Targeting natural killer cells to enhance HIV vaccine responses

针对自然杀伤细胞增强艾滋病毒疫苗反应

• 批准号: 10217993
• 负责人: Stephen N. Waggoner
• 金额: $ 65.73万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217993
• 关键词: ASCL2 gene; Address; Affinity; Animal Model; Antibodies; Antibody Response; Antigens; B-Lymphocytes; BLR1 gene; Bone Marrow; CD4 Positive T Lymphocytes; CRISPR screen; Cell physiology; Cells; Cessation of life; Chimera organism; Clinical; Critical Pathways; Cytolysis; Data; Development; Evolution; Exhibits; Generations; Genes; Genetic Transcription; HIV; HIV Infections; HIV vaccine; HIV-1; Helper-Inducer T-Lymphocyte; Homing; Human; Humoral Immunities; ITGB3 gene; Immune; Immune response; Immunization; Immunoglobulin Somatic Hypermutation; Immunoglobulins; Immunologic Memory; Immunologics; Impairment; Individual; Infection; Infection prevention; Inflammation; Integrins; Invaded; Knock-in Mouse; Knockout Mice; Knowledge; Ligands; Lymphoid Tissue; Malpighian corpuscles; Mediating; Mediator of activation protein; Molecular; Mouse Strains; Mus; Natural Killer Cells; Outcome Study; Pharmacology; Phenotype; Predisposition; Proteins; Recording of previous events; Research; Role; Secretory Vesicles; Site; Somatic Mutation; Structure of germinal center of lymph node; T cell response; T-Lymphocyte; Testing; Transgenic Organisms; Up-Regulation; Vaccination; Vaccines; Work; Yellow Fever Vaccine; adaptive immune response; base; cell killing; cell motility; checkpoint receptors; chemokine receptor; conditional knockout; cytotoxic; experimental study; gene discovery; global health; human model; immune checkpoint; immunoregulation; improved; in vivo; innovation; migration; neutralizing antibody; next generation; novel vaccines; pandemic disease; pathogen; perforin; prevent; prophylactic; public health intervention; public health relevance; receptor; response; restraint; small molecule; small molecule inhibitor; success; tool; transcription factor; translational approach; vaccine efficacy; vaccine response

PI: Waggoner, Stephen Noel, “Targeting natural killer cells to enhance HIV vaccine responses” ABSTRACT Immunization represents one of the most successful public health interventions in human history, preventing more than 2 million deaths each year. Most licensed vaccines work by eliciting antibodies that can prevent infection by neutralizing the invading pathogen. However, vaccine-mediated induction of broadly neutralizing antibodies capable of thwarting infection with a highly mutable pathogen like HIV has proven exceptionally difficult in both humans and animal models. This shortcoming in vaccine success is likely due to intrinsic immune regulatory mechanisms that limit the quantity and quality of immune responses. Development of translational means to overcome these immunological roadblocks holds great promise for advancement of next-generation vaccines to prevent infection and improve global health. Our research focuses on the remarkable capacity of natural killer (NK) cells to suppress T and B cell responses. NK cells limit the magnitude and quality of adaptive immune memory triggered after immunization. This activity of NK cells impairs the generation of protective neutralizing antibody responses by restricting somatic mutation and affinity maturation of these antibodies within germinal centers. We find that a subset of transcriptionally unique NK cells migrates to sites of germinal center formation following immunization and contributes to suppression of follicular helper T cells (Tfh) differentiation via perforin-mediated elimination of activated CD4 T cells. We identify key effector molecules, receptors, and transcription factors that are putatively vital for this immunosuppressive activity of NK cells, and therefore represent innovative targets to enhance vaccine efficacy. The overall objective of this proposal is to test the scientific premise that cytotoxic functions of NK cells limit vaccine-mediated generation of HIV-specific broadly neutralizing antibodies. We propose three thematically connected aims that explore the contributions of various mediators that determine the cytotoxic immunoregulatory capacity of NK cells during immunization. In Aim 1, we will use cutting-edge knock-in mice to test the hypothesis that transient small molecule inhibition of NK-cell cytolytic function during immunization can safely and effective augment germinal center-mediated maturation of HIV-specific antibody responses. In Aim 2, we will use innovative bone marrow chimera and conditional knock-out mice to define the role of a network of transcription factors, chemokine receptors, and integrins in localization of NK cells near developing Tfh to facilitate cytolysis of these target cells. In Aim 3, we will use a new strain of mice and pioneering CRISPR-based screens to discover receptors involved in promotion or restraint of NK-cell killing of CD4 T cells. These experiments will define factors that enable and calibrate NK-cell suppression of adaptive immune responses during infection. Thus, the proposed work will facilitate subsequent development and deployment of innovative strategies to enhance HIV vaccine efficacy.

PI：Waggoner，Stephen诺埃尔，“靶向自然杀伤细胞以增强艾滋病毒疫苗反应” 摘要 免疫接种是人类历史上最成功的公共卫生干预措施之一， 每年超过两百万人死亡。大多数获得许可的疫苗通过引发抗体来预防 通过中和入侵的病原体来感染。然而，疫苗介导的广泛中和的诱导 一种能够阻止像艾滋病毒这样的高度变异病原体感染的抗体已经被证明是非常罕见的 在人类和动物模型中都很困难。这种疫苗成功的缺点可能是由于内在免疫 限制免疫应答的数量和质量的调节机制。发展翻译 克服这些免疫障碍的方法为下一代免疫学的发展带来了巨大的希望。 预防感染和改善全球健康。 我们的研究集中在自然杀伤（NK）细胞抑制T和B细胞反应的显着能力。 NK细胞限制了免疫后触发的适应性免疫记忆的大小和质量。这项活动 NK细胞通过限制体细胞突变削弱保护性中和抗体应答的产生 以及这些抗体在生发中心内的亲和力成熟。我们发现转录上的一个子集 独特的NK细胞在免疫后迁移到生殖中心形成的部位， 通过穿孔素介导的活化的CD4 T细胞的消除抑制滤泡辅助性T细胞（Tfh）分化 细胞我们确定了关键的效应分子、受体和转录因子，它们对此至关重要。 NK细胞的免疫抑制活性，因此代表了增强疫苗功效的创新靶标。 本提案的总体目标是检验NK细胞的细胞毒性功能限制 疫苗介导的HIV特异性广泛中和抗体的产生。我们提出三个主题 连接的目的，探索决定细胞毒性的各种介质的贡献， NK细胞在免疫过程中的免疫调节能力。在目标1中，我们将使用最先进的基因敲入小鼠， 测试免疫过程中NK细胞溶细胞功能的瞬时小分子抑制可以 安全有效地增强生发中心介导的HIV特异性抗体应答的成熟。在Aim中 2，我们将使用创新的骨髓嵌合体和条件性基因敲除小鼠来定义网络的作用， 转录因子、趋化因子受体和整合素在NK细胞定位中的作用， 促进这些靶细胞的细胞溶解。在目标3中，我们将使用一种新的小鼠品系， 筛选以发现参与促进或抑制NK细胞杀伤CD4 T细胞的受体。这些 实验将确定使适应性免疫反应的NK细胞抑制能够实现和校准的因素 在感染期间。因此，拟议的工作将有助于后续开发和部署创新的 提高艾滋病毒疫苗效力的战略。