title: Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity.
abstract: Medullary thymic epithelial cells (mTECs) are specialized for inducing central immunological tolerance to self-antigens. To accomplish this, mTECs must adopt a mature phenotype characterized by expression of the autoimmune regulator Aire, which activates the transcription of numerous genes encoding tissue-restricted self-antigens. The mechanisms that control mature Aire(+) mTEC development in the postnatal thymus remain poorly understood. We demonstrate here that, although either CD4(+) or CD8(+) thymocytes are sufficient to sustain formation of a well-defined medulla, expansion of the mature mTEC population requires autoantigen-specific interactions between positively selected CD4(+) thymocytes bearing autoreactive T cell receptor (TCR) and mTECs displaying cognate self-peptide-MHC class II complexes. These interactions also involve the engagement of CD40 on mTECs by CD40L induced on the positively selected CD4(+) thymocytes. This antigen-specific TCR-MHC class II-mediated crosstalk between CD4(+) thymocytes and mTECs defines a unique checkpoint in thymic stromal development that is pivotal for generating a mature mTEC population competent for ensuring central T cell tolerance.
authors.affiliation: University of Geneva Medical School, CMU, 1 Rue Michel-Servet, CH-1211, Geneva, Switzerland.
authors.forename: Magali
authors.initials: M
authors.lastname: Irla
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Hugues
authors.forename: Jason
authors.initials: J
authors.lastname: Gill
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nitta
authors.forename: Yu
authors.initials: Y
authors.lastname: Hikosaka
authors.forename: Ifor R
authors.initials: IR
authors.lastname: Williams
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Hubert
authors.forename: Hamish S
authors.initials: HS
authors.lastname: Scott
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Takahama
authors.forename: Georg A
authors.initials: GA
authors.lastname: Holländer
authors.forename: Walter
authors.initials: W
authors.lastname: Reith
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000276:immunology / Q000378:metabolism; D017634:Self Tolerance; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015534:Trans-Activators / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism*; D000096927:AIRE Protein
chemical_list: D001324:Autoantigens; D019013:CD40 Antigens; D023201:CD40 Ligand; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000096927:AIRE Protein; C083728:MHC class II transactivator protein