How antigen exposure shapes the subsequent NK cell response to HIV

抗原暴露如何影响随后的 NK 细胞对 HIV 的反应

• 批准号: 10924725
• 负责人: Silke Paust
• 金额: $ 43.88万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10924725
• 关键词: How; antigen; exposure; shapes; subsequent; How; antigen; exposure; shapes; subsequent

The goal of this proposal is to determine how antigen exposure shapes subsequent Natural Killer cell responses to HIV. We propose to identify NK functional subsets in naïve and antigen-primed human NK cells using single-cell sequencing and multi-parametric flow cytometry. We propose to verify the relevance of such functional subsets to NK cell-mediated host protection from HIV disease using our established in vitro and in vivo functional assays. NK cells are innate lymphocytes that live up to their name by their ability to kill infected or tumor cells within minutes of exposure. However, the targeting of NK cell effector functions has not been a significant focus in vaccine development, which has mainly focused on their T and B cell counterparts in the adaptive immune system. Recent findings from the PI of this application indicate that NK cells deserve more attention. We recently published exciting new data that human NK cells remember prior antigen- encounters and mediate enhanced recall responses to HIV-Envelope in humanized mice. Here, we present unpublished new data that HIV-Env-primed memory NK cells suppress HIV viral titers upon experimental viral challenge. These findings have opened the opportunity to harness NK memory functions for vaccine design. However, high NK cell receptor repertoire diversity is associated with an increased risk of HIV acquisition, and NK cell receptor repertoires diversify throughout life, presumably in response to antigen exposure. These data present a challenge for vaccine design, as both protective NK memory responses and potentially risky NK repertoire diversifications are consequences of antigen exposure. The identification of specific functional subsets of HIV-responsive, host-protective NK cells and their mechanisms of host protection is therefore critically needed. Their discovery will open the door for revised vaccine designs that endure the incorporation of NK memory, rather than harmful receptor repertoire diversity, as a host protective outcome. Our data will enable the pre-screening of vaccines for the induction of protective NK functional subsets in pre- clinical models and allow for improved vaccine efficacy evaluations in humans. Thereby, our studies will provide the rationale to develop novel vaccines that exploit the antiviral activity of NK cells to protect humans from HIV infection while avoiding harmful activity.

该提案的目的是确定抗原暴露如何形状随后的天然杀手细胞 对艾滋病毒的反应。我们建议鉴定幼稚和抗原化力的人NK细胞中的NK功能子集 使用单细胞测序和多参数流式细胞仪。我们建议验证 这种功能性亚星用于NK细胞介导的宿主对HIV疾病的保护，使用我们已建立的体外 和体内功能测定。 NK细胞是天生的淋巴细胞，通过杀人的能力辜负其名称 在暴露几分钟内感染或肿瘤细胞。但是，NK细胞效应子功能的靶向尚未 是疫苗开发的重点，主要集中在其T和B细胞对应物上 在自适应免疫系统中。该应用程序的PI的最新发现表明NK细胞应该得到 更多关注。我们最近发布了令人兴奋的新数据，人类NK细胞记得先前的抗原 - 人性化小鼠中的遭遇和中位数增强了对HIV-Envelope的回忆反应。在这里，我们在这里 未发表的新数据，HIV-ENV引发的记忆NK细胞在实验性病毒时抑制HIV病毒滴度 挑战。这些发现为利用疫苗设计的NK内存功能开辟了机会。 但是，高NK细胞受体库的多样性与增加HIV的风险增加有关， NK细胞受体的曲目一生都会多样化，大概是响应抗原暴露的。 这些数据构成了疫苗设计的挑战 有风险的NK曲目多样性是抗原暴露的后果。特定的识别 HIV响应性，宿主保护NK细胞及其宿主保护机制的功能子集为 因此需要至关重要。他们的发现将为经过修订的疫苗设计打开大门 纳入NK记忆，而不是有害受体库的多样性，作为宿主保护结果。 我们的数据将使疫苗预先筛查诱导受保护的NK功能子集中的疫苗 临床模型，并允许改善人类的疫苗效率评估。因此，我们的学习将 提供开发新型疫苗的理由，以利用NK细胞的抗病毒活性保护人类 从艾滋病毒感染中，同时避免有害活动。