The minor histocompatibility antigen HA-3 arises from differential proteasome-mediated cleavage of the lymphoid blast crisis (Lbc) oncoprotein.
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.
Spierings
Eric
E
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Brickner
Anthony G
AG
Caldwell
Jennifer A
JA
Zegveld
Suzanne
S
Tatsis
Nia
N
Blokland
Els
E
Pool
Jos
J
Pierce
Richard A
RA
Mollah
Sahana
S
Shabanowitz
Jeffrey
J
Eisenlohr
Laurence C
LC
van Veelen
Peter
P
Ossendorp
Ferry
F
Hunt
Donald F
DF
Goulmy
Els
E
Engelhard
Victor H
VH
D054758:A Kinase Anchor Proteins; D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000208:Acute Disease; D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002999:Clone Cells / Q000276:immunology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005260:Female; D005838:Genotype; D015788:HLA-A1 Antigen / Q000378:metabolism; D006801:Humans; D007951:Leukemia, Myeloid / Q000276:immunology / Q000628:therapy; D008297:Male; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism*; D010375:Pedigree; D036102:Peripheral Blood Stem Cell Transplantation; D011110:Polymorphism, Genetic; D046988:Proteasome Endopeptidase Complex; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D054758:A Kinase Anchor Proteins; C085467:AKAP13 protein, human; D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D048868:Adaptor Proteins, Signal Transducing; D018984:Epitopes, T-Lymphocyte; D015788:HLA-A1 Antigen; D015778:Minor Histocompatibility Antigens; D009097:Multienzyme Complexes; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; C073119:TAP1 protein, human; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex