Department of Microbiology and Immunology, University of Melbourne, Victoria 3010, Australia.
J Immunol. 2013 Feb 15;190(4):1837-48. doi: 10.4049/jimmunol.1201574. Epub 2013 Jan 14.
A better understanding of immunity to influenza virus is needed to generate cross-protective vaccines. Engagement of Ab-dependent cellular cytotoxicity (ADCC) Abs by NK cells leads to killing of virus-infected cells and secretion of antiviral cytokines and chemokines. ADCC Abs may target more conserved influenza virus Ags compared with neutralizing Abs. There has been minimal interest in influenza-specific ADCC in recent decades. In this study, we developed novel assays to assess the specificity and function of influenza-specific ADCC Abs. We found that healthy influenza-seropositive young adults without detectable neutralizing Abs to the hemagglutinin of the 1968 H3N2 influenza strain (A/Aichi/2/1968) almost always had ADCC Abs that triggered NK cell activation and in vitro elimination of influenza-infected human blood and respiratory epithelial cells. Furthermore, we detected ADCC in the absence of neutralization to both the recent H1N1 pandemic strain (A/California/04/2009) as well as the avian H5N1 influenza hemagglutinin (A/Anhui/01/2005). We conclude that there is a remarkable degree of cross-reactivity of influenza-specific ADCC Abs in seropositive humans. Targeting cross-reactive influenza-specific ADCC epitopes by vaccination could lead to improved influenza vaccines.
为了开发出具有交叉保护作用的疫苗，我们需要更好地了解针对流感病毒的免疫机制。自然杀伤 (NK) 细胞表面的抗体依赖的细胞细胞毒性 (ADCC) 受体与 NK 细胞结合后，可以介导 NK 细胞杀伤病毒感染的细胞，并分泌抗病毒细胞因子和趋化因子。与中和抗体相比，ADCC 抗体可能针对更为保守的流感病毒抗原。近几十年来，人们对流感特异性 ADCC 的关注甚少。在本研究中，我们开发了新的检测方法来评估流感特异性 ADCC 抗体的特异性和功能。我们发现，健康的流感血清阳性的年轻人中，几乎所有人都存在针对 1968 年 H3N2 流感血凝素（A/Aichi/2/1968）的 ADCC 抗体，这些抗体能够触发 NK 细胞激活，并在体外清除感染流感的人血和呼吸道上皮细胞，尽管他们的血清中无法检测到针对该血凝素的中和抗体。此外，我们还在没有中和抗体的情况下检测到了对近期 H1N1 大流行株（A/California/04/2009）和禽流感 H5N1 流感血凝素（A/Anhui/01/2005）的 ADCC 作用。我们的结论是，在血清阳性的人群中，流感特异性 ADCC 抗体存在显著的交叉反应性。通过疫苗接种靶向交叉反应性的流感特异性 ADCC 表位可能会开发出更好的流感疫苗。
