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）：伽马广播病毒是无处不在的持续病原体，这些病原体感染了世界大部分人口。由于存在含有感染的有效免疫反应，因此在大多数健康个体中感染没有有害的后果。在艾滋病患者和其他受抑制免疫系统的患者中，免疫监测的细分可能伴随着威胁生命的伽马胸病毒相关疾病。有必要了解免疫反应，尤其是CD8 T细胞反应的机制，可以保持对感染的最佳控制。我们以前的工作使用鼠伽马病毒模型系统，清楚地表明，记忆CD8 T细胞的分化状态是维持良性持续病毒水平的关键决定因素。记忆T细胞可以分为两种类型 - 效应器记忆T细胞（TEM），具有直接效应子功能但有限的增殖能力，中央记忆T细胞（TCM）具有延迟的效应功能，但具有广泛增殖的能力。 TEM在持续感染中占主导地位，可能对病毒监测至关重要。但是，确定细胞命运对TEM或TCM谱系的因素目前晦涩难懂。我们最近发现，缺乏密钥microRNA的CD8细胞无法适当地分化为效应细胞，而是偏向记忆表型。这些细胞分化为长寿命的记忆细胞，并具有明显的偏向TCM，而野生型细胞主要假设TEM表型。这很重要，因为它表明该microRNA在对MHV-68的免疫监视中起关键作用。此外，控制TCM分化的因素非常积极地寻求，因为这些细胞的产生是针对许多传染性药物和肿瘤的疫苗设计的“圣杯”。这为确定抗病毒CD8 T细胞反应的microRNA调节的功能作用提供了独特的机会。在此提案中，我们解决了三个假设：（i）在感染的急性阶段，短生效应子CD8细胞的产生存在不足，但是记忆前体细胞的产生是完整的。 （ii）TEM无法正确形成，但与TCM的区分完好无损。 （iii）在没有microRNA的情况下，控制MHV-68感染有缺陷，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通过潜在MHV-68定植。我们对MicroRNA功能的了解每年都会增加，使我们能够操纵其活动的工具也会增加。因此，这项工作的主要影响是阐明microRNA在抗维拉免疫反应中的作用，这有可能被操纵以影响对医学上重要病原体（如γ掌病毒）的更好地控制。