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Identification of a ras oncogene peptide that contains both CD4(+) and CD8(+) T cell epitopes in a nested configuration and elicits both T cell subset responses by peptide or DNA immunization.
Cell Immunol 2000; 205(2):73-83CI

Abstract

Mutations in ras proto-oncogenes are commonly found in a diversity of malignancies and may encode unique, non-self epitopes for T cell-mediated antitumor activity. In a BALB/c (H-2(d)) murine model, we have identified a single peptide sequence derived from the ras oncogenes that contained both CD8(+) and CD4(+) T cell epitopes in a nested configuration. This peptide reflected ras sequence 4-16, and contained the substitution of Gly to Val at position 12 ¿i.e., 4-16(Val12)¿. Mice immunized with this 13-mer peptide induced a strong antigen (Ag)-specific CD4(+) proliferative response in vitro. In contrast, mice inoculated with the wild-type ras sequence failed to generate a peptide-specific T cell response. Additionally, mice immunized with the ras 4-16(Val12) peptide concomitantly displayed an Ag-specific CD8(+) cytotoxic T lymphocyte (CTL) response, as determined by lysis of syngeneic tumor target cells incubated with the nominal 9-mer nested epitope peptide ¿i.e., 4-12(Val12)¿, as well as lysis of tumor target cells expressing the corresponding ras codon 12 mutation. Analysis of the Valpha- and Vbeta-chains of the T cell receptor (TCR) expressed by these CTL revealed usage of the Valpha1 and Vbeta9 subunits, consistent with the TCR phenotype of anti-ras Val12 CTL lines produced by in vivo immunization with the nominal peptide epitope alone. Moreover, immunization with the nested epitope peptide, as compared to immunization with either the 9-mer CTL peptide alone or an admixture of the 9-mer CTL peptide with an overlapping 13-mer CD4(+) T cell helper peptide ¿i.e., 5-17(Val12)¿ lacking the class I N-terminus anchor site, enhanced the production of the CD8(+) T cell response. Finally, immunization with plasmid DNA encoding the ras 4-16(Val12) sequence led to the induction of both Ag-specific proliferative and cytotoxic responses. Overall, these results suggested that a single peptide immunogen containing nested mutant ras-specific CD4(+) and CD8(+) T cell epitopes: (1) can be processed in vivo to induce both subset-specific T lymphocyte responses; and (2) leads to the generation of a quantitatively enhanced CD8(+) CTL response, likely due to the intimate coexistence of CD4(+) help, which may have implications in peptide- or DNA-based immunotherapies.

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  • Publisher Full Text

    • Authors+Show Affiliations

    Bristol JA
    Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, Maryland 20892, USA.
    Orsini C
    No affiliation info available
    Lindinger P
    No affiliation info available
    Thalhamer J
    No affiliation info available
    Abrams SI
    No affiliation info available

    MeSH

    AnimalsCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCancer VaccinesCells, CulturedEpitopes, T-LymphocyteFemaleMiceMice, Inbred BALB CMutagenesisPeptidesProto-Oncogene Proteins p21(ras)VaccinationVaccines, DNA

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    11104579

    Citation

    Bristol, J A., et al. "Identification of a Ras Oncogene Peptide That Contains Both CD4(+) and CD8(+) T Cell Epitopes in a Nested Configuration and Elicits Both T Cell Subset Responses By Peptide or DNA Immunization." Cellular Immunology, vol. 205, no. 2, 2000, pp. 73-83.
    Bristol JA, Orsini C, Lindinger P, et al. Identification of a ras oncogene peptide that contains both CD4(+) and CD8(+) T cell epitopes in a nested configuration and elicits both T cell subset responses by peptide or DNA immunization. Cell Immunol. 2000;205(2):73-83.
    Bristol, J. A., Orsini, C., Lindinger, P., Thalhamer, J., & Abrams, S. I. (2000). Identification of a ras oncogene peptide that contains both CD4(+) and CD8(+) T cell epitopes in a nested configuration and elicits both T cell subset responses by peptide or DNA immunization. Cellular Immunology, 205(2), pp. 73-83.
    Bristol JA, et al. Identification of a Ras Oncogene Peptide That Contains Both CD4(+) and CD8(+) T Cell Epitopes in a Nested Configuration and Elicits Both T Cell Subset Responses By Peptide or DNA Immunization. Cell Immunol. 2000 Nov 1;205(2):73-83. PubMed PMID: 11104579.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Identification of a ras oncogene peptide that contains both CD4(+) and CD8(+) T cell epitopes in a nested configuration and elicits both T cell subset responses by peptide or DNA immunization. AU - Bristol,J A, AU - Orsini,C, AU - Lindinger,P, AU - Thalhamer,J, AU - Abrams,S I, PY - 2000/12/6/pubmed PY - 2001/2/28/medline PY - 2000/12/6/entrez SP - 73 EP - 83 JF - Cellular immunology JO - Cell. Immunol. VL - 205 IS - 2 N2 - Mutations in ras proto-oncogenes are commonly found in a diversity of malignancies and may encode unique, non-self epitopes for T cell-mediated antitumor activity. In a BALB/c (H-2(d)) murine model, we have identified a single peptide sequence derived from the ras oncogenes that contained both CD8(+) and CD4(+) T cell epitopes in a nested configuration. This peptide reflected ras sequence 4-16, and contained the substitution of Gly to Val at position 12 ¿i.e., 4-16(Val12)¿. Mice immunized with this 13-mer peptide induced a strong antigen (Ag)-specific CD4(+) proliferative response in vitro. In contrast, mice inoculated with the wild-type ras sequence failed to generate a peptide-specific T cell response. Additionally, mice immunized with the ras 4-16(Val12) peptide concomitantly displayed an Ag-specific CD8(+) cytotoxic T lymphocyte (CTL) response, as determined by lysis of syngeneic tumor target cells incubated with the nominal 9-mer nested epitope peptide ¿i.e., 4-12(Val12)¿, as well as lysis of tumor target cells expressing the corresponding ras codon 12 mutation. Analysis of the Valpha- and Vbeta-chains of the T cell receptor (TCR) expressed by these CTL revealed usage of the Valpha1 and Vbeta9 subunits, consistent with the TCR phenotype of anti-ras Val12 CTL lines produced by in vivo immunization with the nominal peptide epitope alone. Moreover, immunization with the nested epitope peptide, as compared to immunization with either the 9-mer CTL peptide alone or an admixture of the 9-mer CTL peptide with an overlapping 13-mer CD4(+) T cell helper peptide ¿i.e., 5-17(Val12)¿ lacking the class I N-terminus anchor site, enhanced the production of the CD8(+) T cell response. Finally, immunization with plasmid DNA encoding the ras 4-16(Val12) sequence led to the induction of both Ag-specific proliferative and cytotoxic responses. Overall, these results suggested that a single peptide immunogen containing nested mutant ras-specific CD4(+) and CD8(+) T cell epitopes: (1) can be processed in vivo to induce both subset-specific T lymphocyte responses; and (2) leads to the generation of a quantitatively enhanced CD8(+) CTL response, likely due to the intimate coexistence of CD4(+) help, which may have implications in peptide- or DNA-based immunotherapies. SN - 0008-8749 UR - https://www.unboundmedicine.com/medline/citation/11104579/Identification_of_a_ras_oncogene_peptide_that_contains_both_CD4_+__and_CD8_+__T_cell_epitopes_in_a_nested_configuration_and_elicits_both_T_cell_subset_responses_by_peptide_or_DNA_immunization_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0008-8749(00)91712-X DB - PRIME DP - Unbound Medicine ER -