Detection of an autoreactive T-cell population within the polyclonal repertoire that undergoes distinct autoimmune regulator (Aire)-mediated selection

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-05, Vol.109 (20), p.7847-7852
• Main Authors: Taniguchi, Ruth T, DeVoss, Jason J, Moon, James J, Sidney, John, Sette, Alessandro, Jenkins, Marc K, Anderson, Mark S
• Format: Article
• Language: English
• Subjects: AIRE Protein; Animals; Antigen presentation; Antigen processing; Antigen-presenting cells; Antigen-Presenting Cells - immunology; Antigen-Presenting Cells - metabolism; Antigens; Binding sites; Biological Sciences; Bone marrow; Cells; Clonal deletion; Clonal Deletion - genetics; Clonal Deletion - immunology; Cloning; Data processing; Epitopes; Eye Proteins - immunology; Eye Proteins - metabolism; Hybridomas; Immunization; Immunological tolerance; interphotoreceptor retinoid-binding protein; Lymph nodes; Lymphocytes T; Mice; Mice, Inbred C57BL; Mice, Knockout; Negative selection; Proteins; Reagents; Retinol-Binding Proteins - immunology; Retinol-Binding Proteins - metabolism; Rodents; Statistics, Nonparametric; Stroma; T lymphocytes; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Thymocytes; Thymus; Thymus Gland - cytology; Thymus Gland - immunology; Transcription Factors - genetics; Transcription Factors - immunology; Uveitis; Uveitis - immunology; Uveitis - pathology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1120607109

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.