As evidence accumulated that intraepidermal T-cell activation was important in psoriasis, 2 important questions arose. First, were CD4+ and CD8+ T cells both involved in the immune reaction? Second, what was the identity of the inciting agent that triggered T-cell activation? Initial attempts to answer the first question were approached by immunohistochemical staining of biopsy specimens obtained from early, late, and resolving lesions. Conflicting results were obtained, with some investigators observing an initial influx of CD4+ T cells and others finding early infiltration by CD8+ T cells.16- 20 Likewise, when psoriatic plaques were examined after administration of various treatments, the resolving lesions were characterized by prominent reductions in CD4+ and/or CD8+ T cells from the epidermis.9- 11,21- 23 In contrast to these divergent observations, there is more of a consensus that cytokine production by activated T cells resembles a T-helper type-1 profile with interferon gamma (IFN-γ) and interleukin (IL) 12, but not IL-4, IL-5, or IL-10.24,25 To resolve the dilemma regarding relative roles for CD4+ and CD8+ T cells, engrafted PN skin was separately injected with highly purified CD4+ or CD8+ T-cell lines. On one hand, results appeared relatively straightforward: injection of autologous activated CD4+ T cells produced psoriatic plaques, whereas none of the CD8+ T cells produced psoriasis in 5 different patients.26 However, as we examined engrafted skin after introduction of CD4+ T cells, it became apparent that the story was more complex, as the intraepidermal T-cell population displaying acute activation markers such as CD25 (a high-affinity IL-2 receptor) and CD69 included CD8+ cells.27 The experimental result agreed with a recent report finding epidermal-derived activated CD8+ T cells in plaques.28 Thus, we concluded that the injection of CD4+ T cells created an appropriate microenvironment in which dormant intraepidermal CD8+ T cells already present in PN skin became activated following receipt of a "help" signal from CD4+ T cells. The precise nature of this help message is under investigation. Tumor immunologists have also pondered the nature of help signals, and this long-standing question has been recently answered.29 When CD4+ T cells become activated, they express CD40L, which can then interact with antigen-presenting cells (APCs) expressing CD40 to embue them with enhanced APC function, particularly by up-regulating costimulatory molecules such as CD80 (B7-1) and CD86 (B7-2). Following recognition of tumor antigens on activated APCs, cytotoxic CD8+ T cells can then attack and destroy tumor cells. Figure 2 portrays an overview of a dynamic immunologic model for psoriasis highlighting sequential interactions involving CD4+ T cells, dendritic APCs, and CD8+ T cells.