Abstract
Abstract Type I Diabetes (T1D) is a T cell-mediated autoimmune disease that destroys insulin producing β cells found within the pancreatic islets of Langerhans. Insulin and Chromogranin A (ChgA) are the only currently known β cell antigens (βAg) necessary to initiate autoimmune diabetes in the non-obese diabetic (NOD) mice; however, expression of ChgA within medullary thymic epithelial cells (mTECs) has not yet been detected. Therefore, tolerance to ChgA may be due in part to peripheral dendritic cells (DCs) presenting ChgA to developing thymocytes and naïve T cells. For example, post-translational modification (PTM) of ChgA by fusion with an insulin peptide increases epitope immunogenicity by forming the neo-antigen, insulin-ChgA fusion peptide (2.5HIP). Pathogenic T cells that are specific for 2.5HIP, which is uniquely expressed in the pancreas, may escape thymic selection due to immunologic ignorance. The relative contribution of thymic and peripheral derived Ag in the selection of βAg specific CD4+ T cells and regulatory T cells (Tregs) remains unclear. To test the role of peripheral Ag exposure on thymic development of βAg specific Tregs, we generated a 50:50 mixed bone marrow chimera using NOD WT (CD45.2 × CD45.1) and BDC2.5 TCR Tg (CD45.1) bone marrow to study the role of peripheral DCs (CD45.2) on developing ChgA T cells. Next, we targeted thymic Langerin+ DCs with anti-Langerin linked to ChgA peptides in BDC2.5 TCR Tg mice. In both experiments, we found robust increase in the ratio and number of ChgA specific Tregs in the presence of the 2.5HIP, in adult and neonatal mice. The results suggest thymic exposure to PTM peptides by DCs enhances β cell specific Treg development and may alter T1D pathogenesis.
Published Version
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