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: 10524050
• 负责人: Todd Christopher Bradley
• 金额: $ 79.28万
• 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/10524050
• 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 envelope protein; 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; permissiveness; receptor; response; vaccination strategy; vaccine 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，但在 多年的慢性感染后，大约一半的HIV-1感染者。机制的定义 这种使BNAB在感染期间的开发将为能够引起疫苗接种策略铺平道路 bnabs。 BNAB不容易引起的一些原因是它们对高免疫球蛋白基因的要求 需要连续的B细胞亲和力成熟的体细胞超突变，并且 它们受宿主监管控制的限制。我们最近确定，HIV-1感染的人 开发的BNAB具有更多功能失调的天然杀手（NK）细胞，循环频率更高 为B细胞提供关键帮助的CD4+ T卵泡辅助（TFH）细胞。我们进一步证明了激活的 来自HIV副供体的NK细胞可以减少TFH细胞数量，并降低NK-TFH-的B细胞活性 B细胞共培养。这些数据导致了我们提出的科学前提，即NK细胞失调导致 NK细胞对TFH可用性的限制减少，这有助于HIV-1感染期间BNAB的发育。 这将NK细胞确定为HIV-1 BNAB响应的潜在关键调节剂。总体目标 建议是测试我们的中心假设，即NK细胞免疫调节活性的瞬时阻断 通过增加生发来创建一种允许开发HIV-1 BNAB的免疫学环境 中心T和B细胞反应。初步研究的结果支持了这一假设 在恒河猕猴中进行，以解决瞬态NK耗竭对艾滋病毒反应的影响 包膜疫苗接种，其中观察到生发中心TFH和B细胞频率的增加 与没有HIV疫苗的动物相比，在HIV疫苗接种期间NK细胞耗尽的猕猴 NK细胞耗竭。我们的具体目的将检验以下假设：（ AIM 1）来自HIV-1感染的NK细胞 产生BNAB的个体将具有比HIV-的个人更受损害的免疫调节能力 没有bnabs的人； （AIM 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； （AIM 3）确定瞬时NK细胞耗竭的机理 生发中心HIV-1中和抗体反应。这个项目具有创新性，因为我们已经确定 NK细胞功能障碍有助于HIV-1 BNAB发育，并证明了NK的耗竭 免疫后细胞改善生发中心活性。这项贡献很重要，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 细胞曲目和体内功能将识别可在 HIV-1疫苗接种以改善免疫反应。