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Regulation of the Immune Response to Plasmodium by IL-10 Producing Natural Killer Cells

产生 IL-10 的自然杀伤细胞对疟原虫免疫反应的调节

基本信息

批准号：
10333331
负责人：
Sara Elizabeth Hamilton Hart
金额：
$ 46.43万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2019-02-08 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10333331
关键词：
Acute Address Anti-Inflammatory Agents B-Lymphocytes Brain CD8-Positive T-Lymphocytes CD8B1 gene CXCR3 gene Cell Communication Cell physiology Cells Cerebral Malaria Cerebrum Chronic Clinical Complex Cytolysis Data Dendritic Cells Development Disease Endothelium Equilibrium Fc Receptor Generations Goals Growth Homeostasis Human Immune Immune response Immune system Immunity Immunosuppression Impairment Infection Inflammatory Inflammatory Response Interleukin-10 Interleukin-15 Knock-in Mouse Knockout Mice Listeria monocytogenes Location Lymphoid Malaria Mediating Memory Modeling Mouse Strains Mus Natural Killer Cells Nature Parasitemia Parasites Pathogenicity Pathologic Pathology Patients Persons Phenotype Plasmodium Play Population Populations at Risk Production Publishing Reporting Resistance Role Sampling Severity of illness Shapes Source Symptoms T cell response T memory cell T-Lymphocyte Testing Tissues Viral Visual Work cellular targeting cohort conditional knockout cytokine experience global health immunopathology immunoregulation improved in vivo imaging interleukin-10 receptor malaria infection mortality mouse model novel pathogen prevent response trafficking

项目摘要

Project Summary/Abstract Malaria is a significant global health problem in which we still fail to understand many protective features of the immune response. Natural killer (NK) cells produce inflammatory cytokines during the early stages of infection, yet have also been shown in viral models to limit T cell and B cell responses. We recently demonstrated that NK cell- produced IL-10 can limit CD8+ T cell activity during experimental cerebral malaria and thereby rescue mice from fatal, CD8+ T cell-mediated immunopathology. Using newly generated mouse strains, we will visual the location and cellular interactions of NK cells in the brain and establish the cellular targets of NK cell-derived IL-10 during cerebral disease. Our studies will also determine if distinct human NK cell subsets are more efficient at producing IL-10, and if these cells correlate with protection from malaria symptoms in humans. Finally, we will investigate the impact of NK cell-derived IL-10 on the development and function of memory CD8+ T cells. Our objective is to understand how NK cell regulatory functions like IL-10 production decrease immunopathology and symptomatic infection, and shape the developing T cell response. The proposed work will determine the consequences of NK cell-derived IL-10 during the immune response to malaria and reveal ways to exploit regulatory NK cell function, thereby improving immunity in populations at risk for severe disease.

项目总结/摘要疟疾是一个重大的全球健康问题，我们仍然无法了解其中的许多问题，自然杀伤（NK）细胞是免疫反应的保护性特征。炎症细胞因子在感染的早期阶段，但也已显示，病毒模型来限制T细胞和B细胞的反应。我们最近证明，NK细胞-T 产生的IL-10可以限制实验性脑型疟疾期间的CD 8 + T细胞活性，从而拯救小鼠免于致命的CD 8 + T细胞介导的免疫病理学。产生的小鼠品系，我们将可视化NK细胞的位置和细胞相互作用并建立脑内NK细胞源性IL-10的细胞靶点，我们的研究还将确定不同的人类NK细胞亚群是否比其他人的NK细胞亚群更多。如果这些细胞与预防疟疾有关，最后，我们将研究NK细胞衍生的IL-10对人类的影响。记忆性CD 8 + T细胞的发育和功能。我们的目标是了解 NK细胞调节功能如IL-10的产生如何降低免疫病理学，症状感染，并塑造发展中的T细胞反应。拟议的工作将决定免疫应答过程中NK细胞源性IL-10的结果并揭示利用调节NK细胞功能的方法，从而改善在有严重疾病风险的人群中提供免疫力。