Distinct germinal center selection at local sites shapes memory B cell response to viral escape.
Distinct germinal center selection at local sites shapes memory B cell response to viral escape.
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DOI：
10.1084/jem.20142284
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发表时间：
2015-09-21
期刊：
影响因子：
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通讯作者：
Takahashi Y
中科院分区：
文献类型：
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作者：
Adachi Y;Onodera T;Yamada Y;Daio R;Tsuiji M;Inoue T;Kobayashi K;Kurosaki T;Ato M;Takahashi Y
流感病毒感染后肺内持续存在的局部生发中心反应是产生交叉反应性记忆B细胞所必需的。呼吸道流感病毒感染诱导交叉反应性记忆B细胞靶向病毒逃逸突变体的不变区然而，决定交叉反应性记忆B细胞反应的细胞事件仍有待完全定义。在这里，我们证明了在感染部位的肺部驻留记忆隔间，而不是在次级淋巴器官中，窝藏介导病毒逃逸的中和抗体反应的交叉反应性B细胞的频率升高。肺记忆区室中升高的交叉反应性与高数量的VH突变相关，并且依赖于涉及持续性生发中心（GC）反应的发育途径。持续的GC反应集中在感染的肺中，与病毒抗原的持续存在有关。此外，持续的肺GC支持夸大的B细胞增殖和交叉反应性库的克隆选择，这是产生交叉反应性记忆祖细胞的主要位点。因此，我们确定局部位点的独特GC选择是记忆B细胞对病毒逃逸的交叉反应性反应的关键细胞事件，这一发现对开发广泛保护性流感疫苗具有重要意义。
Local germinal center reactions that persist in the lung after influenza infection are required for the generation of cross-reactive memory B cells. Respiratory influenza virus infection induces cross-reactive memory B cells targeting invariant regions of viral escape mutants. However, cellular events dictating the cross-reactive memory B cell responses remain to be fully defined. Here, we demonstrated that lung-resident memory compartments at the site of infection, rather than those in secondary lymphoid organs, harbor elevated frequencies of cross-reactive B cells that mediate neutralizing antibody responses to viral escape. The elevated cross-reactivity in the lung memory compartments was correlated with high numbers of VH mutations and was dependent on a developmental pathway involving persistent germinal center (GC) responses. The persistent GC responses were focused in the infected lungs in association with prolonged persistence of the viral antigens. Moreover, the persistent lung GCs supported the exaggerated B cell proliferation and clonal selection for cross-reactive repertoires, which served as the predominant sites for the generation of cross-reactive memory progenitors. Thus, we identified the distinct GC selection at local sites as a key cellular event for cross-reactive memory B cell response to viral escape, a finding with important implications for developing broadly protective influenza vaccines.