Extrathymic generation of regulatory T cells--chances and challenges for prevention of autoimmune disease.

Fopx3(+) expressing regulatory T cells (Tregs) function as an indispensable cellular constituent of the immune system by establishing and maintaining immunological self-tolerance. T cell receptor (TCR) ligands of high agonist activity, when applied in vivo under subimmunogenic conditions, convert naive but not activated T cells into stable Tregs expressing Foxp3. Tolerogenic vaccination with strong-agonist mimetopes of self-antigens may function as a safe and highly specific instrument in the prevention of autoimmune disease by promoting self-antigen-specific tolerance. In this review, we address the requirements for generation of dominant tolerance exerted by Foxp3(+) Tregs in autoimmune disease with special focus on type 1 diabetes (T1D). Further understanding of differentiation of T cells into Tregs at the cellular and molecular level will facilitate development of additional tolerogenic vaccination strategies that can be used in prevention as well as therapeutically to combat unwanted immunity.