title: Tolerance to p53 by A2.1-restricted cytotoxic T lymphocytes.
abstract: Elevated levels of the p53 protein occur in approximately 50% of human malignancies, which makes it an excellent target for a broad-spectrum T cell immunotherapy of cancer. A major barrier to the design of p53-specific immunotherapeutics and vaccines, however, is the possibility that T cells may be tolerant of antigens derived from wild-type p53 due to its low level of expression in normal thymus and lymphohemopoetic cells. The combination of p53 deficient (p53-/-) and p53+/+ HLA-A2.1/Kb transgenic mice was used as a model to explore the possibility that A2.1-restricted cytotoxic T lymphocytes (CTL) are functionally tolerant of self peptides derived from the wild-type p53 tumor suppressor protein. A2.1-restricted CTL specific for a naturally processed p53 self-epitope spanning residues 187-197 were completely aborted in p53+/+ as opposed to p53-/- transgenic mice. In contrast, CTL specific for a second self-epitope spanning residues 261-269 of the murine p53 sequence were detected in both p53-/- and p53+/+ A2.1/Kb transgenic mice. However, the avidity of the CTL effectors obtained from p53+/+ mice was 10-fold lower than that obtained from p53-/- mice, again suggesting elimination of CTL with high avidity for the A2.1-peptide complex. The circumvention of functional tolerance of high avidity CTL may therefore be a necessary prerequisite for optimizing immunotherapy against A2.1-restricted wild-type p53 epitopes in humans.
authors.affiliation: Department of Immunology, Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: M
authors.initials: M
authors.lastname: Theobald
authors.forename: J
authors.initials: J
authors.lastname: Biggs
authors.forename: J
authors.initials: J
authors.lastname: Hernández
authors.forename: J
authors.initials: J
authors.lastname: Lustgarten
authors.forename: C
authors.initials: C
authors.lastname: Labadie
authors.forename: L A
authors.initials: LA
authors.lastname: Sherman
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D006183:H-2 Antigens / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D008817:Mice, Mutant Strains; D010446:Peptide Fragments / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000276:immunology*
chemical_list: D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53