Advertisement

Immunologic Research

, Volume 54, Issue 1–3, pp 177–190 | Cite as

Thymic epithelial cells: antigen presenting cells that regulate T cell repertoire and tolerance development

  • Konstantina AlexandropoulosEmail author
  • Nichole M. Danzl
Immunology at Mount Sinai

Abstract

During thymocyte development bone marrow-derived precursors in the thymus undergo a series of differentiation steps to produce self-tolerant, mature T lymphocytes. The thymus contains two functionally distinct anatomical compartments, consisting of a centrally located medulla surrounded by the thymic cortex. These compartments in turn are comprised of two major cellular components: (1) the T lymphoid compartment of developing thymocytes and (2) the thymic stroma consisting mainly of thymic epithelial cells (TECs). These epithelial cells are further separated into cortical and medullary TECs (cTECs and mTECs) based on their localization within the thymic cortex or medulla respectively. Reciprocal interactions between thymocytes and epithelial cells are required for the development of both cellular components into a functional thymic organ. Thymocytes provide trophic factors for the development of a complex three-dimensional epithelial cell network, while epithelial cells regulate T cell development through expression and presentation of self-antigens on major histocompatibility molecules. Our work focuses on how thymic epithelial cells regulate T cell development and function and on elucidating the mechanisms of thymic epithelial cell differentiation. Here we review current knowledge and provide our own insight into the development, differentiation and antigen presenting properties of TECs. We focus specifically on how mTECs regulate T cell repertoire selection and central tolerance.

Keywords

Thymic epithelial cells (TECs) Medullary thymic epithelial cells (mTECs) T cells Tolerance Autoimmunity Self-antigens 

Notes

Acknowledgments

The authors would like to thank Dr. Yongwon Choi (University of Pennsylvania) for his kind gift of recombinant RANKL. K.A was supported by the National Institute of Allergy and Infectious Disease (NIAID) grants RO1 AI49387-01; R56 AI049387-05; R01 AI068963-01. N.M.D was supported by Columbia University’s Immunology Program training grant T32 AI007525-10 and by NIAID grant R01 AI068963-01.

References

  1. 1.
    Nitta T, et al. Thymic microenvironments for T-cell repertoire formation. Adv Immunol. 2008;99:59–94.PubMedGoogle Scholar
  2. 2.
    Ritter MA, Boyd RL. Development in the thymus: it takes two to tango. Immunol Today. 1993;14(9):462–9.PubMedGoogle Scholar
  3. 3.
    van Ewijk W, Shores EW, Singer A. Crosstalk in the mouse thymus. Immunol Today. 1994;15(5):214–7.PubMedGoogle Scholar
  4. 4.
    Boehm T, et al. Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LTbetaR. J Exp Med. 2003;198(5):757–69.PubMedGoogle Scholar
  5. 5.
    Anderson G, Jenkinson EJ. Lymphostromal interactions in thymic development and function. Nat Rev Immunol. 2001;1(1):31–40.PubMedGoogle Scholar
  6. 6.
    Lind EF, et al. Mapping precursor movement through the postnatal thymus reveals specific microenvironments supporting defined stages of early lymphoid development. J Exp Med. 2001;194(2):127–34.PubMedGoogle Scholar
  7. 7.
    Petrie HT, et al. Precursor thymocyte proliferation and differentiation are controlled by signals unrelated to the pre-TCR. J Immunol. 2000;165(6):3094–8.PubMedGoogle Scholar
  8. 8.
    Mombaerts P, et al. RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992;68(5):869–77.PubMedGoogle Scholar
  9. 9.
    Spanopoulou E, et al. Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-1-deficient mice. Genes Dev. 1994;8(9):1030–42.PubMedGoogle Scholar
  10. 10.
    Nehls M, et al. New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature. 1994;372(6501):103–7.PubMedGoogle Scholar
  11. 11.
    Bhandoola A, et al. Early T lineage progenitors: new insights, but old questions remain. J Immunol. 2003;171(11):5653–8.PubMedGoogle Scholar
  12. 12.
    Benz C, et al. The stream of precursors that colonizes the thymus proceeds selectively through the early T lineage precursor stage of T cell development. J Exp Med. 2008;205(5):1187–99.PubMedGoogle Scholar
  13. 13.
    Saint-Ruf C, et al. Analysis and expression of a cloned pre-T cell receptor gene. Science. 1994;266(5188):1208–12.PubMedGoogle Scholar
  14. 14.
    Shinkai Y, et al. Restoration of T cell development in RAG-2-deficient mice by functional TCR transgenes. Science. 1993;259(5096):822–5.PubMedGoogle Scholar
  15. 15.
    Ashton-Rickardt PG, et al. Peptide contributes to the specificity of positive selection of CD8+ T cells in the thymus. Cell. 1993;73(5):1041–9.PubMedGoogle Scholar
  16. 16.
    Takahama Y, et al. Positive selection of CD4+ T cells by TCR ligation without aggregation even in the absence of MHC. Nature. 1994;371(6492):67–70.PubMedGoogle Scholar
  17. 17.
    Allen PM. Peptides in positive and negative selection: a delicate balance. Cell. 1994;76(4):593–6.PubMedGoogle Scholar
  18. 18.
    Kyewski B, Derbinski J. Self-representation in the thymus: an extended view. Nat Rev Immunol. 2004;4(9):688–98.PubMedGoogle Scholar
  19. 19.
    Kyewski B, et al. Promiscuous gene expression and central T-cell tolerance: more than meets the eye. Trends Immunol. 2002;23(7):364–71.PubMedGoogle Scholar
  20. 20.
    Kyewski B, Klein L. A central role for central tolerance. Annu Rev Immunol. 2006;24:571–606.PubMedGoogle Scholar
  21. 21.
    Klein L, et al. Antigen presentation in the thymus for positive selection and central tolerance induction. Nat Rev Immunol. 2009;9(12):833–44.PubMedGoogle Scholar
  22. 22.
    Takahama Y, et al. Role of thymic cortex-specific self-peptides in positive selection of T cells. Semin Immunol. 2010;22(5):287–93.PubMedGoogle Scholar
  23. 23.
    Livak F, et al. Characterization of TCR gene rearrangements during adult murine T cell development. J Immunol. 1999;162(5):2575–80.PubMedGoogle Scholar
  24. 24.
    Krangel MS. Mechanics of T cell receptor gene rearrangement. Curr Opin Immunol. 2009;21(2):133–9.PubMedGoogle Scholar
  25. 25.
    Kruisbeek AM, et al. Branching out to gain control: how the pre-TCR is linked to multiple functions. Immunol Today. 2000;21(12):637–44.PubMedGoogle Scholar
  26. 26.
    Michie AM, Zuniga-Pflucker JC. Regulation of thymocyte differentiation: pre-TCR signals and beta-selection. Semin Immunol. 2002;14(5):311–23.PubMedGoogle Scholar
  27. 27.
    Starr TK, Jameson SC, Hogquist KA. Positive and negative selection of T cells. Annu Rev Immunol. 2003;21:139–76.PubMedGoogle Scholar
  28. 28.
    Carpenter AC, Bosselut R. Decision checkpoints in the thymus. Nat Immunol. 2010;11(8):666–73.PubMedGoogle Scholar
  29. 29.
    Jordan MS, et al. Thymic selection of CD4+ CD25+ regulatory T cells induced by an agonist self-peptide. Nat Immunol. 2001;2(4):301–6.PubMedGoogle Scholar
  30. 30.
    Apostolou I, et al. Origin of regulatory T cells with known specificity for antigen. Nat Immunol. 2002;3(8):756–63.PubMedGoogle Scholar
  31. 31.
    Aschenbrenner K, et al. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat Immunol. 2007;8(4):351–8.PubMedGoogle Scholar
  32. 32.
    Ignatowicz L, Kappler J, Marrack P. The repertoire of T cells shaped by a single MHC/peptide ligand. Cell. 1996;84(4):521–9.PubMedGoogle Scholar
  33. 33.
    Fukui Y, et al. Positive and negative CD4+ thymocyte selection by a single MHC class II/peptide ligand affected by its expression level in the thymus. Immunity. 1997;6(4):401–10.PubMedGoogle Scholar
  34. 34.
    Wang B, et al. A single peptide-MHC complex positively selects a diverse and specific CD8 T cell repertoire. Science. 2009;326(5954):871–4.PubMedGoogle Scholar
  35. 35.
    Oono T, et al. Organ-specific autoimmunity in mice whose T cell repertoire is shaped by a single antigenic peptide. J Clin Invest. 2001;108(11):1589–96.PubMedGoogle Scholar
  36. 36.
    Murata S, Takahama Y, Tanaka K. Thymoproteasome: probable role in generating positively selecting peptides. Curr Opin Immunol. 2008;20(2):192–6.PubMedGoogle Scholar
  37. 37.
    Murata S, et al. Regulation of CD8+ T cell development by thymus-specific proteasomes. Science. 2007;316(5829):1349–53.PubMedGoogle Scholar
  38. 38.
    Kloetzel PM. The proteasome and MHC class I antigen processing. Biochim Biophys Acta. 2004;1695(1–3):225–33.PubMedGoogle Scholar
  39. 39.
    Kloetzel PM, Ossendorp F. Proteasome and peptidase function in MHC-class-I-mediated antigen presentation. Curr Opin Immunol. 2004;16(1):76–81.PubMedGoogle Scholar
  40. 40.
    Tanaka K, Kasahara M. The MHC class I ligand-generating system: roles of immunoproteasomes and the interferon-gamma-inducible proteasome activator PA28. Immunol Rev. 1998;163:161–76.PubMedGoogle Scholar
  41. 41.
    Honey K, Rudensky AY. Lysosomal cysteine proteases regulate antigen presentation. Nat Rev Immunol. 2003;3(6):472–82.PubMedGoogle Scholar
  42. 42.
    Nakagawa T, et al. Cathepsin L: critical role in Ii degradation and CD4 T cell selection in the thymus. Science. 1998;280(5362):450–3.PubMedGoogle Scholar
  43. 43.
    Honey K, et al. 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. 2002;195(10):1349–58.PubMedGoogle Scholar
  44. 44.
    Bowlus CL, et al. Cloning of a novel MHC-encoded serine peptidase highly expressed by cortical epithelial cells of the thymus. Cell Immunol. 1999;196(2):80–6.PubMedGoogle Scholar
  45. 45.
    Carrier A, et al. Differential gene expression in CD3epsilon- and RAG1-deficient thymuses: definition of a set of genes potentially involved in thymocyte maturation. Immunogenetics. 1999;50(5–6):255–70.PubMedGoogle Scholar
  46. 46.
    Viken MK, et al. Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex. Genes Immun. 2009;10(4):323–33.PubMedGoogle Scholar
  47. 47.
    Viret C, et al. Thymus-specific serine protease contributes to the diversification of the functional endogenous CD4 T cell receptor repertoire. J Exp Med. 2011;208(1):3–11.PubMedGoogle Scholar
  48. 48.
    Viret C, et al. Thymus-specific serine protease controls autoreactive CD4 T cell development and autoimmune diabetes in mice. J Clin Invest. 2011;121(5):1810–21.PubMedGoogle Scholar
  49. 49.
    Gommeaux J, et al. Thymus-specific serine protease regulates positive selection of a subset of CD4+ thymocytes. Eur J Immunol. 2009;39(4):956–64.PubMedGoogle Scholar
  50. 50.
    Nedjic J, et al. Macroautophagy, endogenous MHC II loading and T cell selection: the benefits of breaking the rules. Curr Opin Immunol. 2009;21(1):92–7.PubMedGoogle Scholar
  51. 51.
    Munz C. Enhancing immunity through autophagy. Annu Rev Immunol. 2009;27:423–49.PubMedGoogle Scholar
  52. 52.
    Virgin HW, Levine B. Autophagy genes in immunity. Nat Immunol. 2009;10(5):461–70.PubMedGoogle Scholar
  53. 53.
    Wong AS, Cheung ZH, Ip NY. Molecular machinery of macroautophagy and its deregulation in diseases. Biochim Biophys Acta. 2011;1812(11):1490–7.PubMedGoogle Scholar
  54. 54.
    Nedjic J, Aichinger M, Klein L. Autophagy and T cell education in the thymus: eat yourself to know yourself. Cell Cycle. 2008;7(23):3625–8.PubMedGoogle Scholar
  55. 55.
    Nedjic J, Aichinger M, Klein L. A novel role for autophagy in T cell education. Autophagy. 2008;4(8):1090–2.PubMedGoogle Scholar
  56. 56.
    Nedjic J, et al. Autophagy in thymic epithelium shapes the T-cell repertoire and is essential for tolerance. Nature. 2008;455(7211):396–400.PubMedGoogle Scholar
  57. 57.
    Klein L, et al. Autonomous versus dendritic cell-dependent contributions of medullary thymic epithelial cells to central tolerance. Trends Immunol. 2011;32(5):188–93.PubMedGoogle Scholar
  58. 58.
    Derbinski J, Kyewski B. How thymic antigen presenting cells sample the body’s self-antigens. Curr Opin Immunol. 2010;22(5):592–600.PubMedGoogle Scholar
  59. 59.
    Tykocinski LO, Sinemus A, Kyewski B. The thymus medulla slowly yields its secrets. Ann N Y Acad Sci. 2008;1143:105–22.PubMedGoogle Scholar
  60. 60.
    Gotter J, et al. Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes colocalized in chromosomal clusters. J Exp Med. 2004;199(2):155–66.PubMedGoogle Scholar
  61. 61.
    Klein L, Kyewski B. Self-antigen presentation by thymic stromal cells: a subtle division of labor. Curr Opin Immunol. 2000;12(2):179–86.PubMedGoogle Scholar
  62. 62.
    Mathis D, Benoist C. Back to central tolerance. Immunity. 2004;20(5):509–16.PubMedGoogle Scholar
  63. 63.
    McCaughtry TM, Wilken MS, Hogquist KA. Thymic emigration revisited. J Exp Med. 2007;204(11):2513–20.PubMedGoogle Scholar
  64. 64.
    Klein L, Kyewski B. “Promiscuous” expression of tissue antigens in the thymus: a key to T-cell tolerance and autoimmunity? J Mol Med (Berl). 2000;78(9):483–94.Google Scholar
  65. 65.
    Klein L, et al. CD4 T cell tolerance to human C-reactive protein, an inducible serum protein, is mediated by medullary thymic epithelium. J Exp Med. 1998;188(1):5–16.PubMedGoogle Scholar
  66. 66.
    Anderson MS, et al. Projection of an immunological self shadow within the thymus by the aire protein. Science. 2002;298(5597):1395–401.PubMedGoogle Scholar
  67. 67.
    Derbinski J, et al. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol. 2001;2(11):1032–9.PubMedGoogle Scholar
  68. 68.
    Derbinski J, et al. Promiscuous gene expression patterns in single medullary thymic epithelial cells argue for a stochastic mechanism. Proc Natl Acad Sci U S A. 2008;105(2):657–62.PubMedGoogle Scholar
  69. 69.
    Mathis D, Benoist C. A decade of AIRE. Nat Rev Immunol. 2007;7(8):645–50.PubMedGoogle Scholar
  70. 70.
    Mathis D, Benoist C. Aire. Annu Rev Immunol. 2009;27:287–312.Google Scholar
  71. 71.
    Kyewski B, Peterson P. Aire, master of many trades. Cell. 2010;140(1):24–6.PubMedGoogle Scholar
  72. 72.
    Derbinski J, et al. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J Exp Med. 2005;202(1):33–45.PubMedGoogle Scholar
  73. 73.
    Org T, et al. The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EMBO Rep. 2008;9(4):370–6.PubMedGoogle Scholar
  74. 74.
    Koh AS, et al. Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity. Proc Natl Acad Sci U S A. 2008;105(41):15878–83.PubMedGoogle Scholar
  75. 75.
    Abramson J, et al. Aire’s partners in the molecular control of immunological tolerance. Cell. 2010;140(1):123–35.PubMedGoogle Scholar
  76. 76.
    Fan Y, et al. Thymus-specific deletion of insulin induces autoimmune diabetes. EMBO J. 2009;28(18):2812–24.PubMedGoogle Scholar
  77. 77.
    Giraud M, et al. An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature. 2007;448(7156):934–7.PubMedGoogle Scholar
  78. 78.
    Anderson MS, et al. The cellular mechanism of Aire control of T cell tolerance. Immunity. 2005;23(2):227–39.PubMedGoogle Scholar
  79. 79.
    Gavanescu I, et al. Loss of Aire-dependent thymic expression of a peripheral tissue antigen renders it a target of autoimmunity. Proc Natl Acad Sci U S A. 2007;104(11):4583–7.PubMedGoogle Scholar
  80. 80.
    Nagamine K, et al. Positional cloning of the APECED gene. Nat Genet. 1997;17(4):393–8.PubMedGoogle Scholar
  81. 81.
    Aaltonen J, Bjorses P. Cloning of the APECED gene provides new insight into human autoimmunity. Ann Med. 1999;31(2):111–6.PubMedGoogle Scholar
  82. 82.
    Rossi SW, et al. Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature. 2006;441(7096):988–91.PubMedGoogle Scholar
  83. 83.
    Bleul CC, et al. Formation of a functional thymus initiated by a postnatal epithelial progenitor cell. Nature. 2006;441(7096):992–6.PubMedGoogle Scholar
  84. 84.
    Irla M, Hollander G, Reith W. Control of central self-tolerance induction by autoreactive CD4+ thymocytes. Trends Immunol. 2010;31(2):71–9.PubMedGoogle Scholar
  85. 85.
    Rossi SW, et al. Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells. Blood. 2007;109(9):3803–11.PubMedGoogle Scholar
  86. 86.
    Gillard GO, Farr AG. Contrasting models of promiscuous gene expression by thymic epithelium. J Exp Med. 2005;202(1):15–9.PubMedGoogle Scholar
  87. 87.
    Gray D, et al. Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire. J Exp Med. 2007;204(11):2521–8.PubMedGoogle Scholar
  88. 88.
    Gabler J, Arnold J, Kyewski B. Promiscuous gene expression and the developmental dynamics of medullary thymic epithelial cells. Eur J Immunol. 2007;37(12):3363–72.PubMedGoogle Scholar
  89. 89.
    Klug DB, et al. Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment. Proc Natl Acad Sci U S A. 1998;95(20):11822–7.PubMedGoogle Scholar
  90. 90.
    Su DM, et al. A domain of Foxn1 required for crosstalk-dependent thymic epithelial cell differentiation. Nat Immunol. 2003;4(11):1128–35.PubMedGoogle Scholar
  91. 91.
    Blackburn CC, et al. The nu gene acts cell-autonomously and is required for differentiation of thymic epithelial progenitors. Proc Natl Acad Sci U S A. 1996;93(12):5742–6.PubMedGoogle Scholar
  92. 92.
    Corbeaux T, et al. Thymopoiesis in mice depends on a Foxn1-positive thymic epithelial cell lineage. Proc Natl Acad Sci U S A. 2010;107(38):16613–8.PubMedGoogle Scholar
  93. 93.
    Manley NR, Condie BG. Transcriptional regulation of thymus organogenesis and thymic epithelial cell differentiation. Prog Mol Biol Transl Sci. 2010;92:103–20.PubMedGoogle Scholar
  94. 94.
    Chen L, Xiao S, Manley NR. Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner. Blood. 2009;113(3):567–74.PubMedGoogle Scholar
  95. 95.
    Akiyama T, et al. The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity. 2008;29(3):423–37.PubMedGoogle Scholar
  96. 96.
    Hikosaka Y, et al. The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity. 2008;29(3):438–50.PubMedGoogle Scholar
  97. 97.
    Akiyama T, et al. Dependence of self-tolerance on TRAF6-directed development of thymic stroma. Science. 2005;308(5719):248–51.PubMedGoogle Scholar
  98. 98.
    Irla M, et al. Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity. Immunity. 2008;29(3):451–63.PubMedGoogle Scholar
  99. 99.
    Venanzi ES, et al. Lymphotoxin pathway and Aire influences on thymic medullary epithelial cells are unconnected. J Immunol. 2007;179(9):5693–700.PubMedGoogle Scholar
  100. 100.
    Alexandropoulos K, Baltimore D. Coordinate activation of c-Src by SH3- and SH2-binding sites on a novel p130Cas-related protein, Sin. Genes Dev. 1996;10(11):1341–55.PubMedGoogle Scholar
  101. 101.
    Ishino M, et al. Molecular cloning of a cDNA encoding a phosphoprotein, Efs, which contains a Src homology 3 domain and associates with Fyn. Oncogene. 1995;11(11):2331–8.PubMedGoogle Scholar
  102. 102.
    Alexandropoulos K, et al. Sin: good or bad? A T lymphocyte perspective. Immunol Rev. 2003;192:181–95.PubMedGoogle Scholar
  103. 103.
    Danzl NM, Donlin LT, Alexandropoulos K. Regulation of medullary thymic epithelial cell differentiation and function by the signaling protein Sin. J Exp Med. 2010;207(5):999–1013.PubMedGoogle Scholar
  104. 104.
    Kurts C, et al. Constitutive class I-restricted exogenous presentation of self antigens in vivo. J Exp Med. 1996;184(3):923–30.PubMedGoogle Scholar
  105. 105.
    Harbers SO, et al. Antibody-enhanced cross-presentation of self antigen breaks T cell tolerance. J Clin Invest. 2007;117(5):1361–9.PubMedGoogle Scholar
  106. 106.
    Finch PW, Rubin JS. Keratinocyte growth factor/fibroblast growth factor 7, a homeostatic factor with therapeutic potential for epithelial protection and repair. Adv Cancer Res. 2004;91:69–136.PubMedGoogle Scholar
  107. 107.
    Erickson M, et al. Regulation of thymic epithelium by keratinocyte growth factor. Blood. 2002;100(9):3269–78.PubMedGoogle Scholar
  108. 108.
    auf demKeller U, et al. Keratinocyte growth factor: effects on keratinocytes and mechanisms of action. Eur J Cell Biol. 2004; 83(11–12): 607–12.Google Scholar
  109. 109.
    Alexandropoulos K, Cheng G, Baltimore D. Proline-rich sequences that bind to Src homology 3 domains with individual specificities. Proc Natl Acad Sci U S A. 1995;92(8):3110–4.PubMedGoogle Scholar
  110. 110.
    Klint P, et al. Contribution of Src and Ras pathways in FGF-2 induced endothelial cell differentiation. Oncogene. 1999;18(22):3354–64.PubMedGoogle Scholar
  111. 111.
    Boilly B, et al. FGF signals for cell proliferation and migration through different pathways. Cytokine Growth Factor Rev. 2000;11(4):295–302.PubMedGoogle Scholar
  112. 112.
    Roux E, et al. Recovery of immune reactivity after T-cell-depleted bone marrow transplantation depends on thymic activity. Blood. 2000;96(6):2299–303.PubMedGoogle Scholar
  113. 113.
    Shlomchik WD. Graft-versus-host disease. Nat Rev Immunol. 2007;7(5):340–52.PubMedGoogle Scholar
  114. 114.
    van den Brink MR, et al. Graft-versus-host-disease-associated thymic damage results in the appearance of T cell clones with anti-host reactivity. Transplantation. 2000;69(3):446–9.PubMedGoogle Scholar
  115. 115.
    Alpdogan O, et al. Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration. Blood. 2006;107(6):2453–60.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Konstantina Alexandropoulos
    • 1
    Email author
  • Nichole M. Danzl
    • 2
  1. 1.Division of Clinical Immunology, Department of Medicine, The Immunology InstituteMount Sinai School of MedicineNew YorkUSA
  2. 2.Center for Translational ImmunologyColumbia University Medical CenterNew YorkUSA

Personalised recommendations