Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance

François Xavier Hubert, Sarah A. Kinkel, Gayle M. Davey, Belinda Phipson, Scott N. Mueller, Adrian Liston, Anna I. Proietto, Ping Z.F. Cannon, Simon Forehan, Gordon K. Smyth, Li Wu, Christopher C. Goodnow, Francis R. Carbone, Hamish S. Scott*, William R. Heath

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    160 Citations (Scopus)

    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 OVAunder 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.

    Original languageEnglish
    Pages (from-to)2462-2472
    Number of pages11
    JournalBlood
    Volume118
    Issue number9
    DOIs
    Publication statusPublished - 1 Sept 2011

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