Nguyen Huan H, Zemlin Michael, Ivanov Ivaylo I, Andrasi Judit, Zemlin Cosima, Vu Huong L, Schelonka Robert, Schroeder Harry W, Mestecky Jiri
Department of Microbiology, The University of Alabama at Birmingham, Birmingham, Alabama 35294-2170, USA.
J Virol. 2007 Sep;81(17):9331-8. doi: 10.1128/JVI.00751-07. Epub 2007 Jun 13.
Heterosubtypic immunity (HSI) is defined as cross-protection to infection with an influenza A virus serotype other than the one used for primary infection. Although HSI has been thought to be mediated by serotype cross-reactive cytotoxic T lymphocytes (CTL) that recognize conserved epitopes of structural proteins, recent studies suggest that antibodies (Abs) may make a significant contribution. In this study, we provide further evidence for the role of Abs in HSI using transgenic mice lacking terminal deoxyribonucleotidyltransferase (TdT), which adds N nucleotides to V-D and D-J junctions of the complementary determining region 3 (CDR3) (TdT(-/-)) and mice with altered Ab repertoires due to replacement of the complete locus of heavy chain diversity segments (D(H)) with an altered D(H) segment (namely, Delta D-iD). Both types of mice failed to generate complete HSI, although they were able to mount protective immunity to a homologous challenge. Lower levels of virus-specific antibodies along with more severely impaired HSI were observed in TdT(-/-) mice compared to those in Delta D-iD mice, while CTL activity remained unchanged in both types of mice. These findings indicate that a properly diversified antibody repertoire is required for HSI and that N addition by TdT is a more effective mechanism in the induction of a properly diversified antibody repertoire and, therefore, complete HSI. The results suggest that the diversity of the antibody repertoire as determined by the composition of the D region of HCDR3 and by N addition are among the mechanisms selected for in evolution to create a favorable environment to resolve infections with mutated viruses.
异源亚型免疫（HSI）被定义为对初次感染所用甲型流感病毒血清型以外的其他血清型感染的交叉保护作用。尽管一直认为HSI是由识别结构蛋白保守表位的血清型交叉反应性细胞毒性T淋巴细胞（CTL）介导的，但最近的研究表明抗体（Ab）可能起重要作用。在本研究中，我们利用缺乏末端脱氧核苷酸转移酶（TdT）的转基因小鼠为抗体在HSI中的作用提供了进一步证据，TdT可将N核苷酸添加到互补决定区3（CDR3）的V-D和D-J连接点上（TdT(-/-)），以及由于用改变的重链多样性片段（D(H)）取代完整的重链多样性片段基因座而导致抗体库改变的小鼠（即ΔD-iD）。尽管这两种类型的小鼠都能够对同源攻击产生保护性免疫，但它们均未能产生完全的HSI。与ΔD-iD小鼠相比，在TdT(-/-)小鼠中观察到病毒特异性抗体水平较低，HSI受损更严重，而两种类型小鼠的CTL活性均保持不变。这些发现表明，完全的HSI需要适当多样化的抗体库，并且TdT添加N是诱导适当多样化抗体库从而产生完全HSI的更有效机制。结果表明，由HCDR3的D区组成和N添加所决定的抗体库多样性是进化过程中选择的机制之一，以创造一个有利于解决突变病毒感染的环境。
