title: Detection of an autoreactive T-cell population within the polyclonal repertoire that undergoes distinct autoimmune regulator (Aire)-mediated selection.
abstract: The autoimmune regulator (Aire) plays a critical role in central tolerance by promoting the display of tissue-specific antigens in the thymus. To study the influence of Aire on thymic selection in a physiological setting, we used tetramer reagents to detect autoreactive T cells specific for the Aire-dependent tissue-specific antigen interphotoreceptor retinoid-binding protein (IRBP), in the polyclonal repertoire. Two class II tetramer reagents were designed to identify T cells specific for two different peptide epitopes of IRBP. Analyses of the polyclonal T-cell repertoire showed a high frequency of activated T cells specific for both IRBP tetramers in Aire(-/-) mice, but not in Aire(+/+) mice. Surprisingly, although one tetramer-binding T-cell population was efficiently deleted in the thymus in an Aire-dependent manner, the second tetramer-binding population was not deleted and could be detected in both the Aire(-/-) and Aire(+/+) T-cell repertoires. We found that Aire-dependent thymic deletion of IRBP-specific T cells relies on intercellular transfer of IRBP between thymic stroma and bone marrow-derived antigen-presenting cells. Furthermore, our data suggest that Aire-mediated deletion relies not only on thymic expression of IRBP, but also on proper antigen processing and presentation of IRBP by thymic antigen-presenting cells.
authors.affiliation: Diabetes Center, University of California, San Francisco, CA 94143, USA.
authors.forename: Ruth T
authors.initials: RT
authors.lastname: Taniguchi
authors.forename: Jason J
authors.initials: JJ
authors.lastname: DeVoss
authors.forename: James J
authors.initials: JJ
authors.lastname: Moon
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Marc K
authors.initials: MK
authors.lastname: Jenkins
authors.forename: Mark S
authors.initials: MS
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D017637:Clonal Deletion / Q000235:genetics / Q000276:immunology*; D005136:Eye Proteins / Q000276:immunology* / Q000378:metabolism; D007114:Immunization; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012177:Retinol-Binding Proteins / Q000276:immunology* / Q000378:metabolism; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*; D014605:Uveitis / Q000276:immunology* / Q000473:pathology; D000096927:AIRE Protein; D000099214:Retinol-Binding Proteins, Interstitial
chemical_list: D005136:Eye Proteins; D012177:Retinol-Binding Proteins; D014157:Transcription Factors; D000096927:AIRE Protein; D000099214:Retinol-Binding Proteins, Interstitial