The Role of the Autoimmune Regulator Gene in the Control of MHC II Antigen-Processing and Presentation by Medullary Thymic Epithelial Cells.

The autoimmune regulator (AIRE) gene deficiency in humans causes the autoimmune polyglandular syndrome type 1 (APS-1). AIRE contributes to self-tolerance and prevents autoimmunity via the regulation of tissue-restricted antigen (TRA) expression in medullary thymic epithelial cells (mTECs). Using a murine Aire-deficient mTEC line (Aire-/-), we previously reported that Aire regulates cell adhesion genes, affecting homotypic mTEC/mTEC and heterotypic mTEC/thymocyte interaction in vitro. Transcriptional analysis comparing AireWT with Aire-/- mTECs indicates that Aire modulates antigen processing and presentation genes. Aire-/- mTECs, but not AireWT, exhibited delayed expression of MHC II and CD74 molecules, suggesting that Aire influences the MHC II presentation pathway. However, AireWT and Aire-/- mTECs did not directly present the OVA323-339 peptide to OT-II TCR transgenic single-positive CD4+ T cells. When cocultured with splenocytes and dendritic cells, both mTEC types induce T cell activation and present the OVA323-339 peptide to OT-II TCR transgenic T cells. To further understand Aire's role in MHC II antigen processing/presentation, we evaluated the expression of the MHC II transactivator (Ciita), IFN-γ receptors and IFN-γ-induced GTPases, as well as lysosome and cathepsin L activities. After IFN-γ treatment, Aire-/- mTECs, but not AireWT, delayed the expression of Ciita. Our results suggest that Aire controls some steps of the MHC II antigen processing/presentation-related proteins.