[Function of Aire in central and peripheral immune tolerance]

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Context:

• Central tolerance, mediated by medullary thymic epithelial cells (mTECs), prevents autoimmunity by deleting self-reactive T cells.
• The autoimmune regulator (Aire) transcription factor is crucial for expressing tissue-specific antigens (TSAs) in mTECs for negative selection.
• The ATF7ip-MBD1 complex has been identified as a key partner for Aire in targeting TSA loci.

Purpose:

• To elucidate the detailed mechanisms by which Aire targets TSA loci for T cell deletion.
• To investigate the developmental stages of mTECs and the role of Aire in their terminal differentiation.
• To characterize extrathymic Aire-expressing cells (eTACs) and their function in peripheral tolerance.

Summary:

• Aire deletion of self-reactive T cells is essential for central tolerance.
• Aire targets TSA loci via the ATF7ip-MBD1 complex, and is required for mTEC terminal differentiation.
• Extrathymic Aire-expressing cells (eTACs) found in lymphoid organs eliminate self-reactive CD8+ T cells and induce unresponsiveness in CD4+ T cells, independent of regulatory T cells.

Impact:

• Identifies a novel role for peripheral Aire in maintaining immune homeostasis.
• Suggests that eTACs play a complementary role to central tolerance in preventing autoimmunity.
• Provides insights into the molecular mechanisms of Aire-mediated gene regulation and T cell tolerance.