title: Self-tolerance does not restrict the CD4+ T-helper response against the p53 tumor antigen.
abstract: Tumorigenesis is frequently associated with mutation and overexpression of p53, which makes it an attractive target antigen for T cell-mediated immunotherapy of cancer. However, the magnitude and breadth of the p53-specific T-cell repertoire may be restricted due to the ubiquitous expression of wild-type p53 in normal somatic tissues. In view of the importance of the CD4+ T-helper cell responses in effective antitumor immunity, we have analyzed and compared the p53-specific reactivity of this T cell subset in p53+/+ and p53-/- C57Bl/6 mice. This response was found to be directed against the same three immunodominant epitopes in both mouse types. Fine-specificity, magnitude, and avidity were not affected by self-tolerance. Immunization of p53-/- and p53+/+ mice with synthetic peptide vaccines comprising the identified epitopes induced equal levels of Th1 immunity. Our findings imply that the p53-specific CD4+ T-cell repertoire is not restricted by self-tolerance and is fully available for the targeting of cancer.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Marjolein M
authors.initials: MM
authors.lastname: Lauwen
authors.forename: Sander
authors.initials: S
authors.lastname: Zwaveling
authors.forename: Linda
authors.initials: L
authors.lastname: de Quartel
authors.forename: S Carmela
authors.initials: SC
authors.lastname: Ferreira Mota
authors.forename: Janine A C
authors.initials: JA
authors.lastname: Grashorn
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
authors.forename: Rienk
authors.initials: R
authors.lastname: Offringa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000915:Antibody Affinity; D017951:Antigen Presentation; D019496:Cancer Vaccines / Q000276:immunology; D003429:Cross Reactions; D018984:Epitopes, T-Lymphocyte; D005260:Female; D016219:Immunotherapy, Adoptive; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy; D017634:Self Tolerance / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D016159:Tumor Suppressor Protein p53