T cell function in murine gammaherpesvirus infection

鼠伽马疱疹病毒感染中的 T 细胞功能

• 批准号: 8660592
• 负责人: Edward J Usherwood
• 金额: $ 40.5万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660592
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Affect; Antiviral Agents; Attention; B-Lymphocytes; Benign; Biological Models; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Data; Defect; Development; Disease; Effectiveness; Effector Cell; Equilibrium; Event; Gene Targeting; Generations; Genes; Genetic; Goals; Herpesviridae; Human Herpesvirus 4; Immune; Immune response; Immune system; Immunocompromised Host; Immunologic Surveillance; Immunotherapy; Individual; Infection; Infection Control; Infectious Agent; Intrinsic factor; Kaposi Sarcoma; Knowledge; Laboratories; Life; Mediating; Memory; MicroRNAs; Multicentric Angiofollicular Lymphoid Hyperplasia; Mus; Natural Immunity; Patients; Phase; Phenotype; Physiological Processes; Population; Process; Production; Regulation; Research; Risk; Role; Staging; System; T cell differentiation; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; Vaccine Design; Virus; Virus Diseases; Work; adaptive immunity; base; cell type; gammaherpesvirus; innovation; latent infection; new therapeutic target; pathogen; precursor cell; primary effusion lymphoma; programs; public health relevance; response; therapy development; tool; tumor

DESCRIPTION (provided by applicant): Gammaherpesviruses are ubiquitous persistent pathogens that infect a substantial majority of the world's population. Infection does not have deleterious consequences in most healthy individuals, due to the presence of a potent immune response that contains the infection. In AIDS patients and others with suppressed immune systems, breakdown in immune surveillance can be accompanied by life-threatening gammaherpesvirus-associated disease. There is a pressing need to understand the mechanism by which the immune response, particularly the CD8 T cell response, maintains optimal control of the infection. Our previous work, using the murine gammaherpesvirus model system, clearly indicates that the differentiation state of memory CD8 T cells is a key determinant to maintain benign levels of persistent virus. Memory T cells can be categorized into two types - effector memory T cells (TEM), with the capacity for immediate effector function but limited proliferation, and central memory T cells (TCM) with delayed effector function but the capacity for extensive proliferation. TEM predominate in persistent infections, and are likely critical for surveillance o the virus. However the factors that determine cell fate toward TEM or TCM lineage are currently obscure. We have recently discovered that CD8 cells lacking a key microRNA fail to differentiate appropriately into effector cells, instead skewing toward the memory phenotype. These cells differentiate poorly into long-lived memory cells, and have a marked skewing towards TCM, whereas wild type cells predominantly assume the TEM phenotype. This is important because it indicates a pivotal role for this microRNA in immune surveillance to MHV-68. In addition, factors controlling TCM differentiation are very actively sought, as the generation of these cells is the 'holy grail' of vaccine design against many infectious agents and tumors. This presents a unique opportunity to determine the functional role for microRNA regulation of antiviral CD8 T cell responses. In this proposal we address three hypotheses: (i) During the acute phase of the infection, there is a deficit in the production of short-lived effector CD8 cells, but the generatin of memory precursor cells is intact. (ii) TEM fail to form correctly but differentiation to TCM is intact. (iii) Control of MHV-68 infection is defective in the absence of microRNA, for two reasons. Firstly the T cell response is unable to control the infection. Secondly B cell colonization by latent MHV-68 is altered in the absence of microRNA. Our knowledge of the functions of microRNAs increases each year, as do the tools that enable us to manipulate their activity. Therefore the major impact of this work will be to illuminate the roles of microRNA in the antivira immune response, which have the potential to be manipulated to affect better control of medically important pathogens such as the gammaherpesviruses.

描述（由申请人提供）：伽玛疱疹病毒是普遍存在的持久性病原体，感染世界上绝大多数人口。由于存在包含感染的有效免疫反应，因此感染不会对大多数健康个体产生有害后果。在艾滋病患者和其他免疫系统受到抑制的患者中，免疫监视的崩溃可能会伴随着危及生命的伽玛疱疹病毒相关疾病。迫切需要了解免疫反应（特别是 CD8 T 细胞反应）维持对感染的最佳控制的机制。我们之前的工作使用鼠伽马疱疹病毒模型系统，清楚地表明记忆 CD8 T 细胞的分化状态是维持持久性病毒良性水平的关键决定因素。记忆T细胞可分为两种类型：效应记忆T细胞（TEM），具有立即效应功能，但增殖能力有限；中央记忆T细胞（TCM），具有延迟效应功能，但具有广泛增殖能力。 TEM 在持续性感染中占主导地位，并且可能对于病毒监测至关重要。然而，决定细胞向 TEM 或 TCM 谱系命运的因素目前尚不清楚。我们最近发现，缺乏关键 microRNA 的 CD8 细胞无法适当分化为效应细胞，而是偏向记忆表型。这些细胞很难分化为长寿记忆细胞，并且明显偏向中医，而野生型细胞主要呈现 TEM 表型。这很重要，因为它表明这种 microRNA 在 MHV-68 免疫监视中发挥着关键作用。此外，人们非常积极地寻找控制中药分化的因素，因为这些细胞的产生是针对许多传染原和肿瘤的疫苗设计的“圣杯”。这提供了一个独特的机会来确定 microRNA 调节抗病毒 CD8 T 细胞反应的功能作用。在该提案中，我们提出了三个假设：（i）在感染的急性期，短寿命效应 CD8 细胞的产生存在缺陷，但记忆前体细胞的生成完整。 (ii) TEM 无法正确形成，但与 TCM 的分化完整。 (iii) 在没有 microRNA 的情况下，MHV-68 感染的控制是有缺陷的，原因有两个。 首先，T细胞反应无法控制感染。其次，在没有 microRNA 的情况下，潜在 MHV-68 的 B 细胞定植会发生改变。我们对 microRNA 功能的了解逐年增加，使我们能够操纵其活动的工具也在不断增加。因此，这项工作的主要影响将是阐明 microRNA 在抗病毒免疫反应中的作用，它有可能被操纵以更好地控制医学上重要的病原体，例如伽马疱疹病毒。