Generating intrathymic microenvironments to establish T-cell tolerance (original) (raw)

• Davis, M. M. et al. T-cells as a self-referential, sensory organ. Ann. Rev. Immunol. 25, 681–695 (2007).
  Article CAS Google Scholar
• Takahama, T. Journey through the thymus: stromal guides for T-cell development and selection. Nature Rev. Immunol. 6, 127–135 (2006).
  Article CAS Google Scholar
• Hayday, A. C. & Pennington, D. J. Key factors in the organised chaos of early T-cell development. Nature Immunol. 8, 137–144 (2007).
  Article CAS Google Scholar
• Lind, E. F., Prockop, S. E., Porritt, H. E. & Petrie, H. T. Mapping precursor movement through the postnatal thymus reveals specific microenvironments supporting defined stages of early lymphoid development. J. Exp. Med. 194, 127–134 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Kampinga, J. et al. Thymic epithelial antibodies: immunohistological analysis and introduction of nomenclature. Thymus 13, 165–173 (1989).
  CAS PubMed Google Scholar
• van de Wijngaert, F. P., Kendall, M. D., Schuurman, H. J., Rademakers, L. H. & Kater, L. Heterogeneity of epithelial cells in the human thymus. An ultrastructural study. Cell Tissue Res. 237, 227–237 (1984).
  Article CAS PubMed Google Scholar
• Boehm, T. & Bleul, C. C. Thymus-homing precursors and the thymic microenvironment. Trends Immunol. 27, 477–484 (2006).
  Article CAS PubMed Google Scholar
• Gordon, J. et al. Functional evidence for a single endodermal origin for the thymic epithelium. Nature Immunol. 5, 546–553 (2004).
  Article CAS Google Scholar
• Gray, D. H. D. et al. Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood 108, 3777–3785 (2006).
  Article CAS PubMed Google Scholar
• Klug, D. B. et al. Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment. Proc. Natl Acad. Sci. USA 95, 11822–11827 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Klug, D. B., Carter, C., Giminez-Conti, I. B. & Richie, E. R. Thymocyte-independent and thymocyte dependent phases of epithelial patterning in the fetal thymus. J. Immunol. 169, 2842–2845 (2002).
  Article CAS PubMed Google Scholar
• Rossi, S. W., Jenkinson, W. E., Anderson, G. & Jenkinson, E. J. Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature 441, 988–991 (2006).
  Article CAS PubMed Google Scholar
• Bleul, C. C. et al. Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature 441, 992–996 (2006). Together with reference 12, this study provides the first evidence for the existence of bipotent TEC progenitors that give rise to both cTECs and mTECs.
  Article CAS PubMed Google Scholar
• Gill, J., Malin, M., Hollander, G. & Boyd, R. L. Generation of a complete thymic microenvironment by MTS24+ thymic epithelial cells. Nature Immunol. 3, 635–642 (2002).
  Article CAS Google Scholar
• Bennett, A. R. et al. Identification and characterization of thymic epithelial progenitor cells. Immunity 16, 803–814 (2002).
  Article CAS PubMed Google Scholar
• Nijhof, J. G. et al. The cell-surface marker MTS24 identifies a novel population of follicular keratinocytes with characteristics of progenitor cells. Development 133, 3027–3037 (2006).
  Article CAS PubMed Google Scholar
• Rossi, S. W. et al. Redefining epithelial progenitor potential in the developing thymus. Eur. J. Immunol. 37, 2411–2418 (2007).
  Article CAS PubMed Google Scholar
• Barthlott, T., Keller, M. P., Krenger, W. & Hollander, G. A. A short primer on early molecular and cellular events in thymus organogenesis and replacement. Swiss Med. Weekly 136, 365–369 (2006).
  CAS Google Scholar
• Redvers, R. P., Li, A. & Kaur, P. Side population in adult murine epidermis exhibits phenotypic and functional characteristics of keratinocyte stem cells. Proc. Natl Acad. Sci. USA 103, 13168–13173 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• 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, 267–1272 (2007). This study identifies an intrathymic CD3 − CD4+ cell population as the provider of RANK signals that lead to the development of AIRE-expressing mTECs.
  Article CAS Google Scholar
• Jenkinson, W. E., Jenkinson, E. J. & Anderson, G. Differential requirement for mesenchyme in the proliferation and maturation of thymic epithelial progenitors. J. Exp. Med. 198, 325–332 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Jenkinson, W. E., Rossi, S. W., Parnell, S. M., Jenkinson, E. J. & Anderson, G. PDGFRα-expressing mesenchyme regulates thymus growth and the availability of intrathymic niches. Blood 109, 954–960 (2007).
  Article CAS PubMed Google Scholar
• Terszowski, G. et al. Evidence for a functional second thymus in mice. Science 312, 284–287 (2006).
  Article CAS PubMed Google Scholar
• Dooley, J., Erickson, M., Gillard, G. O. & Farr, A. G. Cervical thymus in the mouse. J. Immunol. 176, 6484–6489 (2006).
  Article CAS PubMed Google Scholar
• Jenkinson, W. E., Rossi, S. W., Jenkinson, E. J. & Anderson, G. Development of functional thymic epithelial cells occurs independently of lymphostromal interactions. Mech. Dev. 122, 1294–1299 (2005).
  Article CAS PubMed Google Scholar
• Hens, J. R. & Wysolmerski, J. J. Key stages of mammary gland development: molecular mechanisms involved in the formation of the embryonic mammary gland. Breast Cancer Res. 7, 220–224 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Blanpain, C., Horsley, V. & Fuchs, E. Epithelial stem cells: turning over new leaves. Cell 128, 445–458 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Bockman, D. E. & Kirby M. L. Dependence of thymus development on derivatives of the neural crest. Science 223, 498–500 (1984).
  Article CAS PubMed Google Scholar
• Yamazaki, H. et al. Presence and distribution of neural crest-derived cells in the murine developing thymus and their potential for differentiation. Int. Immunol. 17, 549–558 (2005).
  Article CAS PubMed Google Scholar
• Revest, J. M., Suniara, R. K., Kerr, K., Owen, J. J. & Dickson, C. Development of the thymus requires signaling through the fibroblast growth factor receptor R2-IIIb. J. Immunol. 167, 1954–1961 (2001).
  Article CAS PubMed Google Scholar
• Muller, S. M. et al. Gene targeting of VEGF-A in thymus epithelium disrupts thymus blood vessel architecture. Proc. Natl Acad. Sci. USA 102, 10587–10592 (2005). This study describes the use of a nude mouse blastocyst complementation strategy to investigate the role of candidate genes in TEC development.
  Article PubMed CAS PubMed Central Google Scholar
• Gray, D. H. et al. A unique thymic fibroblast population revealed by the monoclonal antibody MTS-15. J. Immunol. 178, 4956–4965 (2007).
  Article CAS PubMed Google Scholar
• Senoo, M., Pinto, F., Crum, C. P. & McKeon, F. p63 is essential for proliferative potential of stem cells in stratified epithelia. Cell 129, 523–536 (2007).
  Article CAS PubMed Google Scholar
• Prockop, S. E. & Petrie, H. T. Regulation of thymus size by competition for stromal niches among early T cell progenitors. J. Immunol. 173, 1604–1611 (2004).
  Article CAS PubMed Google Scholar
• Rossi, S. W. et al. Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells. Blood 109, 3803–3811 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Penit, C., Lucas, B., Vasseur, F., Rieker, T. & Boyd, R. L. Thymic medulla epithelial cells acquire specific markers by post-mitotic maturation. Dev. Immunol. 5, 25–36 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• Derbinksi, J., Schulte, A., Kyewski, B. & Klein, L. Promiscuous gene expression medullary thymic epithelial cells mirrors the peripheral self. Nature Immunol. 2, 1032–1039 (2001).
  Article CAS Google Scholar
• Osada, M. et al. The Wnt signaling antagonist Kremen1 is required for development of thymic architecture. Clin. Dev. Immunol. 13, 299–319 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Kuragichi, M. et al. Adenomatous polyposis coli (APC) is required for normal development of skin and thymus. PLoS Genetics 2, 1362–1374 (2006).
  Google Scholar
• Pongracz, J., Hare, K., Harman, B., Anderson, G. & Jenkinson, E. J. Thymic epithelial cells provide Wnt signals to developing thymocytes. Eur. J. Immunol. 33, 1949–1956 (2003).
  Article CAS PubMed Google Scholar
• Goldman, K. P., Park, C. S., Kim, M., Matzinger, P. & Anderson, C. C. Thymic cortical epithelium induces self-tolerance. Eur. J. Immunol. 35, 709–717 (2005).
  Article CAS PubMed Google Scholar
• Anderson, G., Owen, J. J., Moore, N. C. & Jenkinson, E. J. Thymic epithelial cells provide unique signals for positive selection of CD4+8+ thymocytes in vitro. J. Exp. Med. 179, 2027–2031 (1994).
  Article CAS PubMed Google Scholar
• Fujimoto, Y. et al. CD83 expression influences CD4+ T-cell development in the thymus. Cell 108, 755–767 (2002).
  Article CAS PubMed Google Scholar
• 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).
  Article CAS PubMed Google Scholar
• Murata, S. et al. Regulation of CD8+ T-cell development by thymus-specific proteases. Science 316, 1349–1353 (2007). This study identifies a new mechanism of MHC class I antigen processing and presentation in TECs that influences positive selection of CD8+ T cells.
  Article CAS PubMed Google Scholar
• Beers, C., et al. Cathepsin-S controls MHC class II-mediated presentation by epithelial cells in vivo. J. Immunol. 174, 1205–1212 (2005).
  Article CAS PubMed Google Scholar
• 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
• Martinic, M. M. et al. Efficient T-cell repertoire selection in tetraparental chimaeric mice independent of thymic epithelial MHC. Proc. Natl Acad. Sci. USA 100, 1861–1866 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Choi, E. Y. et al. Thymocyte-thymocyte interaction for efficient positive selection and matureation of CD4+ T-cells. Immunity 23, 387–396 (2005).
  Article CAS PubMed Google Scholar
• Berg, L. J. Signalling through TEC kinases regulates conventional versus innate CD8 T-cell development. Nature Rev. Immunol. 7, 479–485 (2007).
  Article CAS Google Scholar
• Anderson, M., Anderson, S. K. & Farr, A. G. Thymic vasculature: organiser of the medullary epithelial compartment? Int. Immunol. 12, 1105–1110 (2000).
  Article CAS PubMed Google Scholar
• Rodewald, H. R., Paul, S., Haller, C., Bluethmann, H. & Blum, C. Thymus medulla consisting of epithelial islets each derived from a single progenitor. Nature 414, 763–768 (2001). This reference provides the first evidence for the existence of clonal TEC progenitors.
  Article CAS PubMed Google Scholar
• Naquet, P, Naspetti, M. & Boyd, R. L. Development, organisation and function of the thymic medulla in normal, immunodeficient or autoimmune mice. Semin. Immunol. 11, 47–55 (1999).
  Article CAS PubMed Google Scholar
• Fontenot, J. D. & Rudensky, A. A well adapted regulatory contrivance: regulatory T-cell development and the forkhead family transcription factor family Foxp3. Nature Immunol. 6, 331–337 (2005).
  Article CAS Google Scholar
• 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, 351–359 (2007).
  Article CAS Google Scholar
• Tai, X., Cowan, M., Feigenbaum, L. & Singer, A. CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T-cell differentiation independently of interleukin-2. Nature Immunol. 6, 152–162 (2005).
  Article CAS Google Scholar
• Bjorses, P., Aaltonen, J., Horelli-Kuitunen, N., Yaspo, M. L. & Peltonen, L. Gene defect behind APECED: a new clue to autoimmunity. Hum. Mol. Genet. 7, 1547–1553 (1998).
  Article CAS PubMed Google Scholar
• Bleschscmidt, K. et al. The mouse Aire gene: comparative genomic sequencing, gene organisation and expression. Genome Res. 9, 158–166 (1999).
  Google Scholar
• Anderson, M. S. et al. Projection of an immunological self-shadow within the thymus by the aire protein. Science 298, 1395–1401 (2002). This study shows that AIRE expression by TECs is necessary for the establishment of tolerance to peripheral antigens.
  Article CAS PubMed Google Scholar
• Liston, A., Lesage, S., Wilson, J., Peltonen, L. & Goodnow, C. C. Aire regulates negative selection of organ-specific T-cells. Nature Immunol. 4, 350–354 (2003).
  Article CAS Google Scholar
• Derbinksi, J. et al. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J. Exp. Med. 202, 33–45 (2005).
  Google Scholar
• Gillard, G. O., Dooley, J. Erikson, M. Peltonen, L. & Farr, A. G. Aire-dependent alterations in medullary thymic epithelium indicate a role for Aire in thymic epithelial differentiation. J. Immunol. 178, 3007–3015 (2007).
  Article CAS PubMed Google Scholar
• Gillard, G. O. & Farr, A. G. Features of medullary thymic epithelium implicate postnatal development in maintaining epithelial heterogeneity and tissue-restricted antigen expression. J. Immunol. 176, 5815–5824 (2006).
  Article CAS PubMed Google Scholar
• Gillard, G. O. & Farr, A. G. Contrasting models of promiscuous gene expression by thymic epithelium. J. Exp. Med. 202, 15–19 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Hamazaki, Y. et al. Medullary thymic epithelial cells expressing Aire represent a unique lineage derived from cells expressing claudin. Nature Immunol. 8, 304–311 (2007).
  Article CAS Google Scholar
• Kim, M. Y. et al. CD4+CD3− accessory cells costimulate primed CD4 T-cells through OX40 and CD30 at sites where T-cells collaborate with B-cells. Immunity 18, 643–654 (2003). This study identifies LTi cells in adult secondary lymphoid tissues and describes their role in T-cell responses.
  Article CAS PubMed Google Scholar
• Kim, M. Y. et al. Function of CD4+CD3− cells in relation to B- and T-zone stroma in spleen. Blood 109, 1602–1610 (2007).
  Article CAS PubMed Google Scholar
• Cupedo, T., Kraal, G. & Mebius R. E. The role of CD45+CD4+CD3− cells in lymphoid organ development. Immunol. Rev. 189, 41–50 (2002).
  Article CAS PubMed Google Scholar
• Derbinski, J. & Kyewski, B. Linking signalling pathways, thymic stroma integrity and autoimmunity. Trends Immunol. 26, 503–506 (2005).
  Article CAS PubMed Google Scholar
• Lomada, D., Liu, B., Coghlan, L., Hu, Y. & Richie, E. R. Thymus medulla formation and central tolerance are restored in IKKα−/− mice that express an IKKα transgene in keratin 5+ thymic epithelial cells. J. Immunol. 178, 829–837 (2007).
  Article CAS PubMed Google Scholar
• 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). This study demonstrates the importance of LTβR signalling in the formation of the thymic medulla.
  Article CAS PubMed PubMed Central Google Scholar
• Chin, R. K. et al. Lymphotoxin pathway directs thymic Aire expression. Nat. Immunol. 11, 1121–1127 (2003).
  Article Google Scholar
• Akiyama, T. et al. Dependence of self-tolerance on TRAF-6 directed development of thymic stroma. Science 308, 248–251 (2005). This paper describes the identification of a TRAF6 signalling pathway essential for the development of AIRE-expressing mTECs.
  Article CAS PubMed Google Scholar
• Nolte, M. A. et al. A conduit system distributes chemokines and small blood-borne molecules through the splenic white pulp. J. Exp. Med. 198, 505–512 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Drumea-Mirancea, M. et al. Characterisation of a conduit system containing laminin-5 in the thymus: a potential transport system for small molecules. J. Cell Sci. 119, 1396–1405 (2006).
  Article CAS PubMed Google Scholar
• Kim, M. Y. et al. OX40 ligand and CD30 ligand are expressed on adult but not neonatal CD4+3− inducer cells: evidence that IL-7 signals regulate CD30 ligand but not OX40 ligand expression. J. Immunol. 174, 6686–6691 (2005).
  Article CAS PubMed Google Scholar
• Kelly, K. A. & Scollay, R. Seeding of neonatal lymph nodes by T-cells and identification of a novel population of CD3−CD4+ cells. Eur. J. Immunol. 22, 329–334 (1992).
  Article CAS PubMed Google Scholar
• Mebius, R. E., Rennert, P. & Weissman, I. L. Developing lymph nodes collect CD4+CD3− LTβ+ cells that can differentiate into APC, NK cells, and follicular cells but not T or B cells. Immunity 7, 493–504 (1997).
  Article CAS PubMed Google Scholar
• Mebius, R. E., Streeter, P. R., Michie, S., Butcher, E. C. & Weissman, I. L. A developmental switch in lymphocyte homing receptor and endothelial vascular addressin expression regulates lymphocyte homing and permits CD4+CD3− cells to colonise lymph nodes. Proc. Natl Acad. Sci. USA 93, 11019–11024 (1996). References 77–79 provide the first characterization of CD3 − CD4+ LTi cells in secondary lymphoid tissues.
  Article CAS PubMed PubMed Central Google Scholar
• Eberl, G. et al. An essential function for the nuclear receptor RORγt in the generation of fetal lymphoid tissue inducer cells. Nature Immunol. 5, 64–73 (2004). This study identifies RORγt as a key molecule during LTi development and the subsequent development of secondary lympoid tissues.
  Article CAS Google Scholar
• Boos, M. D., Yokota, Y., Eberl. G. & Kee B. L. Mature natural killer cell and lymphoid-tissue inducing cell development requires Id2-mediated suppression of E protein activity. J. Exp. Med. 204, 1119–1130 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Cupedo, T., Jansen, W., Kraal, G. & Mebius R. E. Induction of secondary and tertiary lymphoid structures in the skin. Immunity 21, 655–667 (2004).
  Article CAS PubMed Google Scholar
• Meier, D. et al. Ectopic lymphoid-organ development occurs through interleukin-7 mediated enhanced survival of lymphoid tissue inducer cells. Immunity 26, 643–654 (2007).
  Article CAS PubMed Google Scholar
• Nehls, M, Pfeifer, D., Schorpp, M., Hedrich, H. & Boehm, T. New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature 372, 103–107 (1994). This is the first report identifying the genetic nature of the thymus defect in nude rodents.
  Article CAS PubMed Google Scholar
• Nehls, M. et al. Two genetically separable steps in the differentiation of thymic epithelium. Science 272, 886–889 (1996).
  Article CAS PubMed Google Scholar
• Blackburn, C. C. et al. The nu gene acts cell-autonomously and is required for differentiation of thymic epithelial progenitors. Proc. Natl Acad. Sci. USA 93, 5742–5746 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• Dooley, J., Erickson, M. & Farr, A. G. An organised medullary epithelial structure in the normal thymus expresses molecules of respiratory epithelium and resembles the epithelial thymic rudiment of nude mice. J. Immunol. 175, 4331–4337 (2005).
  Article CAS PubMed Google Scholar
• Su, D. M., Navarre, S., Oh, W. J., Condie, B. G. & Manley N. R. A domain of Foxn1 required for crosstalk-dependent thymic epithelial cell differentiation. Nature Immunol. 4, 1128–1135 (2003).
  Article CAS Google Scholar
• Jerome, L. A. & Papaioannou, V. E. DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nature Genet. 27, 286–291 (2001).
  Article CAS PubMed Google Scholar
• Ivins, S. et al. Microarray analysis detects differentially expressed genes in the pharyngeal region of mice lacking Tbx1. Dev. Biol. 285, 554–549 (2005).
  Article CAS PubMed Google Scholar
• Manley, N. R., Selleri, L., Brendolan, A., Gordon, J. & Cleary M. L. Abnormalities of caudal pharyngeal pouch development by Pbx1 knockout mice mimic loss of Hoxa3 paralogs. Dev. Biol. 276, 301–312 (2004).
  Article CAS PubMed Google Scholar
• Xu, P. X. et al. Eya1 is required for the morphogenesis of mammalian thymus, parathyroid and thyroid. Development 129, 3033–3044 (2002).
  CAS PubMed Google Scholar
• Zou, D. et al. Patterning of the third pharyngeal pouch into thymus/parathyroid by Six and Eya1. Dev. Biol. 293, 499–512 (2006).
  Article CAS PubMed Google Scholar
• Laclef, C., Souil, E., Demignon, J. & Maire, P. Thymus, kidney and craniofacial abnormalities in Six 1 deficient mice. Mech. Dev. 120, 669–679 (2003).
  Article CAS PubMed Google Scholar
• Wallin, J. et al. Pax1 is expressed during development of the thymus epithelium and is required for normal T-cell maturation. Development 122, 23–30 (1996).
  CAS PubMed Google Scholar
• Su, D. M., Ellis, S., Napier, A., Lee, K. & Manley, N. R. Hoxa3 and pax1 regulate epithelial cell death and proliferation during thymus and parathyroid organogenesis. Dev. Biol. 236, 316–329 (2001).
  Article CAS PubMed Google Scholar
• Su, D. M. & Manley, N. R. Hoxa3 and pax1 transcription factors regulate the ability of fetal thymic epithelial cells to promote thymocyte development. J. Immunol. 164, 5753–5760 (2000).
  Article CAS PubMed Google Scholar
• Peters, H., Neubuser, A., Kratochwil, K. & Balling, R. Pax9-deficient mice lack pharyngeal pouch derivatives and teeth and exhibit craniofacial and limb abnormalities. Genes Dev. 12, 2735–2747 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Hetzer-Egger, C. et al. Thymopoiesis requires Pax9 function in thymic epithelial cells. Eur. J. Immunol. 32, 1175–1181 (2002).
  Article CAS PubMed Google Scholar
• Manley, N. R. & Capecchi, M. R. The role of Hoxa-3 in mouse thymus and parathyroid development. Development 121, 1989–2003 (1995).
  CAS PubMed Google Scholar