CD4 T cell respnse to Human herpesvirus-6

CD4 T 细胞对人类疱疹病毒 6 的反应

• 批准号: 9226033
• 负责人: Lawrence J. Stern
• 金额: $ 47.69万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9226033
• 关键词: Acute; Antiviral Agents; Autoimmune Diseases; Autoimmune thyroiditis; Biochemical; Biological Assay; Blood Cells; Bone Marrow Suppression; CD4 Positive T Lymphocytes; Cell Line; Cessation of life; Characteristics; Child; Childhood; Chronic; Clinical; Collaborations; Complication; Cytomegalovirus; Data; Diagnosis; Diagnostic; Encephalitis; Epitopes; Exanthema Subitum; Febrile Convulsions; Goals; Hospitalization; Human; Human Herpesvirus 4; Human Herpesvirus 6; Immune; Immune response; Immunocompetent; Immunosuppression; Infection; Infectious Agent; Interleukin-10; Interleukin-2; Kidney Transplantation; Life; MHC Class II Genes; Mediating; Medical; Memory; Molecular; Mus; National Institute of Allergy and Infectious Disease; Natural Killer Cells; Nature; Neurologic; Organ; Organ Transplantation; Pathology; Patients; Pattern; Population; Primary Infection; Process; Proteins; Pulmonary Inflammation; Reagent; Regulation; Reporting; Role; Sampling; Solid; Stem cells; System; T cell regulation; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Epitopes; Techniques; Testing; Therapeutic immunosuppression; Transplant Recipients; Transplantation; Vaccination; Viral; Virus; Virus Diseases; Work; antiviral immunity; base; clinical development; cognitive function; cross reactivity; cytokine; early childhood; experience; experimental study; immunosuppressed; improved; multiple sclerosis patient; novel; pathogen; peripheral blood; reactivation from latency; response; seropositive; tool

This project is a comprehensive look into the CD4 T cell response to human herpesvirus 6 (HHV-6), an emergent / re-emergent human pathogen. In most people infection in childhood resolves uneventfully to a chronic life-long infection held in check by cellular immune responses. However, viral reactivation after immunosuppression can cause serious illness, neurological complications, and even death, and is an important complication following organ transplantation. One aim of the project is to characterize memory T cell responses to this chronic infection, and compare them to responses to acute infection. CD4 and CDS T cell responses to HHV-6 will be characterized in healthy immune donors and also in kidney transplant recipients experiencing viral reactivation. A possible role for IL-10 in regulating these responses will be investigated. These analysis will involve ex vivo analysis of, peripheral blood and primary cell lines, using functional assays and newly-developed class II MHC oligomers, and will be pursued in collaboration with project 2, which is investigating analogous CD4 T cell functional subsets in mice. A second aim of the project is to understand the role of NK cells in regulating T cell responses to HHV-6. Preliminary data indicate that NK populations present in peripheral blood regulate CD4 T cells responding to HHV-6. Several mechanistic hypotheses will be explored using ex vivo analysis of human peripheral blood and primary cell lines. This work will be pursued in collaboration with project 1, which is investigating similar NK phenomenon in other systems. A third aim of the project is to investigate and functionally characterize CD4 T cell responses to HHV-6 that are cross-reactive with other viruses. Several recently identified HHV-6 T cell epitopes are similar to those from other common viral infections. Based on principles established in previous work on CDS cross-reactivity patterns, we predict that the HHV-6 specific CD4 T cell response can recognize heterologous infection by other viruses including EBV, CMV, and lAV. This prediction will be tested using ex vivo analysis of human peripheral blood and primary cell lines, and biochemical and structural analysis of MHC and TCR proteins. This aim will be pursued in collaboration with project 3.

该项目全面研究 CD4 T 细胞对人类疱疹病毒 6 (HHV-6) 的反应，该病毒是一种 新出现/重新出现的人类病原体。对于大多数人来说，童年时期的感染会顺利解决 慢性终生感染受到细胞免疫反应的控制。然而，病毒重新激活后 免疫抑制可导致严重疾病、神经系统并发症，甚至死亡，是一种 器官移植后的重要并发症。该项目的目标之一是表征内存 T 细胞对这种慢性感染的反应，并将它们与对急性感染的反应进行比较。 CD4 和 CDS T HHV-6 的细胞反应将在健康免疫供体和肾移植中表征 接受者经历病毒再激活。 IL-10 在调节这些反应中的可能作用是 调查了。这些分析将涉及外周血和原代细胞系的离体分析，使用 功能测定和新开发的 II 类 MHC 寡聚物，并将与 项目 2，正在研究小鼠中类似的 CD4 T 细胞功能亚群。该组织的第二个目标是 该项目旨在了解 NK 细胞在调节 T 细胞对 HHV-6 反应中的作用。初步数据 表明外周血中存在的 NK 群体调节响应 HHV-6 的 CD4 T 细胞。一些 将利用人外周血和原代细胞的离体分析来探索机制假设 线。这项工作将与项目 1 合作进行，该项目正在调查类似的 NK 其他系统中的现象。该项目的第三个目标是研究 CD4 并对其进行功能表征 T 细胞对 HHV-6 的反应与其他病毒发生交叉反应。最近发现了几个 HHV-6 T 细胞表位与其他常见病毒感染的细胞表位相似。根据中确立的原则 之前关于 CDS 交叉反应模式的工作，我们预测 HHV-6 特异性 CD4 T 细胞反应可以 识别其他病毒（包括 EBV、CMV 和 LAV）的异源感染。这个预测将是 使用人外周血和原代细胞系的离体分析以及生化和 MHC 和 TCR 蛋白的结构分析。该目标将与项目 3 合作实现。