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Coupling of ovalbumin (OVA) to anti–DEC-205 monoclonal antibody (mAb) (αDEC) induced the proliferation of OVA-specific T cells in vivo. Expansion was short-lived, caused by dendritic cells (DCs), and rendered T cells anergic thereafter. Phenotypic analysis revealed the induction of CD25⁺/CTLA-4⁺ T cells suppressing proliferation and interleukin-2 (IL-2) production of effector CD4⁺ T cells. The findings were supported by 2 disease models: (1) CD4⁺ T-cell–mediated hypersensitivity reactions were suppressed by the injection of αDEC-OVA and (2) the application of hapten-coupled αDEC-205 reduced CD8⁺ T-cell–mediated allergic reactions. Thus, targeting of antigens to immature DCs through αDEC antibodies led to the induction of regulatory T cells, providing the basis for novel strategies to induce regulatory T cells in vivo.