Derivation of HLA-B*0702 transgenic mice: functional CTL repertoire and recognition of human B*0702-restricted CTL epitopes.
Transgenic mice expressing chimeric human leukocyte antigen (HLA)-B*0702 and murine H-2K(b) class I molecules were evaluated as a model system to study the immunogenicity of human cytotoxic T lymphocyte epitopes. Immunization of these mice with six known HLA-B*0702-restricted cytotoxic T lymphocyte epitopes emulsified in incomplete Freund's adjuvant induced significant immune responses specific for all six epitopes. A comparison of the immune responses between HLA-B*0702/K(b) and HLA-A*0201/K(b) transgenic mice demonstrated that the HLA-B*0702/K(b) mice possess a T-cell receptor repertoire capable of recognizing human B*0702 epitopes. However, the magnitude of B*0702-specific responses induced in B*0702/K(b) mice were approximately tenfold lower than A*0201-specific responses induced in HLA-A*0201/K(b) transgenic mice. A panel of 24 B*0702 motif-bearing peptides was used to examine the relationship between immunogenicity and HLA-B*0702 binding capacity. All seven peptides with high binding affinities of 50% inhibitory concentration < or =50 NM (IC(50) 50 nM or less) were immunogenic. Similarly, 75% (9 of 12) of the intermediate binders (IC(50) nM of 50-500) were also immunogenic. Finally, only two of five peptides with binding capacity > 500 nM were found to have marginal immunogenicity, whereas the other three were completely negative. HLA-B*0702/K(b) transgenic mice were found to induce B*0702-specific responses after immunization with whole DNA genes or minigenes, suggesting that, at least to some degree, B*0702 epitopes were generated as a result of natural in vivo processing and presentation.
Alexander
Jeff
J
Epimmune Inc., San Diego, California 92121, USA. jalexander@epimmune.com
Oseroff
Carla
C
Sidney
John
J
Sette
Alessandro
A
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005805:Genes, MHC Class I; D005813:Genes, Synthetic; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology; D015789:HLA-A2 Antigen; D015235:HLA-B Antigens / Q000235:genetics* / Q000276:immunology; D015793:HLA-B7 Antigen; D006801:Humans; D007114:Immunization; D016056:Immunodominant Epitopes / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D015235:HLA-B Antigens; C477444:HLA-B*07:02 antigen; D015793:HLA-B7 Antigen; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma