Antigen-Specific NK Cell Memory Against SIV and SIV Vaccines

针对 SIV 的抗原特异性 NK 细胞记忆和 SIV 疫苗

• 批准号: 9078188
• 负责人: Roger Keith Reeves
• 金额: $ 71.7万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9078188
• 关键词: Address; Adenoviruses; Animals; Antigens; Cells; Chronic; Containment; Coupled; Cytolysis; Data; Dendritic Cells; Development; Disease; Disease Progression; Epidemiology; Exhibits; Gagging; Genotype; Grant; HIV; HIV Infections; HIV-1; Health; Hepatic; Hepatitis C virus; Human; Immune; Immune response; Immunoglobulins; In Vitro; Incidence; Individual; Infection; Kinetics; Life; Ligands; Liver; Longevity; Macaca; Macaca mulatta; Maintenance; Mann-Whitney U Test; Mediating; Memory; Molecular; Mus; Natural Immunity; Natural Killer Cells; Outcome; Peptides; Phenotype; Physiologic pulse; Play; Primates; Property; Proteins; Recombinants; Relative (related person); Role; SIV; Sampling; Series; Shapes; Specificity; Spleen; Structure; Techniques; Testing; Time; Tissues; Vaccinated; Vaccination; Vaccine Antigen; Vaccine Research; Vaccines; Vertical Disease Transmission; Viral; Viral Antigens; Virus; Virus Diseases; Work; antigen processing; arm; base; cytotoxic; field study; in vivo; memory recall; mouse model; natural killer cell protein 44-kDa; neoplastic cell; pathogen; peripheral blood; pressure; receptor function; research study; response; trafficking; vector; vector vaccine

 DESCRIPTION (provided by applicant): 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. Interestingly, memory NK cell responses in peripheral blood were marginal, 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 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) To evaluate mobilization and recall of memory NK cells elicited against SIV vaccine antigens; (2) To evaluate mobilization and maintenance of memory NK cells after SIV challenge in vaccinated and unvaccinated macaques; and (3) To explore cellular and molecular mechanisms of memory NK cell recognition and specificity.

 描述（由申请人提供）：自然杀伤（NK）细胞对病毒感染提供快速的早期反应，因此可以显著促进疾病调节和疫苗保护。传统上，NK细胞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，NK细胞也可以表现出抗原特异性记忆的特征。直到最近，人们还不清楚这种现象是否存在于灵长类动物中，但我们的初步数据首次证明了任何灵长类物种中抗原特异性NK细胞记忆的证据。与未感染猕猴的NK细胞相比，猴免疫缺陷病毒（SIV）感染动物的脾和肝NK细胞对Gag和Env脉冲树突状细胞（DC）具有高度反应性，但对模拟脉冲DC或不匹配的抗原对照没有反应。有趣的是，外周血中的记忆NK细胞应答是边缘性的，表明记忆NK细胞主要存在于组织中。我们还发现，在用表达HIV-1 Env或SIV Gag的重组Ad 26载体接种后，恒河猴中的NK细胞记忆应答持续超过5年，表明抗原特异性NK细胞记忆是持久的，并且不需要持续的抗原刺激。灵长类动物记忆NK细胞应答的寿命、功能和特异性表明它们的功能相关性及其对HIV-1和其他病原体的潜在重要性。在这个新的提案中，我们将解决这个新的研究领域的主要缺陷，包括使用最先进的技术确定这些反应的机制，动力学，分布和功效。我们将评估以下总体假设：即使在没有复制病毒的情况下，针对SIV和腺病毒疫苗载体引起的记忆NK细胞应答也是长寿命的，并且可以被动员以抗原特异性方式参与和裂解病毒感染的细胞。我们将评估这一假设与三个重点具体目标：（1）以评估动员和回忆的记忆NK细胞引起的SIV疫苗抗原;（2）以评估动员和维持记忆NK细胞后SIV攻击免疫和未接种猕猴;（3）探索记忆NK细胞识别和特异性的细胞和分子机制。