Alternative splicing due to an intronic SNP in HMSD generates a novel minor histocompatibility antigen
Alternative splicing due to an intronic SNP in HMSD generates a novel minor histocompatibility antigen
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DOI：
10.1182/blood-2007-02-075911
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发表时间：
2007-08-01
期刊：
影响因子：
20.3
通讯作者：
Takahashi, Toshitada
中科院分区：
文献类型：
--
作者：
Kawase, Takakazu;Akatsuka, Yoshiki;Takahashi, Toshitada
在这里，我们报告了一种新的人类白细胞抗原（HLA）-B44限制性次要组织相容性抗原（mHA）的鉴定与表达限于造血细胞。cDNA表达克隆研究表明，目的细胞毒性T淋巴细胞（CTL）表位由HMSD的一个新的等位基因剪接变体编码，下文称为HMSD-v。该表位的免疫原性是由选择性剪接引起的差异蛋白表达产生的，该选择性剪接完全由位于外显子5'剪接位点的1个内含子单核苷酸多态性控制。HMSD-v和HMSD转录本在成熟树突状细胞和原代白血病细胞中选择性表达，尤其是髓系细胞。mHA（+）髓性白血病干细胞在非肥胖糖尿病/严重联合免疫缺陷（NOD/SCID）/γ c（null）小鼠中的植入被mHA特异性CTL克隆体外预孵育完全抑制，表明这种mHA在白血病干细胞上表达。从其中的CTL克隆分离的患者表现出显着增加的mHA特异性T细胞在移植后的外周血中，而mHA特异性T细胞是无法检测到在移植前的外周血和外周血从他的供体。这些发现表明，HMSD-v编码的mHA（命名为ACC-6）可以作为针对血液恶性肿瘤的免疫治疗的靶抗原。
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)/gamma c(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.