McBride Kevin, Baron Chantal, Picard Serge, Martin Stéphanie, Boismenu Daniel, Bell Alex, Bergeron John, Perreault Claude
Department of Molecular Biology, Compatigene Inc., Montreal, Quebec, Canada.
Immunogenetics. 2002 Nov;54(8):562-9. doi: 10.1007/s00251-002-0502-4. Epub 2002 Oct 2.
The B6(dom1) minor histocompatibility antigen (MiHA) is a model antigen, since it is both the epitome of an immunodominant epitope and an ideal target for adoptive cancer immunotherapy. Based on DNA sequencing and MS/MS analyses, we report that B6(dom1) corresponds to amino acids 770-778 (KAPDNRETL) of a protein we propose to call SIMP (source of immunodominant MHC-associated peptides) that is encoded by a mouse homolog of the yeast STT3gene. STT3, a member of the oligosaccharyltransferase complex, is essential for cell proliferation. Phenotypic and genotypic analyses among eight strains of mice revealed a precise correlation between susceptibility or resistance to B6(dom1)-specific cytotoxic T lymphocytes (CTLs) and the presence of a Glu vs Asp amino acid at position 776 of the SIMP protein, respectively. Strikingly, while the difference in the amino acid sequence 770-778 encoded by the two SIMP alleles represents a very conservative substitution, these allelic peptides were not crossreactive at the CTL level, and both peptides were immunodominant when presented to mice homozygous for the opposite allele. In addition, we have cloned a human ortholog of SIMP whose predicted protein shares 97% amino acid identity with mouse SIMP. These results strengthen the concept that MHC class-I-associated MiHAs originate as a consequence of rare polymorphisms among highly conserved genes. Furthermore, the notion that a peptide differing from a self analog by a single methylene group can be immunodominant has implications regarding our understanding of the mechanisms of immunodominance.
B6(dom1) 次要组织相容性抗原（MiHA）是一种模型抗原，因为它既是免疫显性表位的典范，又是过继性癌症免疫疗法的理想靶点。基于DNA测序和串联质谱分析，我们报告称B6(dom1) 对应于一种蛋白质的第770 - 778位氨基酸（KAPDNRETL），我们提议将该蛋白质称为SIMP（免疫显性MHC相关肽的来源），它由酵母STT3基因的小鼠同源物编码。STT3是寡糖基转移酶复合物成员，对细胞增殖至关重要。对八个小鼠品系进行的表型和基因型分析显示，对B6(dom1)特异性细胞毒性T淋巴细胞（CTL）的易感性或抗性分别与SIMP蛋白第776位氨基酸为谷氨酸或天冬氨酸精确相关。引人注目的是，虽然两个SIMP等位基因编码的770 - 778位氨基酸序列差异代表非常保守性的替换，但这些等位基因肽在CTL水平上无交叉反应性；当将这两种肽呈递给对相反等位基因纯合子的小鼠时，二者均具有免疫显性作用。此外，我们克隆了SIMP的人类直系同源物，其预测的蛋白质与小鼠SIMP具有97%的氨基酸同一性匹配。这些结果强化了这样的概念：MHC I类相关的MiHA是高度保守基因中罕见多态性的结果。此外，一种与自身类似物仅相差一个亚甲基的肽可具有免疫显性这一观点，对于我们理解免疫显性机制具有启示意义。
