Identification of overlapping epitopes in mutantras oncogene peptides that activate CD4+ and CD8+ T cell responses
Val) contained a peptide sequence which exhibited specific functional binding to a murine MHC class I molecule; the ability of the mutant, but not the normal sequence to bind selectively to murine MHC class I likely reflected the generation of a C-terminal anchor residue; and the ras4-12(V12) peptide was immunogenic for the production of antigen-specific CD8+ CTL, which lysed in vitro a syngeneic tumor cell line harboring the mutant K-ras oncogene. -->ISSN: | 1521-4141 0014-2980 |
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DOI: | 10.1002/eji.1830260225 |
Přístupová URL adresa: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bded4032f5339abd0fce2986fb380cca https://doi.org/10.1002/eji.1830260225 |
Rights: | CLOSED |
Přírůstkové číslo: | edsair.doi.dedup.....bded4032f5339abd0fce2986fb380cca |
Autor: | Stephen F. Stanziale, Jeffrey Schlom, Sam Zaremba, Scott I. Abrams, Scott D. Lunin |
Rok vydání: | 1996 |
Předmět: |
CD4-Positive T-Lymphocytes
Cytotoxicity Immunologic T cell Molecular Sequence Data Immunology Major histocompatibility complex Epitope Epitopes Mice MHC class I Genes Overlapping medicine Animals Point Mutation Immunology and Allergy Cytotoxic T cell Amino Acid Sequence Peptide sequence Antigen Presentation Mice Inbred BALB C Base Sequence biology H-2 Antigens MHC restriction Molecular biology CTL Genes ras medicine.anatomical_structure ras Proteins biology.protein Female Protein Binding T-Lymphocytes Cytotoxic |
Zdroj: | European Journal of Immunology. 26:435-443 |
ISSN: | 1521-4141 0014-2980 |
DOI: | 10.1002/eji.1830260225 |
Popis: | Mutant ras p21 proteins contain sequences which distinguish them from normal endogenous ras and, thus, may represent unique epitopes for T cell recognition of antigen bearing tumor cells. Here, we examined the capacity of a mutant K-ras 9-mer peptide to induce in vivo CD8+ cytotoxic T lymphocytes (CTL). The peptide chosen reflected positions 4-12 of the point-mutated sequence of the K-ras oncogene encoding the Gly to Val substitution at codon 12. The overall rationale for selecting this particular 9-mer sequence was threefold: the mutant peptide contained a putative major histocompatibility complex (MHC) class I consensus anchor motif for murine H-2Kd; specific binding to MHC class I may then create an immunogenic complex for the induction of anti-ras CD8+ CTL; and finally, the mutant sequence overlapped with a newly characterized anti-ras CD4+ T helper type 1 epitope, which may have implications for the coordination and activation of both anti-ras immune mechanisms against the same target cell antigenic determinant. A functional interaction with H-2Kd was demonstrated with the mutant ras4-12(V12) peptide, but not the normal ras4-12(G12) peptide, which specifically inhibited an H-2Kd-restricted, anti-nucleoprotein NP147-155 CTL response in a dose-dependent fashion. An anti-ras CD8+ T cell line was then established from immune splenocytes of BALB/c (H-2d) mice injected with ras4-12 (V12) in adjuvant, which mediated peptide-specific lysis of syngeneic P815 tumor targets. Cytotoxicity was restricted by H-2Kd and strongly specific for the mutant ras peptide. Importantly, these anti-ras CTL specifically lysed a syngeneic tumor line (i.e. A20 lymphoma) transduced with the corresponding point-mutated ras oncogene, suggesting T cell receptor recognition of endogenously derived antigen. Overall, these data demonstrated that mutant ras p21 at codon 12(Gly-->Val) contained a peptide sequence which exhibited specific functional binding to a murine MHC class I molecule; the ability of the mutant, but not the normal sequence to bind selectively to murine MHC class I likely reflected the generation of a C-terminal anchor residue; and the ras4-12(V12) peptide was immunogenic for the production of antigen-specific CD8+ CTL, which lysed in vitro a syngeneic tumor cell line harboring the mutant K-ras oncogene. |
Databáze: | OpenAIRE |
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