Antigen-Specific NK Cell Memory Against SIV and HIV Vaccines

自然杀伤(NK)细胞提供对病毒感染的快速早期反应，因此可以 在很大程度上影响到疾病调控和疫苗保护。传统上，NK细胞一直是 被认为是先天免疫的非特异性成分，但最近在老鼠身上的研究已经 研究表明，NK细胞也可以表现出抗原特异性记忆的特征。直到最近，它还 目前尚不清楚这种现象是否存在于灵长类动物中，但我们的初步数据 首次证明了抗原特异性NK细胞记忆在 灵长类物种。与未感染猕猴的NK细胞相比，脾和肝脏 猴免疫缺陷病毒(SIV)感染动物的NK细胞对 GAG和Env冲击的树突状细胞(DC)，但不对抗模拟冲击的DC或错配的抗原 控制。在治疗和未治疗的HIV-1中发现了相似的Gag特异性NK细胞反应。 被感染的病人。有趣的是，外周血中的记忆性NK细胞反应很低 与远端部位相比，提示记忆性NK细胞主要存在于组织中。我们也 恒河猴接种疫苗后5年以上发现NK细胞记忆反应 用表达HIV-1 Env或SIV Gag的重组AD26载体指示抗原特异性 NK细胞的记忆是持久的，不需要持续的抗原刺激。这个 灵长类动物记忆性NK细胞反应的寿命、功能和特异性表明它们 功能相关性及其对HIV-1和其他病原体的潜在重要性。在这 新建议我们将解决这一新研究领域的主要缺陷，包括确定 这些反应的机制、动力学、分布和有效性使用最先进的 技巧。我们将评估记忆NK细胞反应的主要假设 诱导的抗SIV/HIV和腺病毒疫苗载体即使在没有 复制病毒，并可被动员起来参与并裂解抗原中感染病毒的细胞- 具体的方式。我们将以三个有重点的具体目标来评估这个假设：(1)评估 抗HIV和SIV疫苗抗原诱导的记忆NK细胞的动员和召回 在人类和猕猴中；(2)评价记忆NK的动员和维持 免疫和未免疫猕猴SIV攻击后的细胞；(3)探索 记忆NK细胞识别和特异性的细胞和分子机制。

Natural killer (NK) cells provide rapid early responses to viral infections and thus can contribute substantially to disease modulation and vaccine protection. Traditionally, NK cells have been considered to be nonspecific components of innate immunity, but recent studies in mice have shown that NK cells can also demonstrate features of antigen-specific memory. Until recently it was unclear whether this phenomenon might exist in primates, but our preliminary data demonstrates for the first time evidence of antigen-specific NK cell memory in any primate species. As compared with NK cells from uninfected macaques, splenic and hepatic NK cells from simian immunodeficiency virus (SIV)-infected animals were highly reactive to Gag- and Env-pulsed dendritic cells (DCs) but not to mock-pulsed DCs or mis-matched antigen controls. Similar Gag-specific NK cell responses were found in treated and untreated HIV-1- infected patients. Interestingly, memory NK cell responses in peripheral blood were low compared to distal sites, suggesting memory NK cells reside predominantly in tissues. We also found NK cell memory responses in rhesus macaques for over 5 years following vaccination with recombinant Ad26 vectors expressing HIV-1 Env or SIV Gag indicating antigen-specific NK cell memory is durable and does not require ongoing antigenic stimulation. The longevity, functionality, and specificity of memory NK cell responses in primates suggest their functional relevance and their potential importance against HIV-1 and other pathogens. In this new proposal we will address major deficits to this new field of study including identifying the mechanisms, kinetics, distribution, and efficacy of these responses using state-of-the-art techniques. We will evaluate the overarching hypothesis that memory NK cell responses elicited against SIV/HIV and adenovirus vaccine vectors are long-lived even in the absence of replicating virus and can be mobilized to engage and lyse virus-infected cells in an antigen- specific manner. We will evaluate this hypothesis with three focused Specific Aims: (1) Evaluate mobilization and recall of memory NK cells elicited against HIV and SIV vaccine antigens in humans and macaques; (2) Evaluate mobilization and maintenance of memory NK cells after SIV challenge in vaccinated and unvaccinated macaques; and (3) Explore cellular and molecular mechanisms of memory NK cell recognition and specificity.