Antigen-Specific NK Cell Memory Against SIV and HIV Vaccines

自然杀伤（NK）细胞对病毒感染提供快速的早期反应，因此可以做出贡献 基本上用于疾病调节和疫苗保护。传统上， 被认为是先天免疫的非特异性成分，但最近在小鼠中的研究表明， 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 目前还不清楚这种现象是否存在于灵长类动物中，但我们的初步数据显示， 首次证明了在任何免疫系统中抗原特异性NK细胞记忆的证据。 灵长类动物与未感染猕猴的NK细胞相比， 来自猴免疫缺陷病毒（SIV）感染动物的NK细胞对 Gag和Env脉冲的树突状细胞（DC），但不与模拟脉冲的DC或错配抗原 对照在治疗的和未治疗的HIV-1 - 1中发现了类似的GAG特异性NK细胞应答。 感染的病人。有趣的是，外周血中的记忆NK细胞应答较低， 与远端部位相比，提示记忆NK细胞主要存在于组织中。我们也 在恒河猴中发现NK细胞记忆反应，在接种疫苗后超过5年 用表达HIV-1 Env或SIV Gag的重组Ad26载体表明抗原特异性 NK细胞记忆是持久的，不需要持续的抗原刺激。的 灵长类动物记忆NK细胞应答的寿命、功能和特异性表明， 功能相关性及其对HIV-1和其他病原体的潜在重要性。在这 我们将解决这一新研究领域的主要不足，包括确定 这些反应的机制、动力学、分布和功效， 技术.我们将评估记忆NK细胞反应的总体假设， 针对SIV/HIV和腺病毒的疫苗载体即使在缺乏 复制病毒，并且可以被动员以在抗原中接合和裂解病毒感染的细胞， 具体方式。我们将通过三个重点具体目标来评估这一假设：（1）评估 HIV和SIV疫苗抗原诱导的记忆NK细胞的动员和回忆 在人类和猕猴中;（2）评估NK细胞的记忆动员和维持 在接种疫苗和未接种疫苗的猕猴中SIV攻击后的细胞;和（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.