Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see)

The fate of developing T cells is specified by the interaction of their antigen receptors with self-peptide–MHC complexes that are displayed by thymic antigen-presenting cells (APCs). Various subsets of thymic APCs are strategically positioned in particular thymic microenvironments and they coordinate the selection of a functional and self-tolerant T cell repertoire. In this Review, we discuss the different strategies that these APCs use to sample and process self antigens and to thereby generate partly unique, 'idiosyncratic' peptide–MHC ligandomes. We discuss how the particular composition of the peptide–MHC ligandomes that are presented by specific APC subsets not only shapes the T cell repertoire in the thymus but may also indelibly imprint the behaviour of mature T cells in the periphery.

[1]  S. Weiss,et al.  MHC class II—Restricted presentation of intracellular antigen , 1991, Cell.

[2]  J. Freed,et al.  Comparison of peptides bound to spleen and thymus class II , 1993, The Journal of experimental medicine.

[3]  J. Sprent,et al.  T-cell apoptosis detected in situ during positive and negative selection in the thymus , 1994, Nature.

[4]  C. Babinet,et al.  Medullary thymic epithelial cells induce tolerance to intracellular proteins. , 1996, Journal of immunology.

[5]  V. Lotteau,et al.  CD4 T cell tolerance to nuclear proteins induced by medullary thymic epithelium. , 1996, Immunity.

[6]  J. Todd,et al.  Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus , 1997, Nature Genetics.

[7]  Camillo Ricordi,et al.  The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes , 1997, Nature Genetics.

[8]  S. Ikehara,et al.  Presence of B cell progenitors in the thymus. , 1997, Journal of immunology.

[9]  A. Grinberg,et al.  CD5 Expression Is Developmentally Regulated By T Cell Receptor (TCR) Signals and TCR Avidity , 1998, The Journal of experimental medicine.

[10]  L. Klein,et al.  CD4 T Cell Tolerance to Human C-reactive Protein, an Inducible Serum Protein, Is Mediated by Medullary Thymic Epithelium , 1998, The Journal of experimental medicine.

[11]  A. Rudensky,et al.  Cathepsin L: critical role in Ii degradation and CD4 T cell selection in the thymus. , 1998, Science.

[12]  Klaus-Armin Nave,et al.  Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells , 2000, Nature Medicine.

[13]  T. Brocker,et al.  Functional comparison of thymic B cells and dendritic cells in vivo. , 2000, Blood.

[14]  I. Weissman,et al.  B Lymphopoiesis in the Thymus1 , 2000, The Journal of Immunology.

[15]  A. Rudensky,et al.  In vivo MHC class II presentation of cytosolic proteins revealed by rapid automated tandem mass spectrometry and functional analyses , 2001, European journal of immunology.

[16]  L. Klein,et al.  Sampling of complementing self‐antigen pools by thymic stromal cells maximizes the scope of central T cell tolerance , 2001, European journal of immunology.

[17]  R. Germain,et al.  Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes , 2002, Nature.

[18]  Christoph Peters,et al.  Cathepsin L Regulates CD4+ T Cell Selection Independently of Its Effect on Invariant Chain , 2002, The Journal of experimental medicine.

[19]  B. Brors,et al.  Medullary Epithelial Cells of the Human Thymus Express a Highly Diverse Selection of Tissue-specific Genes Colocalized in Chromosomal Clusters , 2004, The Journal of experimental medicine.

[20]  B. Evavold,et al.  Modification of peptide interaction with MHC creates TCR partial agonists. , 2004, Cellular immunology.

[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]  Li Wu,et al.  Heterogeneity of thymic dendritic cells. , 2005, Seminars in immunology.

[23]  B. Bogen,et al.  Systemic Autoimmune Disease Caused by Autoreactive B Cells That Receive Chronic Help from Ig V Region-Specific T Cells1 , 2005, The Journal of Immunology.

[24]  Mark S. Anderson,et al.  Spontaneous autoimmunity prevented by thymic expression of a single self-antigen , 2006, The Journal of experimental medicine.

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

[26]  R. Bonasio,et al.  Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus , 2006, Nature Immunology.

[27]  Keiji Tanaka,et al.  Regulation of CD8+ T Cell Development by Thymus-Specific Proteasomes , 2007, Science.

[28]  C. Benoist,et al.  A decade of AIRE , 2007, Nature Reviews Immunology.

[29]  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.

[30]  X. Ke,et al.  An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus , 2007, Nature.

[31]  E. Butcher,et al.  CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease , 2008, Nature Immunology.

[32]  P. Naquet,et al.  Intercellular MHC transfer between thymic epithelial and dendritic cells , 2008, European journal of immunology.

[33]  Li Wu,et al.  Distinct functional capacities of mouse thymic and splenic dendritic cell populations , 2008, Immunology and cell biology.

[34]  J. Villadangos,et al.  Antigen-presentation properties of plasmacytoid dendritic cells. , 2008, Immunity.

[35]  K. Hogquist,et al.  Clonal deletion of thymocytes can occur in the cortex with no involvement of the medulla , 2008, The Journal of experimental medicine.

[36]  E. Caron,et al.  The MHC class I peptide repertoire is molded by the transcriptome , 2008, The Journal of experimental medicine.

[37]  B. Kyewski,et al.  Promiscuous gene expression patterns in single medullary thymic epithelial cells argue for a stochastic mechanism , 2008, Proceedings of the National Academy of Sciences.

[38]  P. Peterson,et al.  The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression , 2008, EMBO Reports.

[39]  Pärt Peterson,et al.  Transcriptional regulation by AIRE: molecular mechanisms of central tolerance , 2008, Nature Reviews Immunology.

[40]  C. Benoist,et al.  Ectopic expression of peripheral-tissue antigens in the thymic epithelium: Probabilistic, monoallelic, misinitiated , 2008, Proceedings of the National Academy of Sciences.

[41]  Or Gozani,et al.  Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity , 2008, Proceedings of the National Academy of Sciences.

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

[43]  A. Carrier,et al.  Thymus‐specific serine protease regulates positive selection of a subset of CD4+ thymocytes , 2009, European journal of immunology.

[44]  L. Klein.  Dead man walking: how thymocytes scan the medulla , 2009, Nature Immunology.

[45]  E. Unanue,et al.  Thymus-Blood Protein Interactions Are Highly Effective in Negative Selection and Regulatory T Cell Induction1 , 2009, The Journal of Immunology.

[46]  L. Klein,et al.  Antigen presentation in the thymus for positive selection and central tolerance induction , 2009, Nature Reviews Immunology.

[47]  C. Münz.  Enhancing immunity through autophagy. , 2009, Annual review of immunology.

[48]  H. Fehling,et al.  Deletion of Notch1 converts pro-T cells to dendritic cells and promotes thymic B cells by cell-extrinsic and cell-intrinsic mechanisms. , 2009, Immunity.

[49]  J. Park,et al.  Thymus-homing peripheral dendritic cells constitute two of the three major subsets of dendritic cells in the steady-state thymus , 2009, The Journal of experimental medicine.

[50]  M. Gross,et al.  An endogenous peptide positively selects and augments the activation and survival of peripheral CD4+ T cells , 2009, Nature Immunology.

[51]  B. Kyewski,et al.  The thymic medulla: a unique microenvironment for intercellular self-antigen transfer , 2009, The Journal of experimental medicine.

[52]  L. Klein,et al.  Macroautophagy, endogenous MHC II loading and T cell selection: the benefits of breaking the rules. , 2009, Current opinion in immunology.

[53]  Rainer A Böckmann,et al.  Low-affinity peptides and T-cell selection. , 2009, Trends in immunology.

[54]  J. Lafaille,et al.  TCR-dependent differentiation of thymic Foxp3+ cells is limited to small clonal sizes , 2009, The Journal of experimental medicine.

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

[56]  Doktorgrades Der Naturwissenschaften.  Autophagy in Thymic Epithelium Shapes the T cell Repertoire and is Essential for Tolerance , 2009 .

[57]  M. Davis,et al.  An endogenous positively selecting peptide enhances mature T cell responses and becomes an autoantigen in the absence of microRNA miR-181a , 2009, Nature Immunology.

[58]  A. Rudensky,et al.  Intraclonal competition limits the fate determination of regulatory T cells in the thymus , 2009, Nature Immunology.

[59]  I. Weissman,et al.  Differential contribution of chemotaxis and substrate restriction to segregation of immature and mature thymocytes. , 2009, Immunity.

[60]  L. Klein,et al.  Regulatory T cell differentiation of thymocytes does not require a dedicated antigen-presenting cell but is under T cell-intrinsic developmental control , 2009, Proceedings of the National Academy of Sciences.

[61]  M. Trucco,et al.  Thymus‐specific deletion of insulin induces autoimmune diabetes , 2009, The EMBO journal.

[62]  N. Mukaida,et al.  Tolerance against Blood-Borne Antigens in a Conventional Dendritic Cells to Central + α Crucial Contribution of Thymic Sirp , 2009 .

[63]  H. Overkleeft,et al.  Activity-based profiling reveals reactivity of the murine thymoproteasome-specific subunit beta5t. , 2010, Chemistry & biology.

[64]  C. Benoist,et al.  Aire's Partners in the Molecular Control of Immunological Tolerance , 2010, Cell.

[65]  J. Sprent,et al.  T cell receptor-dependent regulation of lipid rafts controls naive CD8+ T cell homeostasis. , 2010, Immunity.

[66]  A. Waisman,et al.  B Cells Participate in Thymic Negative Selection of Murine Auto-reactive CD4+ T Cells , 2010, PloS one.

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

[68]  Insulin Gene VNTR Genotype Associates with Frequency and Phenotype of the Autoimmune Response to Proinsulin , 2010 .

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

[70]  Keiji Tanaka,et al.  Thymoproteasome shapes immunocompetent repertoire of CD8+ T cells. , 2010, Immunity.

[71]  R. de Waal Malefyt,et al.  Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development , 2011, The Journal of experimental medicine.

[72]  E. Unanue,et al.  Functional Redundancy between Thymic CD8α+ and Sirpα+ Conventional Dendritic Cells in Presentation of Blood-Derived Lysozyme by MHC Class II Proteins , 2011, The Journal of Immunology.

[73]  A. Liston,et al.  Models of Aire-Dependent Gene Regulation for Thymic Negative Selection , 2011, Front. Immun..

[74]  Nicole R. Cunningham,et al.  T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse , 2011, The Journal of experimental medicine.

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

[76]  L. Klein,et al.  Regulatory T‐cell differentiation versus clonal deletion of autoreactive thymocytes , 2011, Immunology and cell biology.

[77]  R. Bronson,et al.  Impaired thymic tolerance to α-myosin directs autoimmunity to the heart in mice and humans. , 2011, The Journal of clinical investigation.

[78]  N. Mizushima.  Autophagy in protein and organelle turnover. , 2011, Cold Spring Harbor symposia on quantitative biology.

[79]  D. Lauffenburger,et al.  Signaling thresholds govern heterogeneity in IL-7-receptor-mediated responses of naïve CD8+ T cells , 2011, Immunology and cell biology.

[80]  E. Palmer,et al.  Signaling in thymic selection. , 2011, Current opinion in immunology.

[81]  Self-Tolerance Checkpoints in CD4 T Cells Specific for a Peptide Derived from the B Cell Antigen Receptor , 2011, The Journal of Immunology.

[82]  Scott N. Mueller,et al.  Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance. , 2011, Blood.

[83]  S. Stevanović,et al.  Insights into MHC class I antigen processing gained from large-scale analysis of class I ligands , 2011, Cellular and Molecular Life Sciences.

[84]  G. Trinchieri,et al.  Plasmacytoid dendritic cells: one-trick ponies or workhorses of the immune system? , 2011, Nature Reviews Immunology.

[85]  M. Juan,et al.  Association of an SNP with intrathymic transcription of TSHR and Graves' disease: a role for defective thymic tolerance. , 2011, Human molecular genetics.

[86]  R. Young,et al.  Aire unleashes stalled RNA polymerase to induce ectopic gene expression in thymic epithelial cells , 2011, Proceedings of the National Academy of Sciences.

[87]  L. Klein,et al.  Regulatory T cell lineage commitment in the thymus. , 2011, Seminars in immunology.

[88]  Richard T. Lee,et al.  Myocardial Infarction Triggers Chronic Cardiac Autoimmunity in Type 1 Diabetes , 2012, Science Translational Medicine.

[89]  K. Katagiri,et al.  Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus , 2012, Nature Communications.

[90]  N. Mukaida,et al.  Novel Process of Intrathymic Tumor-Immune Tolerance through CCR2-Mediated Recruitment of Sirpα+ Dendritic Cells: A Murine Model , 2012, PloS one.

[91]  O. Joffre,et al.  Cross-presentation by dendritic cells , 2012, Nature Reviews Immunology.

[92]  E. Butcher,et al.  Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance. , 2012, Immunity.

[93]  C. Hsieh,et al.  Selection of regulatory T cells in the thymus , 2012, Nature Reviews Immunology.

[94]  Mark S. Anderson,et al.  Detection of an autoreactive T-cell population within the polyclonal repertoire that undergoes distinct autoimmune regulator (Aire)-mediated selection , 2012, Proceedings of the National Academy of Sciences.

[95]  K. Hogquist,et al.  Distinct Temporal Patterns of T Cell Receptor Signaling During Positive Versus Negative Selection in Situ , 2013, Science Signaling.

[96]  B. Malissen,et al.  Highly self-reactive naive CD4 T cells are prone to differentiate into regulatory T cells , 2013, Nature Communications.

[97]  S. Jameson,et al.  Thymoproteasome subunit-β5T generates peptide-MHC complexes specialized for positive selection , 2013, Proceedings of the National Academy of Sciences.

[98]  C. Goodnow,et al.  Helios marks strongly autoreactive CD4+ T cells in two major waves of thymic deletion distinguished by induction of PD-1 or NF-κB , 2013, The Journal of experimental medicine.

[99]  Andrew J. Yates,et al.  Models of Self-Peptide Sampling by Developing T Cells Identify Candidate Mechanisms of Thymic Selection , 2013, PLoS Comput. Biol..

[100]  F. Canals,et al.  Peptides presented by HLA class I molecules in the human thymus. , 2013, Journal of proteomics.

[101]  M. Ciudad,et al.  Composition of the HLA‐DR‐associated human thymus peptidome , 2013, European journal of immunology.

[102]  R. Toes,et al.  A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis , 2013, The Journal of experimental medicine.

[103]  J. Caamaño,et al.  The thymic medulla is required for Foxp3+ regulatory but not conventional CD4+ thymocyte development , 2013, The Journal of experimental medicine.

[104]  Kristin A. Hogquist,et al.  Murine thymic selection quantified using a unique method to capture deleted T cells , 2013, Proceedings of the National Academy of Sciences.

[105]  B. Blom,et al.  Alternative splicing and differential expression of the islet autoantigen IGRP between pancreas and thymus contributes to immunogenicity of pancreatic islets but not diabetogenicity in humans , 2013, Diabetologia.

[106]  K. Rohr,et al.  Overlapping gene coexpression patterns in human medullary thymic epithelial cells generate self-antigen diversity , 2013, Proceedings of the National Academy of Sciences.

[107]  S. Lemieux,et al.  Transcriptome sequencing of neonatal thymic epithelial cells , 2013, Scientific Reports.

[108]  J. Drijfhout,et al.  Posttranslational Modification of HLA-DQ Binding Islet Autoantigens in Type 1 Diabetes , 2013, Diabetes.

[109]  M. Yuseff,et al.  How B cells capture, process and present antigens: a crucial role for cell polarity , 2013, Nature Reviews Immunology.

[110]  Ronald N Germain,et al.  T cell-positive selection uses self-ligand binding strength to optimize repertoire recognition of foreign antigens. , 2013, Immunity.

[111]  Thymic nurse cells provide microenvironment for secondary T cell receptor α rearrangement in cortical thymocytes , 2013 .

[112]  Nina Hillen,et al.  Exploring the MHC-peptide matrix of central tolerance in the human thymus , 2013, Nature Communications.

[113]  L. Klein,et al.  Macroautophagy substrates are loaded onto MHC class II of medullary thymic epithelial cells for central tolerance , 2013, The Journal of experimental medicine.

[114]  Nicholas D. Socci,et al.  Aire-Dependent Thymic Development of Tumor-Associated Regulatory T Cells , 2013, Science.

[115]  L. Meng,et al.  Autoreactive thymic B cells are efficient antigen-presenting cells of cognate self-antigens for T cell negative selection , 2013, Proceedings of the National Academy of Sciences.

[116]  O. Lantz,et al.  Analysis of APC Types Involved in CD4 Tolerance and Regulatory T Cell Generation Using Reaggregated Thymic Organ Cultures , 2013, Journal of Immunology.

[117]  B. Kyewski,et al.  Misinitiation of intrathymic MART‐1 transcription and biased TCR usage explain the high frequency of MART‐1‐specific T cells , 2014, European journal of immunology.

[118]  P. Allen,et al.  Intrinsic CD4+ T cell sensitivity and response to pathogen are set and sustained by avidity for thymic and peripheral self-pMHC , 2014, Nature Immunology.