Abstract
Minor histocompatibility (H) antigens crucially affect the outcome of human leukocyte antigen (HLA)-identical allogeneic stem cell transplantation (SCT). To understand the basis of alloimmune responses against minor H antigens, identification of minor H peptides and their antigenicity-determining mechanisms is essential. Here we report the identification of HA-3 and its encoding gene. The HA-3 peptide, VTEPGTAQY (HA-3T), is encoded by the lymphoid blast crisis (Lbc) oncogene. We thus show for the first time that a leukemia-associated oncogene can give rise to immunogenic T-cell epitopes that may have participated in antihost and antileukemic alloimmune responses. Genotypic analysis of HA-3- individuals revealed the allelic counterpart VMEPGTAQY (HA-3M). Despite the lack of T-cell recognition of HA-3- cells, the Thr-->Met substitution had only a modest effect on peptide binding to HLA-A1 and a minimal impact on recognition by T cells when added exogenously to target cells. This substitution did not influence transporter associated with antigen processing (TAP) transport, but, in contrast to the HA-3T peptide, HA-3M is destroyed by proteasome-mediated digestion. Thus, the immunogenicity of minor H antigens can result from proteasome-mediated destruction of the negative allelic peptide.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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A Kinase Anchor Proteins
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ATP Binding Cassette Transporter, Subfamily B, Member 2
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ATP-Binding Cassette Transporters / metabolism
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Acute Disease
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Adaptor Proteins, Signal Transducing
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Alleles
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Amino Acid Sequence
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Amino Acid Substitution
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Antigen Presentation
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CD8-Positive T-Lymphocytes / immunology
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Clone Cells / immunology
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Cysteine Endopeptidases / metabolism*
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Epitopes, T-Lymphocyte / genetics*
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Epitopes, T-Lymphocyte / immunology
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Epitopes, T-Lymphocyte / metabolism
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Female
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Genotype
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HLA-A1 Antigen / metabolism
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Humans
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Leukemia, Myeloid / immunology
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Leukemia, Myeloid / therapy
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Male
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Minor Histocompatibility Antigens
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Molecular Sequence Data
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Multienzyme Complexes / metabolism*
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Pedigree
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Peripheral Blood Stem Cell Transplantation
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Polymorphism, Genetic
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Proteasome Endopeptidase Complex
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Protein Processing, Post-Translational*
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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Sequence Alignment
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Sequence Homology, Amino Acid
Substances
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A Kinase Anchor Proteins
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AKAP13 protein, human
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ATP Binding Cassette Transporter, Subfamily B, Member 2
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ATP-Binding Cassette Transporters
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Adaptor Proteins, Signal Transducing
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Epitopes, T-Lymphocyte
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HLA-A1 Antigen
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Minor Histocompatibility Antigens
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Multienzyme Complexes
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Protein Isoforms
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Proto-Oncogene Proteins
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TAP1 protein, human
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex