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

J Clin Invest. 2004 Aug;114(4):551-9. doi: 10.1172/JCI21695.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology*
  • Autoantigens / immunology*
  • Cell Line
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic
  • Epitopes
  • Freund's Adjuvant / immunology
  • Histocompatibility Antigens Class I / immunology*
  • Humans
  • Immune Tolerance*
  • Immunization
  • Kinetics
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / pathology
  • Membrane Glycoproteins / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Immunological
  • Neoplasm Proteins / immunology
  • Neoplasm Transplantation
  • Peptides / chemistry
  • Peptides / immunology*
  • Spleen / cytology
  • T-Lymphocytes / immunology
  • Time Factors
  • gp100 Melanoma Antigen


  • Antigens, Neoplasm
  • Autoantigens
  • Epitopes
  • Histocompatibility Antigens Class I
  • Membrane Glycoproteins
  • Neoplasm Proteins
  • PMEL protein, human
  • Peptides
  • Pmel protein, mouse
  • gp100 Melanoma Antigen
  • Freund's Adjuvant