title: Partial tyrosinase-specific self tolerance by HLA-A*0201-restricted cytotoxic T lymphocytes in mice and man.
abstract: The human tyrosinase (hTyr) (369-377) cytotoxic T lymphocyte (CTL) epitope is presented by malignant melanoma and various nontransformed cells in association with human leukocyte antigen (HLA)-A*0201 (A2.1) and used for vaccination-based immunotherapy of melanoma patients. Its mouse homologue, mTyr (369-377), is naturally processed and bound by A2.1 with equivalent efficacy and thus enabled us to explore the effect of self tolerance on Tyr-specific T cells in different lines of A2.1 transgenic (Tg) mice and man. We found that self Tyr-reactive CTL in Tg mice and, importantly, in man were affected by partial tolerance resulting in only residual T lymphocytes of higher avidity for self Tyr along with low-avidity T cells to be present in the periphery. Immunizing mice with the xenogeneic nonself Tyr peptide facilitated the generation of self Tyr-reactive CTL. As compared to Tyr-reactive CTL induced by high amounts of the self Tyr epitope, however, the nonself antigen (Ag) had no effect on improving the avidity of self Tyr-specific mouse and human T cells. Depleting mice of CD25(+) T cells with and without CTL-associated Ag 4 (CTLA-4) blockade demonstrated that tolerance of Tyr-specific CTL was not regulated by CD4(+)CD25(+) T regulatory cells (Treg) or CTLA-4. Our studies have important implications for the design of anti-Tyr-based immunotherapeutics.
authors.affiliation: Department of Hematology and Oncology, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Lotz
authors.forename: Edite Antunes
authors.initials: EA
authors.lastname: Ferreira
authors.forename: Ingo
authors.initials: I
authors.lastname: Drexler
authors.forename: Sarah Abdel
authors.initials: SA
authors.lastname: Mutallib
authors.forename: Christoph
authors.initials: C
authors.lastname: Huber
authors.forename: Gerd
authors.initials: G
authors.lastname: Sutter
authors.forename: Matthias
authors.initials: M
authors.lastname: Theobald
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology; D060908:CTLA-4 Antigen; D000939:Epitopes / Q000276:immunology; D005822:Genetic Vectors; D015234:HLA-A Antigens / Q000276:immunology*; D015789:HLA-A2 Antigen; D006801:Humans; D007167:Immunotherapy; D008545:Melanoma / Q000201:enzymology* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D014442:Monophenol Monooxygenase / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D017634:Self Tolerance; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014611:Vaccination
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D000939:Epitopes; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D015375:Receptors, Interleukin-2; D014442:Monophenol Monooxygenase