title: Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance.
abstract: To investigate the role of Aire in thymic selection, we examined the cellular requirements for generation of ovalbumin (OVA)-specific CD4 and CD8 T cells in mice expressing OVA under the control of the rat insulin promoter. Aire deficiency reduced the number of mature single-positive OVA-specific CD4(+) or CD8(+) T cells in the thymus, independent of OVA expression. Importantly, it also contributed in 2 ways to OVA-dependent negative selection depending on the T-cell type. Aire-dependent negative selection of OVA-specific CD8 T cells correlated with Aire-regulated expression of OVA. By contrast, for OVA-specific CD4 T cells, Aire affected tolerance induction by a mechanism that operated independent of the level of OVA expression, controlling access of antigen presenting cells to medullary thymic epithelial cell (mTEC)-expressed OVA. This study supports the view that one mechanism by which Aire controls thymic negative selection is by regulating the indirect presentation of mTEC-derived antigens by thymic dendritic cells. It also indicates that mTECs can mediate tolerance by direct presentation of Aire-regulated antigens to both CD4 and CD8 T cells.
authors.affiliation: Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Hubert
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Kinkel
authors.forename: Gayle M
authors.initials: GM
authors.lastname: Davey
authors.forename: Belinda
authors.initials: B
authors.lastname: Phipson
authors.forename: Scott N
authors.initials: SN
authors.lastname: Mueller
authors.forename: Adrian
authors.initials: A
authors.lastname: Liston
authors.forename: Anna I
authors.initials: AI
authors.lastname: Proietto
authors.forename: Ping Z F
authors.initials: PZ
authors.lastname: Cannon
authors.forename: Simon
authors.initials: S
authors.lastname: Forehan
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
authors.forename: Francis R
authors.initials: FR
authors.lastname: Carbone
authors.forename: Hamish S
authors.initials: HS
authors.lastname: Scott
authors.forename: William R
authors.initials: WR
authors.lastname: Heath
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000276:immunology / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D017637:Clonal Deletion / Q000276:immunology*; D003433:Crosses, Genetic; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007328:Insulin / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011828:Radiation Chimera; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000096927:AIRE Protein
chemical_list: D000941:Antigens; D016207:Cytokines; D007328:Insulin; D010047:Ovalbumin; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D000096927:AIRE Protein