title: Binding of BCR/ABL junctional peptides to major histocompatibility complex (MHC) class I molecules: studies in antigen-processing defective cell lines.
abstract: Leukaemia-specific proteins may be recognized by T-lymphocytes as neoantigens if peptides corresponding to mutated sequences bind to major histocompatibility complex (MHC) molecules on leukaemic cells. We studied the ability of a series of synthetic peptides corresponding to the junctional sequences of BCR/ABL proteins to bind to class I molecules in two human cell lines, LBL 721.174 (T2) (HLA-A2, B5) and BM36.1 (HLA-A1, B35), and one murine cell line RMA-S (H-2Kb, Db). These cell lines are defective in intracellular peptide loading of class I molecules, resulting in markedly reduced cell surface class I expression: class I expression can be rescued by provision of peptides binding to the alleles expressed by the mutant cell. Eighteen peptides spanning the junctional sequences of the b2a2 and b3a2 proteins were tested for their ability to rescue expression of the class I alleles borne by these cells using flow cytometry. Allele-specific control peptides known to bind HLA-A2, HLA-B35, H-2Kb and H-2Db increased expression of these alleles 2- to 3-fold: 0/18 BCR/ABL peptides enhanced HLA-A2, HLA-B35 or H-2Kb expression, but three b2a2 peptides consistently increased H-2Db expression. These results suggest that BCR/ABL junctional peptides are unlikely to be presented to T-cells in association with HLA-A2, HLA-B35 or H-2Kb. Conversely, the finding that some b2a2 peptides bind specifically to H-2Db suggests that a murine model of graft-versus-leukaemia (GVL) could be constructed.
authors.affiliation: Department of Haematology, Royal Postgraduate Medical School, London, UK.
authors.forename: J O
authors.initials: JO
authors.lastname: Cullis
authors.forename: A J
authors.initials: AJ
authors.lastname: Barrett
authors.forename: J M
authors.initials: JM
authors.lastname: Goldman
authors.forename: R I
authors.initials: RI
authors.lastname: Lechler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line / Q000276:immunology; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism* / Q000494:pharmacology; D015395:Histocompatibility Antigens Class I / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D016399:Lymphoma, T-Cell / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D014407:Tumor Cells, Cultured / Q000276:immunology
chemical_list: D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments; D016044:Fusion Proteins, bcr-abl