Significance and regulatory mechanisms of Fas/Fas L expression in the process of epidermal injury mediated by T cells

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We previously established a murine model for cutaneous graft-versus-host disease (GVHD) in which selective destruction of epidermal structures can be induced by local injection of αβィイD1+ィエD1, CD4ィイD1+ィエD1 autoreactive T cells capable of invading and destroying the epidermis in a site-restricted manner. In this custaneous GVHD, the epidermis spontaneously recovered from the destruction became resistant to subsequent attempt to induce the GVHD. In this study, we asked whether Fas/Fas L interactions could be involved in the induction of the GVHD and the subsequent induction of the resistance to the custaneous GVHD.1. Our immunohistochemical studies and PCR analyses demonstrated that Fas antigen was expressed on keratinocytes in the lesional epidermis during the cutaneous GVHD and after spontaneous recovery; and Fas L-bearing keratinocytes were also observed during the GVHD but not after spontaneous recovery. The injected autoreactive T cells were found to express both Fas and Fas L at bo … More th time points. These expression was confirmed at protein and mRNA levels.2. We next investigated whether the GVHD and the subsequent resistance after recovery could be induced in lpr and gld mice which have been shown to have defects in the genes encoding Fas and Fas L, respectively. Although the GVHD was also induced in B6 lpr/lpr mice, the grade was much less prominent than control mice. Of interest was that the resistance was never induced in those lpr mice after spontaneous recovery. In contrast, the ability to induce GVHD and the resistance was not impaired in these gld mice.3. We next asked whether monoclonal antibodies (mAb) to Fas L could affect the course of GVHD and the induction of the resistance. Injection with anti-Fas L mAb marginally inhibited the induction of GVHD, while the induction of the resistance was totally prevented by injection of anti-Fas L mAb. These results indicate that Fas/Fas L interactions play an important role in inducing the GVHD resistance rather than inducing GVHD and that Fas expression on lesional keratinocytes serves to allow their destruction by Fas L-bearing autoaggressive T cells. Less