Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virus
Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virus
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DOI：
10.1073/pnas.1609316113
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发表时间：
2016-10-18
影响因子：
11.1
通讯作者：
Miller, Matthew S.
中科院分区：
文献类型：
--
作者：
He, Wenqian;Tan, Gene S.;Miller, Matthew S.
已知针对甲型流感病毒的毒株特异性中和抗体的产生赋予针对同源感染的有效保护。这些抗体中的大多数与血凝素（HA）头部结构域结合，并通过阻断受体结合位点发挥作用，从而防止宿主细胞感染。近年来，针对保守的HA茎结构域的广泛中和抗体的诱导已经成为一种有希望的“通用”流感病毒疫苗策略。这些抗体引发Fc依赖性效应子功能的能力已成为体内实现保护的重要机制。然而，Fc依赖性效应子功能在体内由多克隆流感病毒结合抗体混合物调节的方式从未被定义。在这里，我们证明了不同特异性的病毒糖蛋白结合抗体之间的相互作用调节抗体依赖性细胞介导的细胞毒性诱导的大小。我们表明，负责这种表型的机制依赖于竞争结合HA的感染细胞和病毒颗粒的表面上。非中和抗体是不良诱导剂，不能抑制抗体依赖性细胞介导的细胞毒性。有趣的是，抗神经氨酸酶抗体微弱地诱导抗体依赖性细胞介导的细胞毒性，并且在HA茎结合抗体存在下以相加的方式增强诱导。我们的数据表明，抗体特异性在ADCC的调节中起着重要作用，并且不同特异性的抗体之间的串扰决定了Fc受体介导的效应器功能的大小。
The generation of strain-specific neutralizing antibodies against influenza A virus is known to confer potent protection against homologous infections. The majority of these antibodies bind to the hemagglutinin (HA) head domain and function by blocking the receptor binding site, preventing infection of host cells. Recently, elicitation of broadly neutralizing antibodies which target the conserved HA stalk domain has become a promising "universal" influenza virus vaccine strategy. The ability of these antibodies to elicit Fc-dependent effector functions has emerged as an important mechanism through which protection is achieved in vivo. However, the way in which Fc-dependent effector functions are regulated by polyclonal influenza virus-binding antibody mixtures in vivo has never been defined. Here, we demonstrate that interactions among viral glycoprotein-binding antibodies of varying specificities regulate the magnitude of antibody-dependent cell-mediated cytotoxicity induction. We show that the mechanism responsible for this phenotype relies upon competition for binding to HA on the surface of infected cells and virus particles. Nonneutralizing antibodies were poor inducers and did not inhibit antibody-dependent cell-mediated cytotoxicity. Interestingly, anti-neuraminidase antibodies weakly induced antibody-dependent cell-mediated cytotoxicity and enhanced induction in the presence of HA stalk-binding antibodies in an additive manner. Our data demonstrate that antibody specificity plays an important role in the regulation of ADCC, and that cross-talk among antibodies of varying specificities determines the magnitude of Fc receptor-mediated effector functions.