A SYNTHETIC PEPTIDE DERIVED FROM THE TUMOR-ASSOCIATED PROTEIN MDM2 CAN STIMULATE AUTOREACTIVE, HIGH AVIDITY CYTOTOXIC T-LYMPHOCYTES THAT RECOGNIZE NATURALLY PROCESSED PROTEIN

Studies in melanoma patients have shown that unaltered self proteins c an function as targets for tumor-reactive CTL. Here, we have investiga ted in a murine model whether autoreactive CTL can be found against th e widely expressed proteins cyclin D1, mdm2, and p53, which are freque ntly overexpressed in transformed cells. Sixteen MHC class I binding p eptides were identified in these proteins, and seven of them consisten tly stimulated primary CTL in vitro. Avidity measurements revealed tha t the avidity of peptide-induced CTL differed by > 1000-fold. The high est avidity CTL were induced by a peptide derived from mdm2. These CTL recognized target cells expressing mdma endogenously, while CTL gener ated against the remaining peptides were of lower avidity and did not recognize cells expressing relevant proteins endogenously. Generation of high avidity anti-mdm2 CTL required several cycles of peptide stimu lation, suggesting that the CTL precursor frequency was low. The data show the normal T cell repertoire contains small numbers of potentiall y autoreactive CTL. Expansion of these CTL may lead to beneficial auto immunity against tumors, but, equally, it may be the basis of detrimen tal autoimmune diseases.