BREAKING IMMUNOLOGICAL IGNORANCE TO AN ANTIGENIC PEPTIDE OF SIMIAN-VIRUS-40 LARGE T-ANTIGEN

Expression of antigenic proteins in the periphery may result in immuno logic tolerance, immunologic ignorance, or autoimmunity, It is not cle ar why some Ags induce tolerance, whereas others activate Ag-reactive T cells, The physical nature of the Ag, the developmental timing of Ag expression, the priming of reactive lymphocytes, and the level of Ag expression are possible factors determining the immunologic response t o extra-thymic Ags, Expression of the whole SV40 large T Ag (SV40-T) i nduces transformation of T antigen-expressing cells in vivo, and this phenomenon has been postulated to be the triggering event that leads t o autoimmunity in some transgenic mouse models, Here we present a mode l in which a nononcogenic, yet antigenic, fragment of the SV40-T (SV40 -Tfrag) is expressed specifically in pancreatic islet beta-cells, In c ontrast to whole SV40-T transgenic mice, SV40-Tfrag mice that are also transgenic for a TCR specific for the SV40-T are ignorant of Ag in vi vo, They do not respond in vivo to the tissue-specific SV40-Tfrag Ag e ven after priming, but are fully responsive in vitro, This immunologic ignorance cannot be broken after activated SV40-T reactive T cells ar e transferred into sublethally irradiated mice expressing the islet-sp ecific SV40-Tfrag, However, similar adoptive transfer experiments in m ice co-expressing B7-1 and SV40-Tfrag on islet cells specifically lead to Ag recognition and diabetes, This demonstrates that in some circum stances the presence of (primed) reactive T cells is not sufficient to break tolerance; rather, costimulation is additionally required to el icit an autoimmune response, This also suggests that SV40-T-induced ce llular transformation is important for the autoimmune response directe d against SV40-T in other tissue-specific transgenic models.