Decoding the role of Aire-expressing Thetis cells in peripheral self-tolerance

About This Grant

PROJECT SUMMARY Establishing and maintaining immune tolerance to self-antigens is vital to prevent destructive autoimmune inflammation. Within the thymus, Aire plays a critical role in establishing self-tolerance, acting within medullary thymic epithelial cells (mTECs) to promote ectopic expression of tissue-restricted antigens which in turn leads to deletion of self-reactive T cells and generation of regulatory T (Treg) cells. However, a significant proportion of self-reactive T cells escape deletion in the thymus. A central unresolved question is how these self-reactive T cells are restrained within the periphery. To this end, we recently uncovered a novel lineage of antigen- presenting cells, named Thetis cells (TC), comprising four distinct subsets (TC I-IV). Our work thus far has demonstrated an essential role for TCs in extra-thymic Treg generation and tolerance to commensal and dietary antigens within the intestine. These studies established the tolerogenic potential of TCs. Whether and how TCs also regulate peripheral tolerance to self-antigens remain open questions. In a remarkable parallel, we found that TC I and Aire+ mTECs share a core transcriptional program that includes Aire and are critically dependent on the same transcription factors. These findings raise the tantalizing possibility that Aire+ TCs and Aire+ mTECs have shared immune regulatory functions. We hypothesize that Aire+ TCs restrain self-reactive T cells within the periphery through the expression of tissue-restricted self-antigens and immune-regulatory molecules. In the proposed project, we will determine i) the role of Aire+ TCs and extra-thymic Aire in peripheral immune tolerance, and ii) the molecular mechanisms by which Aire+ TCs mediate immune tolerance. Our preliminary data has established symmetry between Aire+ mTECs and Aire+ TCs and demonstrated the power of parallel analyses of these two cell types. In each aim, we will use novel genetic models and advanced computational approaches to address the Aire-dependent and independent functions of mTECs and TCs. In Aim 1 we will determine the role of Aire+ TC I in peripheral self-tolerance during steady- state and upon inflammation. In aims 2 and 3, we will address the mechanisms by which Aire+ TC I and mTECs regulate T cell tolerance, testing two non-mutually exclusive scenarios: expression of a ‘tolerogenic’ program that endows both Aire+ mTECs and TC I with the ability to induce T cell tolerance upon antigen presentation (Aim 2), and Aire-dependent regulation of tissue-restricted self-antigen expression (Aim 3). We anticipate that these studies will reveal fundamental mechanisms of immune tolerance and establish a new framework for self-tolerance. Elucidation of the role of TCs in peripheral immune tolerance will pave the way towards therapeutic manipulation of TCs with relevance to a broad range of autoimmune and inflammatory diseases.