Antigen Recognition By Autoreactive Cd4+ Thymocytes Drives Homeostasis Of The Thymic Medulla

The thymic medulla is dedicated for purging the T-cell receptor (TCR) repertoire of self-reactive specificities. Medullary thymic epithelial cells (mTECs) play a pivotal role in this process because they express numerous peripheral tissue-restricted self-antigens. Although it is well known that medulla formation depends on the development of single-positive (SP) thymocytes, the mechanisms underlying this requirement are incompletely understood. We demonstrate here that conventional SP CD4+ thymocytes bearing autoreactive TCRs drive a homeostatic process that fine-tunes medullary plasticity in adult mice by governing the expansion and patterning of the medulla. This process exhibits strict dependence on TCR-reactivity with self-antigens expressed by mTECs, as well as engagement of the CD28-CD80/CD86 costimulatory axis. These interactions induce the expression of lymphotoxin α in autoreactive CD4+ thymocytes and RANK in mTECs. Lymphotoxin in turn drives mTEC development in synergy with RANKL and CD40L. Our results show that Ag-dependent interactions between autoreactive CD4+ thymocytes and mTECs fine-tune homeostasis of the medulla by completing the signaling axes implicated in mTEC expansion and medullary organization.

[1]  L. Klein,et al.  Autonomous versus dendritic cell-dependent contributions of medullary thymic epithelial cells to central tolerance. , 2011, Trends in immunology.

[2]  T. Abe,et al.  Lymphotoxin Signal Promotes Thymic Organogenesis by Eliciting RANK Expression in the Embryonic Thymic Stroma , 2011, The Journal of Immunology.

[3]  D. Voehringer,et al.  Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance , 2010, Nature Immunology.

[4]  R. Jaenisch,et al.  Beta 2-microglobulin deficient mice lack CD4-8+ cytolytic T cells. 1990. , 2010, Journal of immunology.

[5]  W. Reith,et al.  Control of central self-tolerance induction by autoreactive CD4+ thymocytes. , 2010, Trends in immunology.

[6]  Arup K. Chakraborty,et al.  The impact of negative selection on thymocyte migration in the medulla , 2009, Nature Immunology.

[7]  A. D'amico,et al.  Dendritic cells in the thymus contribute to T-regulatory cell induction , 2008, Proceedings of the National Academy of Sciences.

[8]  H. Takayanagi,et al.  The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. , 2008, Immunity.

[9]  H. Takayanagi,et al.  The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. , 2008, Immunity.

[10]  W. Reith,et al.  Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity. , 2008, Immunity.

[11]  yang-xin fu,et al.  Coordinating development of medullary thymic epithelial cells. , 2008, Immunity.

[12]  A. Aguzzi,et al.  Overexpression of lymphotoxin in T cells induces fulminant thymic involution. , 2008, The American journal of pathology.

[13]  C. Benoist,et al.  Lymphotoxin Pathway and Aire Influences on Thymic Medullary Epithelial Cells Are Unconnected1 , 2007, The Journal of Immunology.

[14]  K. Hogquist,et al.  Thymic emigration revisited , 2007, The Journal of experimental medicine.

[15]  J. Penninger,et al.  RANK signals from CD4+3− inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla , 2007, The Journal of Experimental Medicine.

[16]  L. Klein,et al.  Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells , 2007, Nature Immunology.

[17]  A. Rudensky,et al.  Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice , 2007, Nature Immunology.

[18]  L. Klein,et al.  A central role for central tolerance. , 2006, Annual review of immunology.

[19]  Mark S. Anderson,et al.  The cellular mechanism of Aire control of T cell tolerance. , 2005, Immunity.

[20]  Clemencia Pinilla,et al.  How the T Cell Repertoire Becomes Peptide and MHC Specific , 2005, Cell.

[21]  Michael J. Bevan,et al.  Central Tolerance to Tissue-specific Antigens Mediated by Direct and Indirect Antigen Presentation , 2004, The Journal of experimental medicine.

[22]  J. Bluestone,et al.  Cutting Edge: CD28 Controls Peripheral Homeostasis of CD4+CD25+ Regulatory T Cells 1 , 2003, The Journal of Immunology.

[23]  S. Scheu,et al.  Thymic Medullary Epithelial Cell Differentiation, Thymocyte Emigration, and the Control of Autoimmunity Require Lympho–Epithelial Cross Talk via LTβR , 2003, The Journal of experimental medicine.

[24]  W. Reith,et al.  Promoter IV of the Class II transactivator gene is essential for positive selection of CD4+ T cells , 2002 .

[25]  Mark S. Anderson,et al.  Projection of an Immunological Self Shadow Within the Thymus by the Aire Protein , 2002, Science.

[26]  D. Green,et al.  The Lymphotoxin-β Receptor Induces Different Patterns of Gene Expression via Two NF-κB Pathways , 2002 .

[27]  D. Green,et al.  The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-kappaB pathways. , 2002, Immunity.

[28]  L. Klein,et al.  Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self , 2001, Nature Immunology.

[29]  W. Reith,et al.  Selective Abrogation of Major Histocompatibility Complex Class II Expression on Extrahematopoietic Cells in Mice Lacking Promoter IV of the Class II Transactivator Gene , 2001, The Journal of experimental medicine.

[30]  O. Lantz,et al.  γ chain required for naïve CD4+ T cell survival but not for antigen proliferation , 2000, Nature Immunology.

[31]  G. Holländer,et al.  Stepwise development of thymic microenvironments in vivo is regulated by thymocyte subsets. , 2000, Development.

[32]  J. Bluestone,et al.  B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. , 2000, Immunity.

[33]  E. Palmer,et al.  Positive Selection Through a Motif in the αβ T Cell Receptor , 1998 .

[34]  W. Heath,et al.  Defective TCR expression in transgenic mice constructed using cDNA‐based α‐ and β‐chain genes under the control of heterologous regulatory elements , 1998, Immunology and cell biology.

[35]  E. Palmer,et al.  Positive selection through a motif in the alphabeta T cell receptor. , 1998, Science.

[36]  E. Simpson,et al.  B7-1 and B7-2 have overlapping, critical roles in immunoglobulin class switching and germinal center formation. , 1997, Immunity.

[37]  J. Miller,et al.  Constitutive class I-restricted exogenous presentation of self antigens in vivo , 1996, The Journal of experimental medicine.

[38]  K. Nakayama,et al.  Essential role for ZAP-70 in both positive and negative selection of thymocytes , 1995, Nature.

[39]  A. Singer,et al.  Crosstalk in the mouse thymus. , 1994, Immunology today.

[40]  Scott F. Smith,et al.  Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. , 1994, Science.

[41]  H. Bluethmann,et al.  Targeted disruption of the MHC class II Aa gene in C57BL/6 mice. , 1993, International immunology.

[42]  K P Lee,et al.  Differential T cell costimulatory requirements in CD28-deficient mice. , 1993, Science.

[43]  G. Anderson,et al.  MHC class II-positive epithelium and mesenchyme cells are both required for T-cell development in the thymus , 1993, Nature.

[44]  A. Hayday,et al.  Expression of The αβ T-Cell Receptor Is Necessary for The Generation of The Thymic Medulla , 1993, Developmental immunology.

[45]  S. Tonegawa,et al.  Mutations in T-cell antigen receptor genes α and β block thymocyte development at different stages , 1992, Nature.

[46]  J. Sprent,et al.  Growth of epithelial cells in the thymic medulla is under the control of mature T cells , 1992, The Journal of experimental medicine.

[47]  S. Rastan,et al.  Lymphoid development in mice congenitally lacking T cell receptor alpha beta-expressing cells. , 1992, Science.

[48]  V. Stewart,et al.  RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement , 1992, Cell.

[49]  M. Rudnicki,et al.  Mutations in T-cell antigen receptor genes alpha and beta block thymocyte development at different stages. , 1992, Nature.

[50]  A. Singer,et al.  Disorganization and restoration of thymic medullary epithelial cells in T cell receptor‐negative scid mice: Evidence that receptor‐bearing lymphocytes influence maturation of the thymic microenvironment , 1991, European journal of immunology.

[51]  R. Jaenisch,et al.  β2-Microglobulin deficient mice lack CD4−8+ cytolytic T cells , 1990, Nature.