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
• 负责人: PETER R PARHAM
• 金额: $ 39.13万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-05 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10326842
• 关键词: Activated Natural Killer Cell; Address; Adolescent; Adult; Affect; Allogenic; Autologous; Blood Cells; Burkitt Lymphoma; Cancer Etiology; Cancer Patient; Cell Line; Cell physiology; Cells; Cellular immunotherapy; Child; Clinical; Coculture Techniques; Communicable Diseases; Complement; Complex; Costs and Benefits; Cytomegalovirus; Data; Development; Diagnosis; Disease; Donor person; Education; Educational Status; Epitopes; Epstein-Barr Virus Infections; Epstein-Barr Virus latency; Equilibrium; Exhibits; Exposure to; Foundations; Frequencies; Gender; Gene Family; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Graft-Versus-Tumor Induction; HLA Class I Genes; HLA-A gene; Haplotypes; High-Throughput RNA Sequencing; Human; Human Genetics; Human Herpesvirus 4; Immune; Immune response; Immunogenetics; Immunoglobulins; Immunotherapy; In Vitro; Individual; Infection; Infectious Mononucleosis; Innate Immune Response; Innate Immune System; Investigation; KLRD1 gene; Killer Cells; Kinetics; Leukocytes; Ligands; Lymphocyte; Lymphoma cell; Lytic Phase; MHC Class I Genes; Malignant Neoplasms; Mediating; Modeling; Molecular; Natural Immunity; Natural Killer Cells; Nature; Patients; Peptides; Peripheral Blood Mononuclear Cell; Phase; Phenotype; Physiological; Population; Predisposition; Receptor Gene; Regulation; Research; Residual Tumors; Resolution; Rest; Signal Transduction; Study models; Surface; System; T cell response; T-Lymphocyte; T-cell receptor repertoire; Variant; Work; adaptive immunity; base; cancer cell; cell killing; cohort; experimental study; hematopoietic cell transplantation; improved; in vitro Model; in vivo; insight; latent infection; leukemia; neoplastic cell; peripheral blood; receptor; receptor expression; responders and non-responders; response; segregation; sex; transcriptome; transcriptome sequencing; treatment choice; tumor; γδ T cells

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