T cell epitopes derived from autoantigens are selected differently than those from exogenous antigens (130.15)

Abstract

Abstract We have established a novel minimalist cell-free MHC class II antigen-processing system for identifying immunodominant epitopes from protein antigens. The system constitutes HLA-DR1, HLA-DM (DM) and three cathepsins. This system not only identifies the immunogenic epitopes from complex protein antigens, but also provides insight to the mechanism of immunodominance. Understanding of how these immunogenic epitopes are selected certainly provides better strategies for developing effective peptide vaccine designs and therapies against infectious diseases, cancer, autoimmune diseases and allergy. Using our cell-free system, and based on the source of the antigens categorized as exogenous antigens versus autoantigens, we find that both DM and cathepsins are crucial in regulating the selection of immunodominant epitopes. Three types of determinants are generated: first, non-dominant epitopes that are sensitive to both DM mediated dissociation, and cathepsins digestion. These epitopes were eliminated immediately from peptide repertoire. Second, T cell epitopes derived from the exogenous antigen are DM resistant and cathepsin sensitive. Third, T cells epitopes derived from an antoantigen that are sensitive to DM mediated dissociation, but resistant to cathepsin digestion. This shows that generation of immunodominant epitopes is regulated differently depending on the source of proteins antigens.