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 system to respond against tumor-associated Ags that are also expressed by normal tissue, we designed experiments in which the same protein was expressed both as a tumor Ag and as a transgene product. Unlike conventional BALB/c mice that rejected renal carcinoma cells transfected with the influenza virus hemagglutinin (Renca-HA), transgenic mice that are tolerant of HA due to its expression as a self-Ag on pancreatic islet β cells, (Ins- HA mice) supported progressive growth of these tumor cells. However, when Ins-HA mice were immunized with a recombinant strain of vaccinia virus expressing the dominant H-2K(d) peptide epitope of HA before receiving Renca- HA cells, they too were able to reject the tumor cells. Rejection of Renca- HA cells by immunized Ins-HA mice was found to be associated with the generation of CTL having much lower avidity for target cells presenting the K(d)HA epitope than CTL from immunized conventional BALB/c mice. Significantly, we show that self-tolerance to the HA Ag is quantitative rather then absolute, and that 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 levels of HA, yet these mice remain tolerant of pancreatic islet β cells expressing HA.