To address the mechanisms of tolerance to extrathymic proteins, we have generated transgenic mice expressing the lymphocytlc chorlomeningltis viral (LCMV) glycoproteln (GP) in the p islet cells of the pancreas. The fate of LCMV GP-specific T cells was followed by breeding the GP transgenlc mice with T cell receptor transgenic m/w, specific for LCMV and H-2Db. These studles suggest that “peripheral tolerance” of self-reactive T ceils does not involve clonal deletion, clonal anergy, or a decrease in the density of T cell receptor3 or accessory molecules. Instead, this model indicates that self-reactive cytotoxic T cells may remain functionally unresponsive, owing to a lack of ap propriate T cell activation. Infection of transgenic mice wlth LCMV readily abolishes peripheral unresponslveness to the self LCMV GP antlgen, resulting in a CD8’T cell-mediated diabetes. These data suggest that similar mechanisms may operate in several socalled 7 cell-mediated autoimmune diseases.” introduction

Over the last several years, considerable progress has been made in understanding immunological tolerance. T cell tolerance to antigens expressed in the thymus results in clonal deletion of self-reactive cells. This has been shown using monoclonal antibodies specific for V8 gene segments (VEX) that recognize particular self determinants (y). Therefore, in animals expressing the “y” self antigen, the majority of self-reactive Vgx cells have been deleted in the thymus (Kappler et al., 1987, 1988; MacDonald et al., 1988; Pullen et al., 1988; Abe et al., 1988). Tolerance by clonal deletion to other antigens has also been demonstrated using various T cell receptor (TCR) transgenic