Extra-thymically induced regulatory T cells: Do they have potential in disease prevention?

Fopx3+ Treg safeguard against autoimmune diseases and immune pathology. The extrathymic conversion of naïve T cells into Foxp3+ regulatory T cells can be achieved in vivo by the delivery of strong-agonist ligands under subimmunogenic conditions. Tolerogenic vaccination with strong-agonist mimetopes of self-antigen to promote self-antigen specific tolerance may represent the most specific and safest means of preventing autoimmunity. This review discusses the requirements for induction of dominant tolerance exerted by Foxp3+ Tregs in autoimmunity with special emphasis on their impact to interfere with T1D. The future goals are the understanding of self-non-self discrimination at the cellular and molecular level, which should then enable investigators to develop clinical vaccination protocols that specifically interfere with unwanted immune responses.

• Subimmunogenic doses of strong-agonistic TCR ligands efficiently induce Foxp3+ Treg.
• Autoantigens are recognized by autoreactive T cell receptors as weak agonists.
• Weakly-agonistic autoantigens fail to efficiently induce extrathymic Tregs.
• Subimmunogenic doses of strongly-agonistic variants of insulin prevent T1D in mice.