Abstract
T cells recognize and respond to self antigens in both cancer and autoimmunity. One strategy to influence this response is to incorporate amino acid substitutions into these T cell-specific epitopes. This strategy is being reconsidered now with the goal of increasing time to regression with checkpoint blockade therapies in cancer and antigen-specific immunotherapies in autoimmunity. We discuss how these amino acid substitutions change the interactions with the MHC class I or II molecule and the responding T cell repertoire. Amino acid substitutions in epitopes that are the most effective in therapies bind more strongly to T cell receptor and/or MHC molecules and cross-react with the same repertoire of T cells as the natural antigen.