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
- 来源:
- 关键词:Activated Natural Killer CellAddressAdolescentAdultAffectAllogenicAutologousBlood CellsBurkitt LymphomaCancer EtiologyCancer PatientCell LineCell physiologyCellsChildClinicalCoculture TechniquesCommunicable DiseasesComplementComplexCosts and BenefitsCytomegalovirusDataDevelopmentDiagnosisDiseaseDonor personEducationEducational StatusEpitopesEpstein-Barr Virus InfectionsEpstein-Barr Virus latencyEquilibriumExhibitsExposure toFoundationsFrequenciesGenderGene FamilyGenesGeneticGenetic PolymorphismGenetic VariationGraft-Versus-Tumor InductionHLA Class I GenesHLA-A geneHaplotypesHigh-Throughput RNA SequencingHumanHuman GeneticsHuman Herpesvirus 4ImmuneImmune responseImmunogeneticsImmunoglobulinsImmunotherapyIn VitroIndividualInfectionInfectious MononucleosisInnate Immune ResponseInnate Immune SystemInvestigationKLRD1 geneKiller CellsKineticsLeukocytesLigandsLymphocyteLymphoma cellLytic PhaseMHC Class I GenesMalignant NeoplasmsMediatingModalityModelingMolecularNatural ImmunityNatural Killer Cell ImmunotherapyNatural Killer CellsNaturePatientsPeptidesPeripheral Blood Mononuclear CellPhasePhenotypePhysiologicalPopulationPredispositionProliferatingReceptor GeneRegulationResearchResidual NeoplasmResolutionRestSignal TransductionStudy modelsSurfaceSystemT cell responseT-LymphocyteT-cell receptor repertoireVariantWorkadaptive immunitycancer cellcell killingcohortexperimental studyhematopoietic cell transplantationimprovedin vitro Modelin vivoinsightlatent infectionleukemianeoplastic cellperipheral bloodreceptorreceptor expressionresponders and non-respondersresponsesegregationsextranscriptometranscriptome sequencingtreatment choicetumorγδ T cells
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先天免疫反应多样化,以应对感染和疾病
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
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
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
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PETER R PARHAM其他文献
PETER R PARHAM的其他文献
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{{ 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:
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:
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