title: Isoaspartyl post-translational modification triggers anti-tumor T and B lymphocyte immunity.
abstract: A hallmark of the immune system is the ability to ignore self-antigens. In attempts to bypass normal immune tolerance, a post-translational protein modification was introduced into self-antigens to break T and B cell tolerance. We demonstrate that immune tolerance is bypassed by immunization with a post-translationally modified melanoma antigen. In particular, the conversion of an aspartic acid to an isoaspartic acid within the melanoma antigen tyrosinase-related protein (TRP)-2 peptide-(181-188) makes the otherwise immunologically ignored TRP-2 antigen immunogenic. Tetramer analysis of iso-Asp TRP-2 peptide-immunized mice demonstrated that CD8+ T cells not only recognized the isoaspartyl TRP-2 peptide but also the native TRP-2 peptide. These CD8+ T cells functioned as cytotoxic T lymphocytes, as they effectively lysed TRP-2 peptide-pulsed targets both in vitro and in vivo. Potentially, post-translational protein modification can be utilized to trigger strong immune responses to either tumor proteins or potentially weakly immunogenic pathogens.
authors.affiliation: Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Hester A
authors.initials: HA
authors.lastname: Doyle
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Wolff
authors.forename: Bohdan P
authors.initials: BP
authors.lastname: Harvey
authors.forename: Robert M
authors.initials: RM
authors.lastname: Roman
authors.forename: Renelle J
authors.initials: RJ
authors.lastname: Gee
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Koski
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Mamula
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D066298:In Vitro Techniques; D026581:Isoaspartic Acid / Q000737:chemistry / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D011499:Protein Processing, Post-Translational; D013601:T-Lymphocytes / Q000276:immunology*; D014611:Vaccination
chemical_list: D000951:Antigens, Neoplasm; D026581:Isoaspartic Acid