Alternative splicing due to an intronic SNP in HMSD generates a novel minor histocompatibility antigen.
Here we report the identification of a novel human leukocyte antigen (HLA)-B44-restricted minor histocompatibility antigen (mHA) with expression limited to hematopoietic cells. cDNA expression cloning studies demonstrated that the cytotoxic T lymphocyte (CTL) epitope of interest was encoded by a novel allelic splice variant of HMSD, hereafter designated as HMSD-v. The immunogenicity of the epitope was generated by differential protein expression due to alternative splicing, which was completely controlled by 1 intronic single-nucleotide polymorphism located in the consensus 5' splice site adjacent to an exon. Both HMSD-v and HMSD transcripts were selectively expressed at higher levels in mature dendritic cells and primary leukemia cells, especially those of myeloid lineage. Engraftment of mHA(+) myeloid leukemia stem cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID)/gammac(null) mice was completely inhibited by in vitro preincubation with the mHA-specific CTL clone, suggesting that this mHA is expressed on leukemic stem cells. The patient from whom the CTL clone was isolated demonstrated a significant increase of the mHA-specific T cells in posttransplantation peripheral blood, whereas mHA-specific T cells were undetectable in pretransplantation peripheral blood and in peripheral blood from his donor. These findings suggest that the HMSD-v-encoded mHA (designated ACC-6) could serve as a target antigen for immunotherapy against hematologic malignancies.
Kawase
Takakazu
T
Division of Immunology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
Akatsuka
Yoshiki
Y
Torikai
Hiroki
H
Morishima
Satoko
S
Oka
Akira
A
Tsujimura
Akane
A
Miyazaki
Mikinori
M
Tsujimura
Kunio
K
Miyamura
Koichi
K
Ogawa
Seishi
S
Inoko
Hidetoshi
H
Morishima
Yasuo
Y
Kodera
Yoshihisa
Y
Kuzushima
Kiyotaka
K
Takahashi
Toshitada
T
D017398:Alternative Splicing / Q000235:genetics* / Q000276:immunology; D000818:Animals; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000276:immunology; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology; D059948:HLA-B44 Antigen; D006801:Humans; D007167:Immunotherapy; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015778:Minor Histocompatibility Antigens / Q000235:genetics* / Q000276:immunology; D014411:Neoplastic Stem Cells; D020641:Polymorphism, Single Nucleotide; D022821:RNA Splice Sites; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D018076:DNA, Complementary; D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; D059948:HLA-B44 Antigen; D015778:Minor Histocompatibility Antigens; D022821:RNA Splice Sites