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.   DOI
42 Lio, C. W., and C. S. Hsieh. 2008. A two-step process for thymic regulatory T cell development. Immunity 28: 100-111.   DOI
43 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.   DOI
44 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.   DOI
45 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.   DOI
46 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.   DOI
47 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.   DOI
48 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.   DOI
49 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.   DOI
50 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.   DOI
51 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.   DOI   ScienceOn
52 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.   DOI
53 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.   DOI
54 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.   DOI
55 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.   DOI
56 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.   DOI
57 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.   DOI
58 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.   DOI
59 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.   DOI
60 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.   DOI
61 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.
62 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.   DOI