Thymic Dominant Tolerance of Type 1 Diabetes

Anti-insulin autoimmunity is one of the primary forces in the initiation and progression of type 1 diabetes. Similar to the other tissue-specific antigens, insulin expression has been found in the thymus, where it is implicated in regulating the negative selection of autoreactive T-cells. To further explore the function of this ectopic insulin expression, the mouse Ins2 gene was specifically knocked out in Aire-expressing medullary thymic epithelial cells (mTECs), without affecting expression in the β-cells. When further crossed to the Ins1 knockout background, both male and female pups (designated as ID-TEC mice for insulin-deleted mTEC) developed diabetes spontaneously around three weeks after birth. β-cell specific autoimmune destruction was observed, as well as islet-specific T-cell infiltration. The presence of insulin-specific effector T-cells was demonstrated by ELISPOT assays and adoptive T-cell transfer experiments. Results from thymus transplantation experiments proved further that depletion of Ins2 expression in mTECs was sufficient to break central tolerance and induce anti-insulin autoimmunity. Indeed, insulin expression by mTECs is essential to establish central tolerance towards pancreatic β–cells. However, the role of insulin expression in antigen-presenting cells (APCs) of hematopoietic lineage remains elusive. We labeled Aire-expressing cells with enhanced yellow fluorescent proteins and found that insulin expression in the spleen was restricted predominantly to a population of Aire+CD11cintB220+ dendritic cells (DCs). Targeted insulin deletion in APCs failed to induce anti-islet autoimmunity in B6 mice. In contrast, elevated levels of T cell infiltration into islets were observed in B6g7 congenic mice when insulin was specifically deleted in their CD11c-expressing DCs (B6g7.CD11c-∆Ins mice). Thus, insulin expression in BM-derived, Aire+ tolerogenic DCs may play an essential role to prevent the activation and expansion of insulin-reactive T-cells in the periphery.