Programming the magnitude and persistence of antibody responses with innate immunity.
Programming the magnitude and persistence of antibody responses with innate immunity.
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DOI：
10.1038/nature09737
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发表时间：
2011-02-24
期刊：
影响因子：
64.8
通讯作者：
Pulendran, Bali
中科院分区：
文献类型：
--
作者：
Kasturi, Sudhir Pai;Skountzou, Ioanna;Albrecht, Randy A.;Koutsonanos, Dimitrios;Hua, Tang;Nakaya, Helder I.;Ravindran, Rajesh;Stewart, Shelley;Alam, Munir;Kwissa, Marcin;Villinger, Francois;Murthy, Niren;Steel, John;Jacob, Joshy;Hogan, Robert J.;Garcia-Sastre, Adolfo;Compans, Richard;Pulendran, Bali
许多成功的疫苗可以诱导持续终生的抗体反应。它们的作用机制尚不清楚，但新出现的证据表明，它们通过Toll样受体(TLRs)激活树突状细胞(DC)。例如，黄热病疫苗YF-17D是有史以来最成功的经验性疫苗之一，它通过多个TLR激活DC，刺激促炎细胞因子。在DC中触发TLRs的特定组合可以诱导细胞因子的协同产生，从而导致增强的T细胞反应，但其对抗体反应的影响尚不清楚。了解安排抗体反应的先天免疫的关键参数仍然是疫苗学中的一个主要挑战。在这里，我们证明了含有抗原的合成纳米颗粒加上Toll样受体(TLR)配体4+7免疫小鼠，与单一TLR配体免疫相比，可以诱导抗原特异性中和抗体的协同增加。与此相一致的是，生发中心(GC)和浆细胞反应的持续性增强，这些反应在淋巴结中持续了1.5年。令人惊讶的是，与单一TLR配体相比，没有增强早期短暂的浆细胞反应。免疫后7天分离的激活的B细胞的分子图谱表明，早期对B细胞的记忆编程。抗体反应依赖于B细胞和树突状细胞(DC)上TLRs的直接触发，以及T细胞的帮助。免疫可完全保护小鼠免受致死性禽流感和猪流感病毒株的侵袭，并在恒河猴体内诱导对甲型H1N1流感大流行的强大免疫力。
Many successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but emerging evidence suggests that they activate dendritic cells (DCs) via Toll-like receptors (TLRs). For example, the yellow fever vaccine YF-17D, one of the most successful empiric vaccines ever developed, activates DCs via multiple TLRs to stimulate pro-inflammatory cytokines. Triggering specific combinations of TLRs in DCs can induce synergistic production of cytokines, which results in enhanced T cell responses, but its impact on antibody responses remain unknown. Learning the critical parameters of innate immunity that programs such antibody responses remains a major challenge in vaccinology. Here we demonstrate that immunization of mice with synthetic nanoparticles containing antigens plus Toll-like receptor (TLR) ligands 4 + 7 induces synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with a single TLR ligand. Consistent with this there was enhanced persistence of germinal centers (GCs), and of plasma cell responses, which persisted in the lymph nodes for >1.5 years. Surprisingly, there was no enhancement of the early short-lived plasma cell response, relative to that observed with single TLR ligands. Molecular profiling of activated B cells, isolated 7 days after immunization, indicated early programming towards B cell memory. Antibody responses were dependent on direct triggering of both TLRs on B cells and dendritic cells (DCs), as well as on T-cell help. Immunization protected completely against lethal avian and swine influenza virus strains in mice, and induced robust immunity against pandemic H1N1 influenza in rhesus macaques.
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