Type 1 Diabetes Immunological Tolerance

Autoimmune Type 1 diabetes is characterized by the loss of self-tolerance to insulin-producing beta cells in the pancreas. Self-antigen specific tolerance strategies that mobilize the body´s own safeguards (regulatory T cells that suppress self-reactive T cells) are required for safe and specific prevention of Type 1 diabetes.

Fopx3+ regulatory T (Treg) cells function as an essential cellular constituent of the immune system in order to maintain immunological self-tolerance. T cell receptor ligation is required for the differentiation of Foxp3+ Treg cells, a process, which can be induced intra- or extrathymically.

We established that extrathymic induction of Foxp3+Treg cells can be best achieved in vivo by the delivery of strong-agonistic T cell receptor ligands under subimmunogenic conditions, avoiding strong activation of T cells and antigen-presenting cells. In contrast, weak agonistic ligands fail to induce stable Foxp3+ Treg cells irrespective of the applied dose.

In mouse models of Type 1 diabetes we found that the weak-agonistic properties of the critical autoantigen insulin (insulin beta chain peptides) result in poor differentiation of naïve insulin-specific T cells into Foxp3+ Treg cells. A strong-agonistic variant of the insulin beta chain peptide (insulin mimetope) was suited to efficiently generate insulin-specific Foxp3+ Treg cells in vivo.

Based on findings in the mouse system, here we are interested in investigating the role of self-antigen presentation and recognition for the induction of human Foxp3+ Treg cells. In addition, we are studying critical factors involved in the regulation of T cell activation in order to characterize their impact on the generation and function of Foxp3+Treg cells in vivo.

The studies aim at improving the understanding of Treg differentiation at the cellular and molecular level with the goal to facilitate the future development of Treg induction strategies in order to combat unwanted immunity such as Type 1 diabetes.