Tumor specific CD8+ T-cells are important in eliciting tumor rejection in the skin, however, in some cases the tumor microenvironment is able to render them dysfunctional. Regulation of CD8+ T-cell responses in the tumor microenvironment is poorly understood. Using a skin grafting model, we aimed to explore the mechanisms involved in the regulation of CD8+ T-cells in the skin microenvironment. Highly purified adjuvant-activated CD8β+ T-cells were introduced into RAG1KO mice to assess CD8+ T-cell deregulation in the absence of conventional T-cells. Autoimmune mediated deregulation of CD8+ T-cell in the ear skin occurred approximately 37 days post CD8β+ T-cells transfer when co-administrated with CD4-depleting antibody. Transfer of activated CD8β+ T-cells alone did not lead to the development of CD8+ T-cell deregulation. The timing of the destruction suggests that the CD4-expressing cell exerts regulation over a CD8+ T-cell memory response. Preliminary assessment revealed immune infiltrates were confined to the skin and cervix, suggesting that the target antigen(s) may be restricted to stratified squamous epithelium. CD4-depleting antibody treatment led to increased numbers of CD8+ T-cells in the skin. Flow-cytometry of lymph nodes 30 days post CD8β+ T-cell transfer showed no evidence of classical CD4+FoxP3+ regulatory T-cells (Treg) indicating regulation is mediated by a separate, distinct cell type. As yet unidentified CD4+expressing cells were observed in RAG1KO skin by immunofluorescent staining. Using gene-knockout mice as a source of donor CD8+ T-cells, it was established that interferon-gamma was a key mediator of destruction, but not interleukin-17 or perforin. The data suggests that the removal of a CD4+ expressing regulatory cell leads to the breakdown in peripheral tolerance resulting in CD8+ T-cell mediated skin destruction. We plan to use our established model to identify the CD4+ expressing cells, which are distinct from classical Treg, and mediate a regulatory influence on CD8+ T-cell function in the skin.