Yu et al. (16) investigate how host CD8⁺ T cells respond to a self peptide presented by MHC-I molecules on tumor cells. The self peptide binds relatively weakly to host MHC molecules. The self peptide ITDQVPFSV (single letter amino acid code), expressed by melanoma cells and normal pigment cells, binds with low affinity to MHC-I HLA-A*0201 molecules. A mutated form of the self peptide, IMDQVPFSV with a threonine to methionine substitution at the second amino acid position, has a high affinity for MHC-I molecules because methionine residues at the second position are more favorable to anchor the peptide to HLA-A*0201 molecules. Naive CD8⁺ T cells against the self peptide are present in the immune repertoire, but they do not respond to either tumor cells presenting the weak self peptide or to immunization with the self peptide because of the instability of self peptide/MHC complex. However, immunization with the mutant self peptide activates the host T cells. The mutant peptide is presented by MHC-I molecules on dendritic cells, which are potent APCs. Once the CD8⁺ T cells are activated, they are competent to recognize and kill host tumor cells presenting the nonmutated self peptide. These results show that T cells recognizing a self antigen are capable of killing tumor cells presenting the self antigen following activation with the mutated form of the antigen.