title: Variation in cytotoxic T-lymphocyte responses to peptides derived from tyrosinase-related protein-2.
abstract: In this study, we developed three optimized peptide ligands (OPL) that demonstrate increased affinities for HLA-A*0201 compared with wild-type tyrosinase-related protein-2 (TRP-2) peptide. The OPL contain amino acids from TRP-2((180-188)) and preferred primary and auxiliary HLA-A*0201 anchor residues. Cytotoxic T lymphocyte (CTL) lines were generated against wild-type TRP-2 peptide and OPL by multiple rounds of peptide stimulation of peripheral blood mononuclear cells from HLA-A2*0201(+) healthy individuals. CTL reactivity profiles to three different OPL were donor-dependent. Among donors, at least one OPL was particularly stimulatory and elicited high levels of CTL that cross-reacted with wild-type TRP-2 peptide. Cytotoxicity assays using CTL raised on wild-type TRP-2 peptide or OPL demonstrated lysis of HLA-A2-positive glioblastoma cells. Molecular models of TRP-2 and OPL peptides docked with HLA-A*0201 demonstrated that substitution of F for S at position 1 (P1) oriented the peptides favoring a pi-pi aromatic interaction with W 167 of HLA-A*0201. This in turn positions P5 and P8 aromatic rings to face solvent that may promote binding to the T-cell receptor, leading to a robust T-cell activation. The results of this study further substantiate the concept that rational design and testing of multiple peptides for the same T-cell epitope should elicit a broader response among different individuals than single peptide immunization. Our results may partially explain why some patients have better clinical responses to peptide-based immunotherapy, whereas others respond poorly.
authors.affiliation: Department of Immunobiology, University of Arizona, Life Sciences North, Tucson, AZ 85724, USA.
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Myers
authors.forename: Sara O
authors.initials: SO
authors.lastname: Dionne
authors.forename: Kishore
authors.initials: K
authors.lastname: Shakalya
authors.forename: Daruka
authors.initials: D
authors.lastname: Mahadevan
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Smith
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Lake
mesh_terms: D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology*; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D015234:HLA-A Antigens / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis; D019746:Intramolecular Oxidoreductases / Q000737:chemistry / Q000276:immunology*; D010455:Peptides / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010455:Peptides; D007371:Interferon-gamma; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase