Hemmi S, Geliebter J, Zeff R A, Melvold R W, Nathenson S G
Department of Microbiology, Albert Einstein College of Medicine, Bronx, New York 10461.
J Exp Med. 1988 Dec 1;168(6):2319-35. doi: 10.1084/jem.168.6.2319.
Sequence analysis of the mutant Dbm13, Dbm14, and Dbm24 genes indicate that they differ from the parental Db gene by 4, 1, and 8 nucleotides, respectively. The mutant sequences substituted into Dbm13 and Dbm24 are identical to those found in the Kb gene, at the homologous positions. Thus, similar to the Kb gene, the Db gene is able to undergo micro-recombination (gene conversion) events with other class I genes. Such data suggest that micro-recombination events could be an important mechanism for the diversification of all H-2 genes. The Db mutant products share a common theme: the alterations in all occur at amino acid residues whose side chains in the homologous class I HLA-A2 molecule project into the postulated peptide antigen-binding cleft, and hence, would be expected to alter the binding of foreign or self peptides. Due to such changes, the bm14 mouse has become a nonresponder in the CTL response to Moloney murine leukemia virus (M-MuLV), as the alteration of one amino acid residue at position 70 (a Gln to His) is sufficient to entirely abrogate the cell-mediated response to the virus. On the other hand, the bm13 mouse has shifted the major part of its M-MuLV restriction to Kb, a profound alteration in CTL responsiveness due to the alteration of three amino acids (Leu to Gln at 114, Phe to Tyr at 116, and Glu to Asp at 119) in a peptide stretch of beta-pleated sheet structure lining the bottom of the antigen-binding cleft. Thus, study of these mutants reveals that, in one step, micro-recombination at the genetic level has resulted at the protein level in profound changes in the immune response to viral infection. Such a mechanism operating at the population level can be a driving force during evolution for modulating the character of CTL immunity.
对突变的Dbm13、Dbm14和Dbm24基因进行序列分析表明，它们与亲本Db基因分别相差4个、1个和8个核苷酸。在同源位置，替换到Dbm13和Dbm24中的突变序列与在Kb基因中发现的序列相同。因此，与Kb基因类似，Db基因能够与其他I类基因发生微重组（基因转换）事件。这些数据表明，微重组事件可能是所有H-2基因多样化的重要机制。Db突变产物有一个共同特点：所有突变都发生在氨基酸残基处，在同源的I类HLA-A2分子中，这些氨基酸残基的侧链伸向假定的肽抗原结合裂隙，因此预计会改变外来或自身肽的结合。由于这些变化，bm14小鼠在对莫洛尼鼠白血病病毒（M-MuLV）的CTL反应中成为无反应者，因为第70位一个氨基酸残基（从谷氨酰胺变为组氨酸）的改变足以完全消除细胞介导的对该病毒的反应。另一方面，bm13小鼠已将其对M-MuLV的主要限制转移到Kb，这是CTL反应性的一个深刻改变，原因是在抗原结合裂隙底部的β折叠片层结构的一段肽中三个氨基酸（114位亮氨酸变为谷氨酰胺、116位苯丙氨酸变为酪氨酸、119位谷氨酸变为天冬氨酸）发生了改变。因此，对这些突变体的研究表明，在一个步骤中，基因水平的微重组在蛋白质水平上导致了对病毒感染免疫反应的深刻变化。在群体水平上起作用的这种机制可能是进化过程中调节CTL免疫特性的驱动力。
