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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.

Authors+Show Affiliations

Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, Maryland 20892, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

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 -