Aire-expressing lymph node cells

• Applicant: Professor Dr. Ludger Klein
• Subject Area: Immunology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 262976230

Mutations in the Autoimmune Regulator (Aire) gene result in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenically inherited autoimmune disease in humans. A critical tolerogenic function of the Aire protein is to promote the ectopic expression of peripheral self-antigens in medullary thymic epithelial cells (mTECs). Through this so-called promiscuous gene expression, an unexpectedly broad spectrum of self-antigens is displayed in the thymus for central T cell tolerance. It remains controversial whether and where Aire might fulfill a similar function outside the thymic microenvironment, for instance in lymph nodes. Recently, work in Aire-reporter mice resulted in the identification of a rare cell-type, so-called eTACs (extrathymic Aire-expressing cells), in lymph nodes of the mouse. These eTACs express Aire mRNA and evidence was presented that eTACs might play a role in peripheral tolerance induction. In preliminary work, we have now identified a second Aire-reporter positive cell type in lymph nodes, which is phenotypically clearly distinct from eTACs. The Aire-LNCs (for Aire expressing lymph node cells) appear to be a novel type of hematopoietic MHC class II-positive antigen presenting cell (APC). Importantly, Aire protein is readily detectable in Aire-LNCs, whereas we could not find Aire protein in eTACs. Furthermore, we have obtained evidence indicating that Aire-LNCs express peripheral antigens in a similar manner as mTECs, and preliminary results suggest that Aire-LNCs are involved in the induction of peripheral tolerance. In the present proposal, we want to (i) clarify the cellular identity of Aire-LNCs, (ii) characterize the Aire-dependent genetic program in Aire-LNCs and (iii) address the function of Aire-LNCs as a novel type of tolerogenic APC in the lymph node.

• DFG Programme: Research Grants