A dogma of immunological tolerance has been established with transgenic mice using keratin promoters, which express neoantigens, not only in thymic epithelial cells, but also in epidermal cells in the periphery. In this study we focused on the peripheral tolerance to desmgolein 3 (Dsg3), the autoantigen in pemphigus vulgaris, and investigated the fate of Dsg3-specific T cells in two different settings. One is a thymus-transplanted chimeric model, in which Dsg3-/- thymus was transplanted to nude mice to create a unique condition where Dsg3 is expressed not in thymus but in the periphery. Then bone-marrow cells were transferred from Dsg3-specific TCR transgenic (Dsg3H1-Rag2-/-) mice to the chimeric mice. Dsg3-specific CD4+ T (Dsg3H1T) cells fully developed in the Dsg3-/- thymus, whereas the number of Dsg3H1T cells was significantly reduced in the spleen and lymph nodes of the chimeric mice when compared with Dsg3-/- recipient mice. The other is an adoptive transfer model of peripheral T cells from Dsg3H1-Dsg3-/- mice, in which Dsg3H1T cells exist in the periphery, to wild type mice. CSFE-labeled Dsg3H1T cells first proliferated on day 3, but sequentially disappeared on day 14. These models indicate the deletion of Dsg3-specific T cells in the peripheral lymphoid organs. Considering importance of antigen-presenting cells (APCs) in the deletion mechanism, we used CCR7-/- mice as recipients for further analysis, where CCR7-dependent migration of APCs is disturbed. In CCR7-/- recipients, Dsg3H1T cells showed only limited proliferation on day 3 and remained on day 14, indicating that CCR7 is critically involved in the process. To summarize these results, the skin as a peripheral tissue harbors a mechanism regulated by CCR7 to prevent harmful response of autoimmune T cells. This experimental model provides a useful tool to dissect the detailed mechanism of peripheral tolerance.