Functional genetics of human innate immunity in the bimodal gamma delta T cell response to Epstein-Barr Virus and in education of NK cells and their re-education to respond to autologous cells

人类先天免疫的功能遗传学在双峰 γδT 细胞对 Epstein-Barr 病毒的反应以及 NK 细胞的教育及其对自体细胞作出反应的再教育中

基本信息

  • 批准号:
    10552637
  • 负责人:
  • 金额:
    $ 39.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-02-05 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

This project investigates how human genetic variation diversifies innate immune responses to infection and cancer. Aim 1 concerns innate immunity to Epstein-Barr Virus (EBV), a cause of cancer. We found humans form two equally sized groups based on their response to EBV. Group 1 make strong Natural Killer (NK) cell and Vγ9Vδ2 T cell responses, whereas Group 2 combine a vigorous NK cell response with a poor Vγ9Vδ2 T cell response. This difference does not correlate with sex, HLA type, prior exposure to EBV or CMV, abundance of Vγ9Vδ2 T cells, or their functionality in the two groups. We propose that this even balance of responders and non-responders arises because of costs and benefits in making a Vγ9Vδ2 T cell response to EBV. Genetic precedents from our previous work are functionally distinctive haplotypes of both the killer cell immunoglobulin-like receptor (KIR) gene family, and the HLA class I gene family. We will determine genetic and functional differences that distinguish Group 1 and 2 donors, with three approaches. First, we will define the γδ T cell receptor repertoires for resting and EBV-activated γδ T cells of Group 1 and 2 donors. Second, we will define the phenotype and function of EBV-responding Vγ9Vδ2 T cells and NK cells in Group 1 and 2 individuals. Third, the γδ T cells of Group 1 and 2 individuals will be compared by high throughput RNA sequencing. Aim 2 examines NK cell and γδ T cell crosstalk in response to EBV. Our preliminary data shows that γδ T cells have an inhibitory effect on NK cell function in the context of EBV, and that this effect is distinct in Group 1 vs Group 2 donors. We propose an examination of NK cell and γδ T cell crosstalk that incorporates both NK cell educational status, and the dichotomous γδ T cell responses to EBV. Aim 3 examines interactions between KIR and HLA-A, B and C that control NK cell development and responses to infected or malignant cells that have low expression of HLA class I. These interactions involve four HLA class I epitopes and four inhibitory KIR (iKIR). The polymorphism of KIR and HLA, their independent segregation and stochastic KIR expression, mean that most humans express ligands without receptors and vice versa. During development, NK cells expressing an HLA epitope and its cognate iKIR, become educated to kill cells that lack the epitope. Consequently, educated NK cells can instigate a graft-versus-tumor (GVT) response in leukemia patients following allogeneic hematopoietic cell transplant. The GVT response clears residual tumor cells and improves patient survival. Preliminary experiments demonstrate that NK cells can be re-educated in vitro to kill malignant cells. We will determine the potential for re-education in a donor cohort representing all 12 common genetic combinations of the 4 HLA epitopes. This will give new insight on NK cell education and provide the foundation for re-educating autologous NK cells as immunotherapy for leukemia. In summary, this work will define the genetic and mechanistic parameters of three phenomena: the dichotomous Vγ9Vδ2 T cell response to EBV, Vγ9Vδ2T cell crosstalk with NK cells, and in vitro NK cell re-education.
该项目研究人类遗传变异如何使对感染和感染的先天免疫反应多样化 癌症。目标 1 涉及对 Epstein-Barr 病毒 (EBV) 的先天免疫,EBV 是癌症的一种原因。我们发现了人类 根据他们对 EBV 的反应分成两个同等规模的小组。第 1 组产生强大的自然杀伤 (NK) 细胞 和 Vγ9Vδ2 T 细胞反应,而第 2 组结合了强烈的 NK 细胞反应和较差的 Vγ9Vδ2 T 细胞反应 细胞反应。这种差异与性别、HLA 类型、之前接触过 EBV 或 CMV 无关, Vγ9Vδ2 T 细胞的丰度,或其在两组中的功能。我们建议,这种均匀平衡 反应者和非反应者的出现是因为 Vγ9Vδ2 T 细胞对 EB病毒。我们之前工作的遗传先例是杀伤细胞的功能独特的单倍型 免疫球蛋白样受体 (KIR) 基因家族和 HLA I 类基因家族。我们将确定遗传 以及区分第 1 组和第 2 组捐赠者的功能差异,采用三种方法。首先,我们将定义 第 1 组和第 2 组供体的静息和 EBV 激活的 γδ T 细胞的 γδ T 细胞受体库。第二,我们 将定义第 1 组和第 2 组中 EBV 反应性 Vγ9Vδ2 T 细胞和 NK 细胞的表型和功能 个人。第三,将通过高通量RNA比较第1组和第2组个体的γδ T细胞 测序。目标 2 检查 NK 细胞和 γδ T 细胞对 EBV 的反应。我们的初步数据显示 γδ T 细胞在 EBV 背景下对 NK 细胞功能具有抑制作用,并且这种作用是明显的 在第 1 组与第 2 组捐赠者中。我们建议对 NK 细胞和 γδ T 细胞串扰进行检查,其中包括 NK 细胞的教育状况以及对 EBV 的二分 γδ T 细胞反应。目标 3 检查相互作用 KIR 与 HLA-A、B 和 C 之间,控制 NK 细胞发育以及对感染或恶性细胞的反应 HLA I 类低表达的细胞。这些相互作用涉及四个 HLA I 类表位和四个 抑制性 KIR (iKIR)。 KIR和HLA的多态性、独立分离和随机KIR 表达,意味着大多数人表达配体而不表达受体,反之亦然。在开发过程中, 表达 HLA 表位及其同源 iKIR 的 NK 细胞被训练去杀死缺乏该表位的细胞。 因此,受过训练的 NK 细胞可以激发白血病患者的移植物抗肿瘤 (GVT) 反应 同种异体造血细胞移植后。 GVT 反应可清除残留肿瘤细胞并改善 患者生存。初步实验表明NK细胞可以在体外进行再教育以杀死恶性细胞 细胞。我们将确定代表所有 12 种常见遗传基因的捐赠者群体接受再教育的可能性 4 个 HLA 表位的组合。这将为 NK 细胞教育提供新的见解并提供基础 用于重新培养自体 NK 细胞作为白血病的免疫疗法。总之,这项工作将定义 三种现象的遗传和机械参数:对 EBV 的二分 Vγ9Vδ2 T 细胞反应, Vγ9Vδ2T 细胞与 NK 细胞的串扰,以及体外 NK 细胞的再教育。

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Natural LILRB1 D1-D2 variants show frequency differences in populations and bind to HLA class I with various avidities.
  • DOI:
    10.1007/s00251-022-01264-7
  • 发表时间:
    2022-12
  • 期刊:
  • 影响因子:
    3.2
  • 作者:
    Liu, Fuguo;Cocker, Alexander T. H.;Pugh, Jason L.;Djaoud, Zakia;Parham, Peter;Guethlein, Lisbeth A.
  • 通讯作者:
    Guethlein, Lisbeth A.
Abundant CpG-sequences in human genomes inhibit KIR3DL2-expressing NK cells.
  • DOI:
    10.7717/peerj.12258
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    2.7
  • 作者:
    Pugh J;Guethlein L;Parham P
  • 通讯作者:
    Parham P
Phosphoantigen-Stimulated γδ T Cells Suppress Natural Killer-Cell Responses to Missing-Self.
  • DOI:
    10.1158/2326-6066.cir-21-0696
  • 发表时间:
    2022-05-03
  • 期刊:
  • 影响因子:
    10.1
  • 作者:
    Walwyn-Brown, Katherine;Pugh, Jason;Cocker, Alexander T. H.;Beyzaie, Niassan;Singer, Bernhard B.;Olive, Daniel;Guethlein, Lisbeth A.;Parham, Peter;Djaoud, Zakia
  • 通讯作者:
    Djaoud, Zakia
CD56-negative NK cells: Frequency in peripheral blood, expansion during HIV-1 infection, functional capacity, and KIR expression.
  • DOI:
    10.3389/fimmu.2022.992723
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    7.3
  • 作者:
    Cocker, Alexander T. H.;Liu, Fuguo;Djaoud, Zakia;Guethlein, Lisbeth A. A.;Parham, Peter
  • 通讯作者:
    Parham, Peter
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

PETER R PARHAM其他文献

PETER R PARHAM的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('PETER R PARHAM', 18)}}的其他基金

Functional genetics of human innate immunity in the bimodal gamma delta T cell response to Epstein-Barr Virus and in education of NK cells and their re-education to respond to autologous cells
人类先天免疫的功能遗传学在双峰 γδT 细胞对 Epstein-Barr 病毒的反应以及 NK 细胞的教育及其对自体细胞作出反应的再教育中
  • 批准号:
    10326842
  • 财政年份:
    2019
  • 资助金额:
    $ 39.13万
  • 项目类别:
Insights into immune-related disease born from population genomics
对群体基因组学产生的免疫相关疾病的见解
  • 批准号:
    8105084
  • 财政年份:
    2010
  • 资助金额:
    $ 39.13万
  • 项目类别:
Insights into immune-related disease born from population genomics
对群体基因组学产生的免疫相关疾病的见解
  • 批准号:
    8292223
  • 财政年份:
    2010
  • 资助金额:
    $ 39.13万
  • 项目类别:
Insights into immune-related disease born from population genomics
对群体基因组学产生的免疫相关疾病的见解
  • 批准号:
    8486379
  • 财政年份:
    2010
  • 资助金额:
    $ 39.13万
  • 项目类别:
Insights into immune-related disease born from population genomics
对群体基因组学产生的免疫相关疾病的见解
  • 批准号:
    7992673
  • 财政年份:
    2010
  • 资助金额:
    $ 39.13万
  • 项目类别:
Insights into immune-related disease born from population genomics
对群体基因组学产生的免疫相关疾病的见解
  • 批准号:
    8676643
  • 财政年份:
    2010
  • 资助金额:
    $ 39.13万
  • 项目类别:
Insights into immune-related disease born from population genomics
对群体基因组学产生的免疫相关疾病的见解
  • 批准号:
    9307690
  • 财政年份:
    2010
  • 资助金额:
    $ 39.13万
  • 项目类别:
Insights into immune-related disease born from population genomics
对群体基因组学产生的免疫相关疾病的见解
  • 批准号:
    9100613
  • 财政年份:
    2010
  • 资助金额:
    $ 39.13万
  • 项目类别:
NK cell Immunity to Influenza
NK细胞对流感的免疫
  • 批准号:
    7657174
  • 财政年份:
    2008
  • 资助金额:
    $ 39.13万
  • 项目类别:
MHC CLASS I AND KIR GENE EVOLUTION IN HIGHER PRIMATES
高等灵长类动物 MHC I 类和 KIR 基因的进化
  • 批准号:
    7349828
  • 财政年份:
    2006
  • 资助金额:
    $ 39.13万
  • 项目类别:

相似海外基金

Enhancing Structural Competency in School-Based Health Centers to Address LGBTQ+ Adolescent Health Equity
增强校本健康中心的结构能力,以解决 LGBTQ 青少年健康公平问题
  • 批准号:
    10608426
  • 财政年份:
    2023
  • 资助金额:
    $ 39.13万
  • 项目类别:
Application and feasability of a brief digital screening tool to address parental and adolescent tobacco and electronic cigarette use in pediatric medical care - a pilot study
简短的数字筛查工具的应用和可行性,以解决儿科医疗中父母和青少年烟草和电子烟的使用问题 - 一项试点研究
  • 批准号:
    486580
  • 财政年份:
    2022
  • 资助金额:
    $ 39.13万
  • 项目类别:
    Studentship Programs
Co-design of an intervention to address alcohol use among adolescent boys and young men in Tanzania
共同设计一项干预措施,解决坦桑尼亚青春期男孩和年轻男性的饮酒问题
  • 批准号:
    MR/V032380/1
  • 财政年份:
    2022
  • 资助金额:
    $ 39.13万
  • 项目类别:
    Research Grant
Complex intervention to optimise adolescent BMI pre-conception to address the double burden of malnutrition: A RCT in rural and urban South Africa
优化青少年孕前体重指数以解决营养不良的双重负担的复杂干预措施:南非农村和城市的随机对照试验
  • 批准号:
    MR/V005790/1
  • 财政年份:
    2021
  • 资助金额:
    $ 39.13万
  • 项目类别:
    Research Grant
Application of a brief digital screening tool to address parental and adolescent tobacco and electronic cigarette use in pediatric medical care
应用简短的数字筛查工具来解决儿科医疗中父母和青少年烟草和电子烟的使用问题
  • 批准号:
    455984
  • 财政年份:
    2021
  • 资助金额:
    $ 39.13万
  • 项目类别:
    Operating Grants
Complex intervention to optimise adolescent BMI pre-conception to address the double burden of malnutrition: A RCT in rural and urban South Africa
优化青少年孕前体重指数以解决营养不良的双重负担的复杂干预措施:南非农村和城市的随机对照试验
  • 批准号:
    MR/V005790/2
  • 财政年份:
    2021
  • 资助金额:
    $ 39.13万
  • 项目类别:
    Research Grant
Development of the Cannabis Actions and Practices (CAP): A Parent-Focused Intervention to Address Adolescent Marijuana Use
大麻行动和实践 (CAP) 的发展:以家长为中心的干预措施,解决青少年大麻使用问题
  • 批准号:
    10057761
  • 财政年份:
    2020
  • 资助金额:
    $ 39.13万
  • 项目类别:
Development of the Cannabis Actions and Practices (CAP): A Parent-Focused Intervention to Address Adolescent Marijuana Use
大麻行动和实践 (CAP) 的发展:以家长为中心的干预措施,解决青少年大麻使用问题
  • 批准号:
    10213683
  • 财政年份:
    2020
  • 资助金额:
    $ 39.13万
  • 项目类别:
Targeted interventions to address the multi-level effects of gender-based violence on PrEP uptake and adherence among adolescent girls and young women in Kenya
有针对性的干预措施,以解决性别暴力对肯尼亚少女和年轻妇女接受和坚持 PrEP 的多层面影响
  • 批准号:
    9403567
  • 财政年份:
    2017
  • 资助金额:
    $ 39.13万
  • 项目类别:
Designing targeted interventions to address HIV vulnerabilities and improve clinical outcomes among conflict affected adolescent girls and young women under 25 in Northern Uganda
设计有针对性的干预措施,以解决乌干达北部受冲突影响的少女和 25 岁以下年轻妇女的艾滋病毒脆弱性并改善临床结果
  • 批准号:
    356145
  • 财政年份:
    2016
  • 资助金额:
    $ 39.13万
  • 项目类别:
    Operating Grants
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了