Key Points
-
Interactions with self-peptide–MHC complexes on thymic epithelial cells are crucial for thymocyte survival (positive selection) and CD4 versus CD8 lineage commitment, but can also result in apoptotic cell death (negative selection). It is increasingly recognized that individual subsets of haematopoietic and epithelial antigen-presenting cells (APCs), residing within distinct thymic microenvironments, use partly unique strategies of antigen processing and handling and thus support T cell selection in a cooperative rather than a redundant manner.
-
Recent data suggest that cortical thymic epithelial cells (cTECs) use unique pathways of self-antigen processing to generate peptide–MHC complexes for positive selection.
-
Thymic dendritic cells (DCs) are more heterogeneous than previously appreciated. Migratory DCs carry peripheral self antigens into the thymus and thereby may extend the scope of intrathymically presented self antigens. Other biological implications of the heterogeneity of thymic DCs and the way in which the various DC subsets may differentially contribute to the intrathymic representation of peripheral tissues are just beginning to emerge.
-
Medullary thymic epithelial cells (mTECs) are not only unique in their ability to promiscuously express tissue-restricted antigens, but they also have adapted their cell biology to focus their MHC class II-bound peptides on this endogenous antigen pool, thus fulfilling an autonomous APC function not only in CD8+ but also in CD4+ T cell tolerance.
-
Constitutive and unidirectional transfer of mTEC-derived self antigens to thymic DCs increases the probability that autoreactive T cells encounter self antigens expressed by rare mTECs.
Abstract
Understanding how thymic selection imparts self-peptide–MHC complex restriction and a high degree of self tolerance on the T cell repertoire requires a detailed description of the parameters that shape the MHC ligand repertoire of distinct thymic antigen-presenting cells and of how these cells communicate with T cells. Several recent discoveries pertaining to cortex-specific pathways of antigen processing, the heterogeneity of thymic dendritic cells and the intercellular transfer of self antigens have uncovered surprising and unique aspects of antigen presentation in the thymic microenvironment. Here, we discuss these new findings in the context of how individual thymic stromal cell types support T cell selection in a cooperative rather than a redundant manner.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Daniels, M. A. et al. Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature 444, 724–729 (2006).
Ahn, S. et al. TSCOT+ thymic epithelial cell-mediated sensitive CD4 tolerance by direct presentation. PLoS Biol. 6, e191 (2008).
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).
Bensinger, S. J., Bandeira, A., Jordan, M. S., Caton, A. J. & Laufer, T. M. Major histocompatibility complex class II-positive cortical epithelium mediates the selection of CD4+25+ immunoregulatory T cells. J. Exp. Med. 194, 427–438 (2001).
Liston, A. et al. Differentiation of regulatory Foxp3+ T cells in the thymic cortex. Proc. Natl Acad. Sci. USA 105, 11903–11908 (2008).
Marrack, P. & Kappler, J. The T cell receptor. Science 238, 1073–1079 (1987).
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).
Ashton-Rickardt, P. G., Van Kaer, L., Schumacher, T. N., Ploegh, H. L. & Tonegawa, S. Peptide contributes to the specificity of positive selection of CD8+ T cells in the thymus. Cell 73, 1041–1049 (1993).
Hogquist, K. A., Gavin, M. A. & Bevan, M. J. Positive selection of CD8+ T cells induced by major histocompatibility complex binding peptides in fetal thymic organ culture. J. Exp. Med. 177, 1469–1473 (1993).
Ashton-Rickardt, P. G. et al. Evidence for a differential avidity model of T cell selection in the thymus. Cell 76, 651–663 (1994).
Sebzda, E. et al. Positive and negative thymocyte selection induced by different concentrations of a single peptide. Science 263, 1615–1618 (1994).
Sebzda, E. et al. Mature T cell reactivity altered by peptide agonist that induces positive selection. J. Exp. Med. 183, 1093–1104 (1996).
Hogquist, K. A. et al. T cell receptor antagonist peptides induce positive selection. Cell 76, 17–27 (1994).
Alam, S. M. et al. T-cell-receptor affinity and thymocyte positive selection. Nature 381, 616–620 (1996).
Palmer, E. & Naeher, D. Affinity threshold for thymic selection through a T-cell receptor-co-receptor zipper. Nature Rev. Immunol. 9, 207–213 (2009).
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).
Hogquist, K. A. et al. Identification of a naturally occurring ligand for thymic positive selection. Immunity 6, 389–399 (1997).
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). References 16 and 18 report that specific peptides present on peripheral APCs can promote the positive selection of particular MHC class II-restricted TCRs when added to fetal thymic organ cultures. Importantly, these peptides also function as co-agonists for mature T cells of the same specificity.
Santori, F. R. et al. Rare, structurally homologous self-peptides promote thymocyte positive selection. Immunity 17, 131–142 (2002).
Goldrath, A. W. & Bevan, M. J. Selecting and maintaining a diverse T-cell repertoire. Nature 402, 255–262 (1999).
Starr, T. K., Jameson, S. C. & Hogquist, K. A. Positive and negative selection of T cells. Annu. Rev. Immunol. 21, 139–176 (2003).
Honey, K. & Rudensky, A. Y. Lysosomal cysteine proteases regulate antigen presentation. Nature Rev. Immunol. 3, 472–482 (2003).
Nakagawa, T. et al. Cathepsin L: critical role in Ii degradation and CD4 T cell selection in the thymus. Science 280, 450–453 (1998). This is the first report describing a cTEC-specific pathway for the generation of peptide–MHC class II complexes.
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).
Barton, G. M. & Rudensky, A. Y. Requirement for diverse, low-abundance peptides in positive selection of T cells. Science 283, 67–70 (1999).
Sant'Angelo, D. B. et al. The imprint of intrathymic self-peptides on the mature T cell receptor repertoire. Immunity 7, 517–524 (1997).
Tourne, S. et al. Selection of a broad repertoire of CD4+ T cells in H-2Ma0/0 mice. Immunity 7, 187–195 (1997).
Ignatowicz, L., Kappler, J. & Marrack, P. The repertoire of T cells shaped by a single MHC/peptide ligand. Cell 84, 521–529 (1996).
Bowlus, C. L., Ahn, J., Chu, T. & Gruen, J. R. Cloning of a novel MHC-encoded serine peptidase highly expressed by cortical epithelial cells of the thymus. Cell. Immunol. 196, 80–86 (1999).
Carrier, A. et al. Differential gene expression in CD3ɛ- and RAG1-deficient thymuses: definition of a set of genes potentially involved in thymocyte maturation. Immunogenetics 50, 255–270 (1999).
Cheunsuk, S. et al. Prss16 is not required for T-cell development. Mol. Cell Biol. 25, 789–796 (2005).
Gommeaux, J. et al. Thymus-specific serine protease regulates positive selection of a subset of CD4+ thymocytes. Eur. J. Immunol. 39, 956–964 (2009). This report shows altered positive selection of two MHC class II-restricted transgenic TCR specificities in mice with a targeted disruption of the cTEC-specific Tssp gene.
Viken, M. K. et al. Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex. Genes Immun. 10, 323–333 (2009).
Kasai, M. et al. Difference in antigen presentation pathways between cortical and medullary thymic epithelial cells. Eur. J. Immunol. 26, 2101–2107 (1996).
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).
Oukka, M. et al. Selectivity of the major histocompatibility complex class II presentation pathway of cortical thymic epithelial cell lines. Eur. J. Immunol. 27, 855–859 (1997).
Klein, L. & Kyewski, B. Self-antigen presentation by thymic stromal cells: a subtle division of labor. Curr. Opin. Immunol. 12, 179–186 (2000).
Munz, C. Enhancing immunity through autophagy. Annu. Rev. Immunol. 27, 423–449 (2009).
Mizushima, N., Yamamoto, A., Matsui, M., Yoshimori, T. & Ohsumi, Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol. Biol. Cell 15, 1101–1111 (2004).
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). Using transplantation of Atg5−/− thymi, this report shows that a macroautophagy deficiency in TECs leads to altered selection of some MHC class II-restricted TCRs and systemic autoimmunity, presumably as a consequence of diminished endogenous MHC class II loading in TECs.
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).
Murata, S. et al. Regulation of CD8+ T cell development by thymus-specific proteasomes. Science 316, 1349–1353 (2007). This paper identified and characterized the cTEC-specific proteasomal subunit β5t. Targeted disruption of the gene encoding β5t is shown to result in a dramatically decreased size of the CD8+ T cell compartment.
Nitta, T. et al. Thymoproteasome shapes immunocompetent repertoire of CD8 T cells. Immunity (in the press).
Murata, S., Takahama, Y. & Tanaka, K. Thymoproteasome: probable role in generating positively selecting peptides. Curr. Opin. Immunol. 20, 192–196 (2008).
Ernst, B., Lee, D. S., Chang, J. M., Sprent, J. & Surh, C. D. The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery. Immunity 11, 173–181 (1999).
Davis, M. M. et al. T cells as a self-referential, sensory organ. Annu. Rev. Immunol. 25, 681–695 (2007).
Stefanova, I., Dorfman, J. R. & Germain, R. N. Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes. Nature 420, 429–434 (2002).
McCaughtry, T. M., Wilken, M. S. & Hogquist, K. A. Thymic emigration revisited. J. Exp. Med. 204, 2513–2520 (2007).
Kurobe, H. et al. CCR7-dependent cortex-to-medulla migration of positively selected thymocytes is essential for establishing central tolerance. Immunity 24, 165–177 (2006).
Srivatsan, S. & Peng, S. L. Cutting edge: Foxj1 protects against autoimmunity and inhibits thymocyte egress. J. Immunol. 175, 7805–7809 (2005).
Boehm, T., Scheu, S., Pfeffer, K. & Bleul, C. C. Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LTβR. J. Exp. Med. 198, 757–769 (2003).
Akiyama, T. et al. Dependence of self-tolerance on TRAF6-directed development of thymic stroma. Science 308, 248–251 (2005).
Akiyama, T. et al. The tumour necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 29, 423–437 (2008).
Hikosaka, Y. et al. The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity 29, 438–450 (2008).
Irla, M. et al. Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity. Immunity 29, 451–463 (2008).
Rossi, S. W. et al. RANK signals from CD4+3− inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J. Exp. Med. 204, 1267–1272 (2007).
Chelly, J., Concordet, J. P., Kaplan, J. C. & Kahn, A. Illegitimate transcription: transcription of any gene in any cell type. Proc. Natl Acad. Sci. USA 86, 2617–2621 (1989).
Sarkar, G. & Sommer, S. S. Access to a messenger RNA sequence or its protein product is not limited by tissue or species specificity. Science 244, 331–334 (1989).
Linsk, R., Gottesman, M. & Pernis, B. Are tissues a patch quilt of ectopic gene expression? Science 246, 261 (1989).
Kyewski, B. & Klein, L. A central role for central tolerance. Annu. Rev. Immunol. 24, 571–606 (2006).
Anderson, M. S. et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 298, 1395–1401 (2002).
Derbinski, J., Schulte, A., Kyewski, B. & Klein, L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nature Immunol. 2, 1032–1039 (2001).
Mathis, D. & Benoist, C. Aire. Annu. Rev. Immunol. 27, 287–312 (2009).
Peterson, P., Org., T. & Rebane, A. Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nature Rev. Immunol. 8, 948–957 (2008).
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).
Gabler, J., Arnold, J. & Kyewski, B. Promiscuous gene expression and the developmental dynamics of medullary thymic epithelial cells. Eur. J. Immunol. 37, 3363–3372 (2007).
Gray, D., Abramson, J., Benoist, C. & Mathis, D. Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire. J. Exp. Med. 204, 2521–2528 (2007).
Zehn, D. & Bevan, M. J. T cells with low avidity for a tissue-restricted antigen routinely evade central and peripheral tolerance and cause autoimmunity. Immunity 25, 261–270 (2006).
Miller, M. J., Hejazi, A. S., Wei, S. H., Cahalan, M. D. & Parker, I. T cell repertoire scanning is promoted by dynamic dendritic cell behaviour and random T cell motility in the lymph node. Proc. Natl Acad. Sci. USA 101, 998–1003 (2004).
Le Borgne, M. et al. The impact of negative selection on thymocyte migration in the medulla. Nature Immunol. 10, 823–830 (2009). This paper provides the first data on how thymocytes scan the medullary microenvironment and thus maximize the chances of self-antigen encounter.
Klein, L. Dead man walking: how thymocytes scan the medulla. Nature Immunol. 10, 809–811 (2009).
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).
Derbinski, J. et al. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J. Exp. Med. 202, 33–45 (2005).
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).
Koble, C. & Kyewski, B. The thymic medulla: a unique microenvironment for intercellular self-antigen transfer. J. Exp. Med. 206, 1505–1513 (2009). A systematic analysis of the directional transfer of mTEC-derived antigens to thymic DCs and the functional consequences. Importantly, unidirectional transfer is also shown for native endogenous self antigens.
Shortman, K. & Naik, S. H. Steady-state and inflammatory dendritic-cell development. Nature Rev. Immunol. 7, 19–30 (2007).
Wu, L. & Shortman, K. Heterogeneity of thymic dendritic cells. Semin. Immunol. 17, 304–312 (2005).
Ardavin, C., Wu, L., Li, C. L. & Shortman, K. Thymic dendritic cells and T cells develop simultaneously in the thymus from a common precursor population. Nature 362, 761–763 (1993).
Donskoy, E. & Goldschneider, I. Two developmentally distinct populations of dendritic cells inhabit the adult mouse thymus: demonstration by differential importation of haematogenous precursors under steady state conditions. J. Immunol. 170, 3514–3521 (2003).
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). This report describes the phenotype, frequency and characteristics of autochthonous and migratory DCs in the mouse thymus.
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). A systematic comparison of the cytokine and chemokine production, Toll-like receptor expression and antigen presentation capacity of autochthonous and migratory thymic cDCs.
Radtke, F. et al. Notch1 deficiency dissociates the intrathymic development of dendritic cells and T cells. J. Exp. Med. 191, 1085–1094 (2000).
Rodewald, H. R., Brocker, T. & Haller, C. Developmental dissociation of thymic dendritic cell and thymocyte lineages revealed in growth factor receptor mutant mice. Proc. Natl Acad. Sci. USA 96, 15068–15073 (1999).
Bonasio, R. et al. Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nature Immunol. 7, 1092–1100 (2006). The first evidence that physiological immigration of peripheral DCs into the thymus can induce negative selection of CD4+ T cells that recognize a peripheral model antigen.
Lahoud, M. H. et al. Signal regulatory protein molecules are differentially expressed by CD8− dendritic cells. J. Immunol. 177, 372–382 (2006).
Liu, K. et al. Origin of dendritic cells in peripheral lymphoid organs of mice. Nature Immunol. 8, 578–583 (2007).
Duncan, S. R., Capetanakis, N. G., Lawson, B. R. & Theofilopoulos, A. N. Thymic dendritic cells traffic to thymi of allogeneic recipients and prolong graft survival. J. Clin. Invest. 109, 755–764 (2002).
Proietto, A. I. et al. Dendritic cells in the thymus contribute to T-regulatory cell induction. Proc. Natl Acad. Sci. USA 105, 19869–19874 (2008). Together with reference 80, this paper identifies the peripheral origin of CD172a+ cDCs. Their suggested specialized role in T Reg cell induction remains controversial (as shown in reference 89).
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).
Rudensky, A., Rath, S., Preston-Hurlburt, P., Murphy, D. B. & Janeway, C. A. Jr. On the complexity of self. Nature 353, 660–662 (1991).
Humblet, C., Rudensky, A. & Kyewski, B. Presentation and intercellular transfer of self antigen within the thymic microenvironment: expression of the Eα peptide-I-Ab complex by isolated thymic stromal cells. Int. Immunol. 6, 1949–1958 (1994).
Viret, C., Barlow, A. K. & Janeway, C. A., Jr. On the intrathymic intercellular transfer of self-determinants. Immunol. Today 20, 8–10 (1999).
Zhang, M. et al. T cell tolerance to a neo-self antigen expressed by thymic epithelial cells: the soluble form is more effective than the membrane-bound form. J. Immunol. 170, 3954–3962 (2003).
Millet, V., Naquet, P. & Guinamard, R. R. Intercellular MHC transfer between thymic epithelial and dendritic cells. Eur. J. Immunol. 38, 1257–1263 (2008). Using somatic and bone marrow chimaeras, this study elegantly shows that intact peptide–MHC complexes are transferred from TECs to DCs and also between TECs.
Birnberg, T. et al. Lack of conventional dendritic cells is compatible with normal development and T cell homeostasis, but causes myeloid proliferative syndrome. Immunity 29, 986–997 (2008).
Ohnmacht, C. et al. Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J. Exp. Med. 206, 549–559 (2009).
Hildner, K. et al. Batf3 deficiency reveals a critical role for CD8α+ dendritic cells in cytotoxic T cell immunity. Science 322, 1097–1100 (2008).
Cisse, B. et al. Transcription factor E2-2 is an essential and specific regulator of plasmacytoid dendritic cell development. Cell 135, 37–48 (2008).
Thery, C., Zitvogel, L. & Amigorena, S. Exosomes: composition, biogenesis and function. Nature Rev. Immunol. 2, 569–579 (2002).
Harshyne, L. A., Watkins, S. C., Gambotto, A. & Barratt-Boyes, S. M. Dendritic cells acquire antigens from live cells for cross-presentation to CTL. J. Immunol. 166, 3717–3723 (2001).
Russo, V. et al. Acquisition of intact allogeneic human leukocyte antigen molecules by human dendritic cells. Blood 95, 3473–3477 (2000).
Neijssen, J. et al. Cross-presentation by intercellular peptide transfer through gap junctions. Nature 434, 83–88 (2005).
Boehm, T. The adaptive phenotype of cortical thymic epithelial cells. Eur. J. Immunol. 39, 944–947 (2009).
Mizushima, N. & Klionsky, D. J. Protein turnover via autophagy: implications for metabolism. Annu. Rev. Nutr. 27, 19–40 (2007).
Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).
Cecconi, F. & Levine, B. The role of autophagy in mammalian development: cell makeover rather than cell death. Dev. Cell 15, 344–357 (2008).
Virgin, H. W. & Levine, B. Autophagy genes in immunity. Nature Immunol. 10, 461–470 (2009).
Brazil, M. I., Weiss, S. & Stockinger, B. Excessive degradation of intracellular protein in macrophages prevents presentation in the context of major histocompatibility complex class II molecules. Eur. J. Immunol. 27, 1506–1514 (1997).
Nimmerjahn, F. et al. Major histocompatibility complex class II-restricted presentation of a cytosolic antigen by autophagy. Eur. J. Immunol. 33, 1250–1259 (2003).
Paludan, C. et al. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307, 593–596 (2005).
Dengjel, J. et al. Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. Proc. Natl Acad. Sci. USA 102, 7922–7927 (2005).
Schmid, D., Pypaert, M. & Munz, C. Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes. Immunity 26, 79–92 (2007).
Kloetzel, P. M. & Ossendorp, F. Proteasome and peptidase function in MHC-class-I-mediated antigen presentation. Curr. Opin. Immunol. 16, 76–81 (2004).
Geenen, V. et al. The neuroendocrine thymus: coexistence of oxytocin and neurophysin in the human thymus. Science 232, 508–511 (1986).
Jolicoeur, C., Hanahan, D. & Smith, K. M. T-cell tolerance toward a transgenic beta-cell antigen and transcription of endogenous pancreatic genes in thymus. Proc. Natl Acad. Sci. USA 91, 6707–6711 (1994).
Smith, K. M., Olson, D. C., Hirose, R. & Hanahan, D. Pancreatic gene expression in rare cells of thymic medulla: evidence for functional contribution to T cell tolerance. Int. Immunol. 9, 1355–1365 (1997).
Aaltonen, J. et al.. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nature Genet. 17, 399–403 (1997).
Nagamine, K. et al. Positional cloning of the APECED gene. Nature Genet. 17, 393–398 (1997).
Bhakta, N. R., Oh, D. Y. & Lewis, R. S. Calcium oscillations regulate thymocyte motility during positive selection in the three-dimensional thymic environment. Nature Immunol. 6, 143–151 (2005).
Bousso, P., Bhakta, N. R., Lewis, R. S. & Robey, E. Dynamics of thymocyte-stromal cell interactions visualized by two-photon microscopy. Science 296, 1876–1880 (2002).
Ebert, P. J., Ehrlich, L. I. & Davis, M. M. Low ligand requirement for deletion and lack of synapses in positive selection enforce the gauntlet of thymic T cell maturation. Immunity 29, 734–745 (2008).
Kishimoto, H. & Sprent, J. Several different cell surface molecules control negative selection of medullary thymocytes. J. Exp. Med. 190, 65–73 (1999).
Page, D. M. Cutting edge: thymic selection and autoreactivity are regulated by multiple co-receptors involved in T cell activation. J. Immunol. 163, 3577–3581 (1999).
Kishimoto, H. & Sprent, J. Negative selection in the thymus includes semimature T cells. J. Exp. Med. 185, 263–271 (1997).
Acknowledgements
L.K. receives support from the Deutsche Forschungsgemeinschaft (grants SFB455, SFB571, KL1228/2-1 and KL1228/3-1) and the Hertie-Foundation. B.K. is supported by the Deutsche Forschungsgemeinschaft (grant SFB405), the German Cancer Research Center and the European Union-funded Consortia for Immunotherapy (grant 14363) and Tolerage (grant 14364).
Author information
Authors and Affiliations
Corresponding authors
Related links
Glossary
- 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.
- Positive selection
-
The process by which immature double-positive thymocytes expressing T cell receptors with intermediate affinity and/or avidity for self-peptide–MHC complexes are induced to differentiate into mature single-positive thymocytes.
- Central tolerance
-
Self tolerance that is created at the level of the central lymphoid organs. Developing T cells in the thymus, and B cells in the bone marrow, that strongly recognize self antigen face deletion or marked suppression.
- CD4+CD25+ regulatory T (TReg) cells
-
A subset of lymphocytes that suppress autoreactive T cells that escape negative selection in the thymus.
- Cathepsins
-
Proteases that are mostly located in lysosomes and lysosome-like organelles and can be divided into cysteine, aspartate and serine cathepsin subgroups according to their active-site amino acid.
- Endocytic pathway
-
A trafficking pathway used by all cells for the internalization of endocytosed molecules from the plasma membrane to lysosomes.
- Macroautophagy
-
(Also known as autophagy). The generally nonspecific autophagic sequestration of cytoplasm into a double- or multiple-membrane-delimited compartment (a macroautophagosome) of non-lysosomal origin. Certain proteins, organelles and pathogens may be selectively degraded by macroautophagy.
- Proteasome
-
A giant multicatalytic protease resident in the cytoplasm and the nucleus. In addition to having a crucial role in protein turnover, the proteasome is thought to carry out the first catalytic step in the MHC class I-restricted processing of most, if not all, antigens.
- Cross-presentation
-
The presentation of exogenous antigen that has been re-routed to the MHC class I pathway of antigen presentation by APCs to CD8+ T cells.
- Plasmacytoid DCs
-
(Plasmacytoid dendritic cells). Immature DCs with a plasmacytoid morphology, which produce type I interferons in response to viral infection.
- Superantigen
-
A protein that binds to and activates all T cells that express a particular set of Vβ T cell receptor genes.
- Lipopolysaccharide
-
(Also known as endotoxin). A constituent of the cell walls of Gram-negative bacteria that is important for eliciting the immune response to Gram-negative bacterial infection.
- Dominant tolerance
-
The active suppression of an autoimmune response, in vitro or in vivo, by suppressor cells including TReg cells. By contrast, deletional tolerance and induction of anergy are types of passive tolerance. Dominant tolerance is transferable to naive recipients, whereas passive tolerance is not.
- Exosome
-
A small lipid-bilayer vesicle that is released from dendritic cells and other cells. They are composed of cell membranes or are derived from the membranes of intracellular vesicles. They might contain antigen–MHC complexes and interact with antigen-specific lymphocytes directly, or they might be taken up by other antigen-presenting cells.
Rights and permissions
About this article
Cite this article
Klein, L., Hinterberger, M., Wirnsberger, G. et al. Antigen presentation in the thymus for positive selection and central tolerance induction. Nat Rev Immunol 9, 833–844 (2009). https://doi.org/10.1038/nri2669
Issue Date:
DOI: https://doi.org/10.1038/nri2669
