T he development and mechanisms of tolerance to allergens are poorly understood. Using the murine low zone tolerance (LZT) model, where contact hypersensitivity (CHS) is prevented by repeated topical low-dose applications of contact allergens, we show that LZT induction is IL-10 dependent. IL-10 is required for the generation of LZT effector cells, that is, CD8⁺ regulatory T cells. Only T cells from tolerized IL-10^+/+ mice or IL-10^–/– mice reconstituted with IL-10 during LZT induction adoptively transferred LZT to naive mice and prevented CHS, whereas T cells from IL-10^–/– mice failed to do so. The IL-10 required for normal LZT development is derived from lymph node CD4⁺ T cells, the only skin or lymph node cell population found to produce relevant amounts of IL-10 after tolerization. CD4⁺ T cells derived from IL-10^+/+ mice, but not from IL-10^–/– mice, allowed the induction of LZT in adoptively transferred T cell–deficient mice. Interestingly, IL-10 injections during tolerization greatly enhanced LZT responses in normal mice. Thus, the generation of CD8⁺ LZT effector T cells by CD4⁺ regulatory T cells via IL-10 may be a promising target of strategies aimed at preventing contact allergies and other harmful immune responses.