Poor immunogenicity of a self/tumor antigen derives from peptide–MHC-I instability and is independent of tolerance

Understanding the mechanisms underlying the poor immunogenicity of human self/tumor antigens is challenging because of experimental limitations in humans.Here, we developed a human-mouse chimeric model that allows us to investigate the roles of the frequency and self-reactivity of antigen-specific T cells in determination of the immunogenicity of an epitope (amino acids 209-217) derived from a human melanoma antigen, gp100.In these transgenic mice, CD8 + T cells express the variable regions of a human T cell receptor (hTCR) specific for an HLA-A*0201-restricted gp100 209-217 .Immunization of hTCR-transgenic mice with gp100 209-217 peptide elicited minimal T cell responses, even in mice in which the epitope was knocked out.Conversely, a modified epitope, gp100 209-217(2M) , was significantly more immunogenic.Both biological and physical assays revealed a fast rate of dissociation of the native peptide from the HLA-A*0201 molecule and a considerably slower rate of dissociation of the modified peptide.In vivo, the time allowed for dissociation of peptide-MHC complexes on APCs prior to their exposure to T cells significantly affected the induction of immune responses.These findings indicate that the poor immunogenicity of some self/tumor antigens is due to the instability of the peptide-MHC complex rather than to the continual deletion or tolerization of self-reactive T cells.Nonstandard abbreviations used: human TCR (hTCR)