Natural killer cell regulation of the germinal center HIV neutralizing antibody response

自然杀伤细胞对生发中心 HIV 中和抗体反应的调节

• 批准号: 10063847
• 负责人: Todd Christopher Bradley
• 金额: $ 68.7万
• 依托单位: CHILDREN'S MERCY HOSP (KANSAS CITY, MO)
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063847
• 关键词: Activated Natural Killer Cell; Address; Affect; Affinity; Animals; Antibody Response; Antigens; B cell repertoire; B-Lymphocytes; Cell Count; Cell physiology; Cells; Coculture Techniques; Data; Development; Environment; Exhibits; Frequencies; Functional disorder; Future; HIV; HIV Antibodies; HIV Seronegativity; HIV immunization; HIV-1; HIV-1 vaccine; Health Priorities; Helper-Inducer T-Lymphocyte; Human; Immune response; Immunization; Immunoglobulin Genes; Immunoglobulin Somatic Hypermutation; Immunologics; Impairment; In Vitro; Individual; Infection; Learning; Ligands; Macaca; Macaca mulatta; Mediating; Memory; Metabolism; Molecular; Monkeys; Mus; Mutate; Mutation; Natural Killer Cells; Pathway interactions; Phenotype; Plasmablast; Publications; Receptor Cell; Recombinants; Regulation; Stimulus; Structure of germinal center of lymph node; System; T-Cell Receptor; T-Lymphocyte; Testing; Vaccinated; Vaccination; Vaccines; antigen binding; chronic infection; cytotoxicity; global health; immunoregulation; improved; in vivo; innovation; neutralizing antibody; novel; receptor; response; vaccination strategy

Project Summary/Abstract: HIV-1 broadly neutralizing antibodies (bnAbs) are difficult to induce with vaccines, but are generated in approximately half of HIV-1-infected individuals after years of chronic infection. Definition of the mechanisms that enable bnAb development during infection will pave the way for vaccination strategies capable of eliciting bnAbs. Some reasons bnAbs are not readily induced are their requirement for high immunoglobulin gene somatic hypermutation that requires successive rounds of B cell affinity maturation in germinal centers and their limitation by host regulatory controls. We have recently identified that HIV-1-infected individuals who developed bnAbs have more dysfunctional natural killer (NK) cells as well as higher frequencies of circulating CD4+ T follicular helper (Tfh) cells that provide critical help to B cells. We further demonstrated that activated NK cells from HIV-seronegative donors could reduce Tfh cell numbers and decrease B cell activity in NK-Tfh- B cell co-cultures. These data led to the scientific premise of our proposal that NK cell dysregulation results in reduced NK cell constraints on Tfh availability which contributes to bnAb development during HIV-1 infection. This identified NK cells as a potential key regulator of the HIV-1 bnAb response. The overall objective of this proposal is to test our central hypothesis that transient blockade of NK cell immunoregulatory activity will create an immunological environment permissive for the development of HIV-1 bnAbs by increasing germinal center T and B cell responses. This hypothesis is supported by results from a preliminary study we have performed in rhesus macaques to address the effects of transient NK depletion on the response to HIV Envelope vaccination, where an increase in germinal center Tfh and B cell frequencies was observed in macaques that had NK cells depleted during HIV vaccination compared with HIV vaccinated animals without NK cell depletion. Our specific aims will test the following hypotheses: (Aim 1) NK cells from HIV-1-infected individuals generating bnAbs will have a more impaired immunoregulatory capacity than those from HIV- infected individuals without bnAbs; (Aim 2) We will define the critical NK cell receptor-Tfh ligands important for NK cell inhibition of Tfh and B cells; (Aim 3) Determine the mechanisms of transient NK cell depletion on the germinal center HIV-1 neutralizing antibody response. This project is innovative because we have identified that NK cell dysfunction contributes to HIV-1 bnAb development and have demonstrated in depletion of NK cells improves germinal center activity after immunization. This contribution is significant because identifying the molecular mechanisms and receptor-ligand interactions that mediate NK cell inhibition of Tfh and B cell responses and determining the effect of NK cell depletion or receptor blockade on germinal center B cell a Tfh cell repertoire and function in vivo will identify novel NK cell-targeting strategies that can be applied during HIV-1 vaccination to improve immune responses.

项目摘要/摘要： HIV-1 广泛中和抗体 (bnAb) 很难用疫苗诱导，但可以在 大约一半的 HIV-1 感染者经过多年的慢性感染。机制的定义 使 bnAb 在感染过程中得以发展，将为能够引发的疫苗接种策略铺平道路 bnAb。 bnAb 不易诱导的一些原因是它们需要高免疫球蛋白基因 体细胞超突变需要在生发中心进行连续几轮的 B 细胞亲和力成熟， 它们受到主机监管控制的限制。我们最近发现 HIV-1 感染者 开发的 bnAb 具有更多功能失调的自然杀伤 (NK) 细胞以及更高的循环频率 CD4+ T 滤泡辅助 (Tfh) 细胞为 B 细胞提供重要帮助。我们进一步证明激活 来自 HIV 血清阴性供体的 NK 细胞可以减少 NK-Tfh 中 Tfh 细胞的数量并降低 B 细胞活性 B 细胞共培养。这些数据为我们的提议提供了科学前提，即 NK 细胞失调会导致 减少 NK 细胞对 Tfh 可用性的限制，这有助于 HIV-1 感染期间 bnAb 的发育。 这表明 NK 细胞是 HIV-1 bnAb 反应的潜在关键调节因子。本次活动的总体目标 建议是测试我们的中心假设，即短暂阻断 NK 细胞免疫调节活性会 通过增加生发创造一个有利于 HIV-1 bnAb 发育的免疫环境 中心 T 和 B 细胞反应。我们的一项初步研究结果支持了这一假设 在恒河猴中进行的研究，旨在解决短暂的 NK 耗竭对 HIV 反应的影响 包膜疫苗接种，观察到生发中心 Tfh 和 B 细胞频率增加 与未接种 HIV 疫苗的动物相比，在 HIV 疫苗接种过程中 NK 细胞被耗尽的猕猴 NK 细胞耗竭。我们的具体目标将检验以下假设：（目标 1）来自 HIV-1 感染者的 NK 细胞 产生 bnAb 的个体的免疫调节能力将比 HIV 个体的免疫调节能力受损更严重。 没有 bnAb 的感染者； （目标 2）我们将定义关键的 NK 细胞受体 - Tfh 配体，对于 NK细胞抑制Tfh和B细胞； （目标 3）确定 NK 细胞瞬时耗竭的机制 生发中心 HIV-1 中和抗体反应。这个项目是创新的，因为我们已经确定 NK 细胞功能障碍有助于 HIV-1 bnAb 的发育，并已在 NK 耗竭中得到证实 细胞在免疫后提高生发中心活性。这一贡献意义重大，因为确定 介导 NK 细胞抑制 Tfh 和 B 细胞的分子机制和受体-配体相互作用 反应并确定 NK 细胞耗竭或受体阻断对生发中心 B 细胞 a Tfh 的影响 细胞库和体内功能将确定新的 NK 细胞靶向策略，可在 HIV-1 疫苗接种可改善免疫反应。