Role of Frizzled 5 in NK cell development and antiviral host immunity

Frizzled 5 在 NK 细胞发育和抗病毒宿主免疫中的作用

• 批准号: 10748776
• 负责人: Mark Owyong
• 金额: $ 4.77万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748776
• 关键词: Ablation; Adult; Affect; Anti-viral Response; Antigens; Antiviral Therapy; Apoptosis; Attenuated; B-Lymphocytes; Binding; Biological Assay; Bone Marrow; CD8-Positive T-Lymphocytes; Cell Count; Cell Maturation; Cell Survival; Cell Therapy; Cell physiology; Cells; Cellular Immunity; Characteristics; Chickenpox; Chimera organism; Clonal Expansion; Complement; Complex; Confocal Microscopy; Cytomegalovirus; Cytomegalovirus Infections; Data; Development; Effector Cell; Event; Exhibits; Family; Genes; Genetic Transcription; Goals; Herpes zoster disease; Homeostasis; Human; Human Herpesvirus 4; Immune; Immunity; Immunologic Memory; Individual; Inflammatory; Innate Immune System; Interferon Type II; Interleukin 2 Receptor Gamma; Interleukin-15; Ligand Binding; Ligands; Ligation; Mass Spectrum Analysis; Measures; Mediating; Mediator; Modeling; Molecular; Murid herpesvirus 1; Mus; Natural Immunity; Natural Killer Cells; Pathway interactions; Peripheral; Phenotype; Play; Predisposition; Production; Proliferating; Research; Role; Signal Transduction; Source; Spleen; T-Cell Development; TFRC gene; Testing; Transcriptional Regulation; Transgenic Mice; Viral; Viral Physiology; Virus Diseases; WNT Signaling Pathway; Western Blotting; Wild Type Mouse; adaptive immunity; antiviral immunity; beta catenin; c-myc Genes; chromatin immunoprecipitation; clinically significant; cytokine; cytotoxicity; factor C; immunoregulation; improved; insight; interest; member; neonatal mice; novel; novel strategies; novel therapeutics; overexpression; pathogen; receptor; receptor binding; response; trait; transcription factor; transcriptome sequencing

PROJECT SUMMARY Natural killer (NK) cells have been shown to play a dominant role in the immune-mediated control of viral infection in both humans and mice. Individuals lacking NK cells or NK cell function succumb to fatal viral infections, such as human cytomegalovirus (HCMV). Similarly neonatal mice, which lack mature peripheral NK cells, and adult mice with NK cell deficiencies are extremely susceptible to murine cytomegalovirus (MCMV) infection. Given the clinical significance of HCMV, MCMV infection in mice represents an appropriate model to study NK cell-mediated antiviral immunity. While NK cells are members of the innate immune system, it is now appreciated that NK cells share many characteristics with CD8+ T cells and can exhibit features of adaptive immunity. Although our understanding of the innate and adaptive features of NK cells has increased in the past decade, the molecular and transcriptional control of their development and optimal antiviral response remains unclear. Given the shared characteristics between NK cells and CD8+ T cells and that Wnt signaling in CD8+ T cells is instrumental for survival and in mediating responses against pathogens, I postulate that Wnt signaling plays an essential role in NK cell survival and antiviral function. However, the role of Wnt signaling in NK cells is largely unexplored. Thus, this proposal seeks to explore 1) how Wnt signaling is mediated in NK cells, 2) what Wnt ligands are modulating NK cells and what is the source of these ligands, and 3) what are the molecular events orchestrated by Wnt signaling in NK cells during development and host antiviral defense. While profiling the Frizzled (Fzd) family of receptors that bind to Wnt ligands, I found that Fzd5 is prominently and exclusively expressed on NK cells compared to other immune cells. To investigate the role of Fzd5 in NK cells, I generated a novel transgenic mouse containing NK cell-specific deletion of Fzd5. In preliminary data, Fzd5-deficient mice had diminished NK cell numbers and, strikingly, in a mixed bone marrow chimera, Fzd5-deficient NK cells were less capable of repopulating mice compared to wildtype NK cells. Additionally, Fzd5 is essential for proper antigen-specific clonal expansion of NK cells in response to MCMV infection. In Specific Aim 1 I will identify the downstream mediators of Fzd5 signaling and identify the Wnt ligand that binds to Fzd5 on NK cells. In Specific Aim 2 I will investigate the molecular mechanism of Wnt signaling in NK cell antiviral responses. At the completion of this F31 we will gain key insights into the complex transcriptional networks that are induced by Fzd5. The mechanistic insights derived from this study will be instrumental in the development of novel therapies that enhance NK cell function and influence strategies aimed at improving antiviral therapies.

项目摘要 天然杀手（NK）细胞已显示在免疫介导的病毒控制中起主要作用 人类和小鼠感染。缺乏NK细胞或NK细胞功能的个体屈服于致命病毒 感染，例如人类巨细胞病毒（HCMV）。类似地，新生儿小鼠，缺乏成熟的外围NK 细胞和NK细胞缺陷的成年小鼠非常容易受到鼠巨细胞​​病毒（MCMV）的影响 感染。鉴于HCMV的临床意义，小鼠的MCMV感染代表了适当的模型 研究NK细胞介导的抗病毒免疫。虽然NK细胞是先天免疫系统的成员，但现在是 理解NK细胞与CD8+ T细胞具有许多特征，并且可以表现出适应性的特征 免疫。尽管我们对NK细胞的先天和适应性特征的理解在过去增加了 十年，其发育的分子和转录控制以及最佳抗病毒反应仍然存在 不清楚。 鉴于NK细胞和CD8+ T细胞之间的共享特征，并且CD8+ T中的Wnt信号传导 细胞对生存和对病原体的介导反应有用，我假设Wnt信号传导 在NK细胞存活和抗病毒功能中起着至关重要的作用。但是，Wnt信号在NK细胞中的作用 在很大程度上没有探索。因此，该提案试图探索1）Wnt信号如何在NK细胞中介导，2） Wnt配体正在调节NK细胞，这些配体的来源是什么，3）什么是什么 WNT信号在发育和宿主抗病毒防御过程中由Wnt信号在NK细胞中策划的分子事件。 在分析与Wnt配体结合的毛躁（FZD）家族时，我发现FZD5是 与其他免疫细胞相比，在NK细胞上显着，仅在NK细胞上表达。调查 NK细胞中的FZD5，我产生了一种新型的转基因小鼠，该小鼠含有FZD5的NK细胞特异性缺失。在 初步数据，FZD5缺陷小鼠的NK细胞数量减少，并在混合的骨髓中引人注目 与野生型NK细胞相比，Chimera，FZD5缺陷的NK细胞能够重新填充小鼠的能力。 此外，FZD5对于响应MCMV的NK细胞的适当抗原特异性克隆膨胀至关重要 感染。在特定目标1中，我将确定FZD5信号的下游介质并确定Wnt 在NK细胞上与FZD5结合的配体。在特定目标2中，我将研究Wnt的分子机制 NK细胞抗病毒反应中的信号传导。 在此F31完成时，我们将获得对复杂转录网络的关键见解 由FZD5诱导。这项研究得出的机械见解将有助于发展 增强NK细胞功能并影响旨在改善抗病毒疗法的策略的新型疗法。