CD4+ CD25+ Foxp3+ regulatory T cells (Treg) are natural suppressors of autoimmunity but they can also dampen the effective clearance of infectious organisms. These cells have the potential to be exploited to prevent transplant rejection and to treat autoimmune disease. A paper in this issue of the European Journal of Immunology details a method to selectively expand antigen-specific Treg from a polyclonal Treg population, by using a specific dendritic cell (DC) subset. Furthermore, the authors show that such Treg can be used to prevent experimental type I diabetes; however, as Treg are positively selected by thymic epithelial cells (TEC) on the basis of self-reactivity, they would systematically suppress protective immune responses unless their repertoire is devoid of recognition towards peripheral antigen-presenting cells. This may be achieved by negative selection of developing Treg on thymic DC, thus creating a 'blind-spot' corresponding to DC-self-antigens in the mature Treg repertoire. Therefore, therapeutic use of DC subsets for the expansion of rare Treg populations should take into account this blind-spot, as peptides that are not accessible to thymic DC may be significantly more effective for the expansion of Treg.