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.
Yu
Zhiya
Z
Surgery Branch, National Cancer Institute/NIH, Building 10, Bethesda, MD 20892, USA.
Theoret
Marc R
MR
Touloukian
Christopher E
CE
Surman
Deborah R
DR
Garman
Scott C
SC
Feigenbaum
Lionel
L
Baxter
Tiffany K
TK
Baker
Brian M
BM
Restifo
Nicholas P
NP
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D002460:Cell Line; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D000939:Epitopes; D005620:Freund's Adjuvant / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D007114:Immunization; D007700:Kinetics; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018448:Models, Immunological; D009363:Neoplasm Proteins / Q000276:immunology; D009368:Neoplasm Transplantation; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D058951:gp100 Melanoma Antigen
D000951:Antigens, Neoplasm; D001324:Autoantigens; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; D010455:Peptides; C548642:Pmel protein, mouse; D058951:gp100 Melanoma Antigen; D005620:Freund's Adjuvant