The function of murine dendritic epidermal cells (dEC) remains largely speculative, probably because of the lack of a suitable in vivo model, although previous studies suggest that gamma/delta+ dEC may have originally evolved to serve as a self-protection mechanism(s). Our previous study demonstrated that the epidermis of mice that had spontaneously recovered from cutaneous graft-vs-host disease (GVHD) induced by local injection of CD4+ autoreactive T cells contained unexpectedly large numbers of dEC and became resistant to subsequent attempts to induce GVHD in a site-restricted manner, suggesting that the resistance is mediated by dEC. However, because alpha/beta+ dEC as well as gamma/delta+ dEC were greatly increased in number in the epidermis, it was unclear whether gamma/delta+ dEC are indeed responsible for this protection. The availability of this murine model and mice selectively lacking gamma/delta T cells as a result of disruption of the T cell receptor C delta gene segment allowed us to investigate the role of gamma/delta+ dEC. In the epidermis of gamma/delta T cell-deficient mice (delta-/-), a congenital lack of gamma/delta+ dEC was substituted for by alpha/beta+ dEC of either a CD4-8+ or a CD4-8- phenotype. After intradermal injection of the autoreactive T cells, delta-/- mice developed significantly enhanced delayed-type hypersensitivity responses and cutaneous GVHD, which persisted longer than in heterozygous littermate controls (delta+/-). Surprisingly, resistance to the cutaneous GVHD was not induced in the epidermis of delta-/- mice after spontaneous recovery from the GVHD, whereas the "susceptible" epidermis of delta-/+ mice contained large numbers of alpha/beta dEC comparable to those in "resistant" epidermis of delta+/- mice. Injection of day 16 fetal thymocytes from wild-type mice into delta-/- mice resulted in the appearance of donor-type gamma/delta+ dEC in the epidermis, and reconstitution with gamma/delta+ dEC restored the protective immune response of the epidermis against the GVHD to nearly normal levels. These results indicate that gamma/delta+ dEC are responsible for the site-restricted protection against cutaneous GVHD.

T cells found within the epidermis in inflammatory dermatoses are generally accepted as making a major contribution to epidermal damage. On the other hand, those T cells residing in the murine epidermis are supposed to play an important role in protecting the epidermis from potentially dangerous immune reactions. Overwhelming evidence has accumulated that dendritic epidermal T cells (DETC) expressing monomorphic TCR gammadelta are responsible for the protection of epidermal structures against skin tumor, bacterial infection, and autoimmune attack. In animals congenitally lacking these gammadelta+ DETC, the epidermis is populated with bone marrow-derived TCR alphabeta+, CD8+ DETC. Although it remains unclear whether this subset of DETC could home to the epidermis to substitute for the physiologic function of gammadelta+ DETC or whether they would be pathologically relevant to epidermal injury, it should be noted that this subset represents the major fraction of T cells present in normal human epidermis and the most abundant in the lesional epidermis of fixed drug eruption (FDE). Because they are shown to kill target cells including keratinocytes upon stimulation and utilize a very limited range of TCR V alpha and Vbeta gene families, localized epidermal injury in FDE lesions would be mediated by activation of these epidermal T cells with autoaggressive potential. Epidermal T cells are thus likely to form several T-cell populations with different immunologic functions that are triggered by different modes of stimulation. Immune homeostasis in the epidermis would rely on a delicate balance between at least two types of epidermal T cells: autoaggressive T cells and protective T cells.

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Skin is known to be one of the worst affected target organs in graft-versus-host disease (GVHD)' (1). The cutaneous lesions are characterized by the epidermal cell death in association with a prominent T cell infiltrate (2). It is therefore thought that the cutaneous lesions occur as the result of a T cell-mediated immune attack on epidermal cells, either directly or via the release of various cytokines from the T cells, although the problem of whether the T cells toward the epidermal antigens cause these lesions has been still unclear (3). While much attention has been directed to effector T cells capable of mediating GVHD, almost nothing is known about the mechanism(s) by which the integrity oforgan structures can be protected from such a T cell-mediated immune attack in GVHD. This is due, in part, to a difficulty in producing experimental models of GVHD to be able to investigate the protection mechanism(s) .We have recently demonstrated that cutaneous GVHD, resembling lichen planus and lupus erythematosus in humans, can be induced in normal mice by intradermal inoculation into the footpads of cloned, autoreactive CD4+ T cells with cytolytic activity (4-6). The experimentally induced cutaneous GVHD is basically composed oftwo types of reactions: delayed-type hypersensitivity (DTH) reactions and epidermal cell damage defined histologically. DTH responses measurable by footpad swelling peaks at 24-48 h and then gradually recedes (5). Histologically, the DTH responses are characterized by the diffuse infiltration ofmononuclear cells and prominent edema in the dermis . In contrast, epidermal lesions characterized by the severe infiltration of T cells associated with the consequent epidermal cell damage reach maximum ' Abbreviations used in this paper: DTH, delayed-type hypersensitivity ; GVHD, graft-vs .-host disease; PLN, popliteal lymph node ; Thy-1 + EC, Thy-1 + epidermal cells. J. Exp. Men.