ACTIVATION OF LOW AVIDITY CTL SPECIFIC FOR A SELF EPITOPE RESULTS IN TUMOR REJECTION BUT NOT AUTOIMMUNITY

To determine how self-tolerance can alter the ability of the immune sy stem to respond against tumor-associated Ags that are also expressed b y normal tissue, we designed experiments in which the same protein was expressed both as a tumor Ag and as a transgene product. Unlike conve ntional BALB/c mice that rejected renal carcinoma cells transfected wi th the influenza virus hemagglutinin (Renca-HA), transgenic mice that are tolerant of HA due to its expression as a self-Ag on pancreatic is let beta cells, (Ins-HA mice) supported progressive growth of these tu mor cells. However, when Ins-HA mice were immunized with a recombinant strain of vaccinia virus expressing the dominant H-2K(d) peptide epit ope of HA before receiving Renca-HA cells, they too were able to rejec t the tumor cells. Rejection of Renca-HA cells by immunized Ins-HA mic e was found to be associated with the generation of CTL having much lo wer avidity for target cells presenting the K(d)HA epitope than CTL fr om immunized conventional BALB/c mice. Significantly, we show that sel f-tolerance to the HA Ag is quantitative rather then absolute, and tha t vaccination of Ins-HA mice can activate low avidity K(d)HA-specific CD8(+) T cells that are able to reject tumor cells expressing high lev els of HA, yet these mice remain tolerant of pancreatic islet beta cel ls expressing HA.