Aire-dependent thymic FoxP3+ regulatory T cells in Type 1 Diabetes

Abstract

Abstract Aire expression within the specialized mTECs has been found to be important for enforcing negative selection of T cells, however, mounting evidence has demonstrated the importance of Aire in Treg differentiation and development. Autoimmune diseases like T1D arise from the failure to restrain immune responses against self. Utilizing a novel mouse model, where the Aire locus drives the selected expression of the high affinity DT receptor, revealed a significant reduction in the number of FoxP3+ Tregs within the thymus following treatment. Thus, we hypothesize that alterations in the thymic self-antigen expression and presentation via ablation of Aire-expressing mTECs, will affect the repertoire and function of Aire-dependent FoxP3+ Tregs. New high-throughput platforms and single-cell DNA barcoding technology will allow us to assess several thousand individual Tregs that have undergone Aire-dependent selection in the thymus. The identification of these unique clones and gene signatures will be further interrogated retrogenically, allowing for qualitative assessment of their function within the model of T1D. The antigen specificities of the Aire-dependent TCRs will be assessed via screening against peptide libraries using MHCII molecule strongly associated with NOD mouse T1D. We anticipate identification of novel sequences that are recognized by Tregs, which may lead to discovery of new self-peptides that contribute to T1D. Our proposed study aims to expand our knowledge on TCR repertoire of Aire-dependent FoxP3+ Tregs and the antigen-specificity in T1D, improving our understanding of the respective function of thymic-derived antigen-specific Treg suppression in peripheral tissues associated with autoimmune T1D.