To analyze immunoregulation of autoreactive T cells specific for epidermal skin antigens, we crossed transgenic mice expressing ovalbumin selectively in keratinocytes under the keratin 5 promoter (K5‐mOVA) with mice expressing a K^b‐restricted OVA‐specific T cell receptor transgene (OT‐I). In athymic double‐transgenic mice, OT‐I cells developed extrathymically and, at 8–12 weeks of age, initiated severe epidermal damage mimicking toxic epidermal necrolysis (TEN). In contrast, euthymic double‐transgenic mice showed thymic deletion of OT‐I cells, had few of these cells in the periphery, and never developed skin changes mimicking TEN. Adoptive transfer of OT‐I cells isolated from euthymic double‐transgenic mice induced TEN in athymic K5‐mOVA single‐transgenic mice. This spontaneous disease in athymic double‐transgenic mice was prevented by transferring lymph node cells from euthymic mice, but was not prevented when CD4⁺ or CD25⁺ cells were depleted from this population. Although purified CD4⁺CD25⁺ cells scarcely prevented the skin disease induced by adoptive transfer of OT‐I cells, they efficiently prevented the disease when co‐transferred with CD11c⁺ dendritic cells. These results suggested that thymus‐derived regulatory T cells cooperate with CD11c⁺ dendritic cells to prevent life‐threatening skin damage such as TEN.