Tags

Type your tag names separated by a space and hit enter

Development of a murine mutant Ras CD8+ CTL peptide epitope variant that possesses enhanced MHC class I binding and immunogenic properties.
J Immunol 1998; 160(5):2433-41JI

Abstract

We recently identified a murine mutant Ras p21 CD8+ CTL epitope reflecting residues 4 to 12, containing the mutation of Gly to Val at codon 12, that bound weakly to H-2Kd in vitro and generated a weak primary CTL response in immunized BALB/c mice. Here, we explored the hypothesis that specific modifications to the Ras4-12 peptide sequence can improve MHC binding, leading to enhanced immunogenicity without altering immune specificity. We synthesized Ras4-12 peptides in which Val at residue 12 was replaced with the more dominant H-2Kd C-terminus anchor residue Leu or Ile. In functional H-2Kd binding assays, Ras4-12(L12 or I12) peptide variants competed more effectively than the Ras4-12(V12) peptide. Ras4-12(L12 or I12) peptide variants enhanced both in vitro cytotoxicity and proliferation responses of anti-Ras4-12 CTL compared with the mutant Ras4-12(V12) peptide. Additionally, the Ras4-12(L12) peptide variant induced a quantitatively greater T cell response in vivo compared with that produced by Ras4-12(V12) as determined by IFN-gamma production. Mice immunized with Ras4-12(L12) peptide elicited CD8+ CTL activity specific for target cells presenting the Ras4-12(V12) epitope exogenously and endogenously. Moreover, both anti-Ras4-12(V12)-derived and anti-Ras4-12(L12)-derived CTL lines were similar insofar as their TCR usage and amino acid contact residues in the Ras4-12(V12) peptide. These experiments demonstrate that modifications can be introduced in tumor-specific peptide epitopes to enhance both in vitro and in vivo immunogenicity. The design of oncogene-specific peptide epitope variants as immunogens may accelerate the generation of anti-tumor T cell responses for cancer immunotherapy.

Authors+Show Affiliations

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

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9498787

Citation

Bristol, J A., et al. "Development of a Murine Mutant Ras CD8+ CTL Peptide Epitope Variant That Possesses Enhanced MHC Class I Binding and Immunogenic Properties." Journal of Immunology (Baltimore, Md. : 1950), vol. 160, no. 5, 1998, pp. 2433-41.
Bristol JA, Schlom J, Abrams SI. Development of a murine mutant Ras CD8+ CTL peptide epitope variant that possesses enhanced MHC class I binding and immunogenic properties. J Immunol. 1998;160(5):2433-41.
Bristol, J. A., Schlom, J., & Abrams, S. I. (1998). Development of a murine mutant Ras CD8+ CTL peptide epitope variant that possesses enhanced MHC class I binding and immunogenic properties. Journal of Immunology (Baltimore, Md. : 1950), 160(5), pp. 2433-41.
Bristol JA, Schlom J, Abrams SI. Development of a Murine Mutant Ras CD8+ CTL Peptide Epitope Variant That Possesses Enhanced MHC Class I Binding and Immunogenic Properties. J Immunol. 1998 Mar 1;160(5):2433-41. PubMed PMID: 9498787.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Development of a murine mutant Ras CD8+ CTL peptide epitope variant that possesses enhanced MHC class I binding and immunogenic properties. AU - Bristol,J A, AU - Schlom,J, AU - Abrams,S I, PY - 1998/3/14/pubmed PY - 1998/3/14/medline PY - 1998/3/14/entrez SP - 2433 EP - 41 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J. Immunol. VL - 160 IS - 5 N2 - We recently identified a murine mutant Ras p21 CD8+ CTL epitope reflecting residues 4 to 12, containing the mutation of Gly to Val at codon 12, that bound weakly to H-2Kd in vitro and generated a weak primary CTL response in immunized BALB/c mice. Here, we explored the hypothesis that specific modifications to the Ras4-12 peptide sequence can improve MHC binding, leading to enhanced immunogenicity without altering immune specificity. We synthesized Ras4-12 peptides in which Val at residue 12 was replaced with the more dominant H-2Kd C-terminus anchor residue Leu or Ile. In functional H-2Kd binding assays, Ras4-12(L12 or I12) peptide variants competed more effectively than the Ras4-12(V12) peptide. Ras4-12(L12 or I12) peptide variants enhanced both in vitro cytotoxicity and proliferation responses of anti-Ras4-12 CTL compared with the mutant Ras4-12(V12) peptide. Additionally, the Ras4-12(L12) peptide variant induced a quantitatively greater T cell response in vivo compared with that produced by Ras4-12(V12) as determined by IFN-gamma production. Mice immunized with Ras4-12(L12) peptide elicited CD8+ CTL activity specific for target cells presenting the Ras4-12(V12) epitope exogenously and endogenously. Moreover, both anti-Ras4-12(V12)-derived and anti-Ras4-12(L12)-derived CTL lines were similar insofar as their TCR usage and amino acid contact residues in the Ras4-12(V12) peptide. These experiments demonstrate that modifications can be introduced in tumor-specific peptide epitopes to enhance both in vitro and in vivo immunogenicity. The design of oncogene-specific peptide epitope variants as immunogens may accelerate the generation of anti-tumor T cell responses for cancer immunotherapy. SN - 0022-1767 UR - https://www.unboundmedicine.com/medline/citation/9498787/Development_of_a_murine_mutant_Ras_CD8+_CTL_peptide_epitope_variant_that_possesses_enhanced_MHC_class_I_binding_and_immunogenic_properties_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=9498787 DB - PRIME DP - Unbound Medicine ER -