Project B11 - Mechanisms of immune activation vs. tolerance in autoimmune Type 1 diabetes
Foxp3+ regulatory T (Treg) cells are involved in autoimmune Type 1 diabetes (T1D), and they may play an important role during the preceding period of islet autoimmunity (pre-T1D) that is then followed by a progressive loss of self-tolerance to insulin-producing beta cells. In immunodeficient humanized HLA-DQ8 NOD-Scid-Il2RgKO mice without autoimmune activation we demonstrated efficient human insulin-specific Foxp3+ Treg cell induction using strong-agonistic human insulin-mimetopes in vivo, while those with autoimmune activation presented with reduced Treg cell frequencies and increased human T cell infiltration in the pancreas. Using Treg cells from NOD mice with very early islet autoimmunity (onset below 30 days of age) or from children with a fast progression to clinical T1D, we identified impairments in Treg cell stability by analyses of the methylation status of the Foxp3 ‘conserved noncoding sequence 2‘ (CNS2). These findings point to a potential causative role of Treg cell instability in promoting autoimmune activation and progression. Here, we aim to investigate Treg cell instability during murine and human early onset islet autoimmunity as well as to test the hypothesis that Treg cell instability is evident in individuals with organ-specific autoimmunity.
