T cell function in murine gammaherpesvirus infection

描述(申请人提供)：伽马疱疹病毒是普遍存在的持久性病原体，感染世界上大部分人口。感染对大多数健康的人来说不会有有害的后果，因为存在一种有效的免疫反应来遏制感染。在艾滋病患者和其他免疫系统受到抑制的患者中，免疫监测的崩溃可能伴随着危及生命的伽马疱疹病毒相关疾病。迫切需要了解免疫反应，特别是CD8T细胞反应，维持对感染的最佳控制的机制。我们之前的工作，使用小鼠伽马疱疹病毒模型系统，清楚地表明记忆CD8T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细胞可分为两类--效应记忆T细胞和中枢记忆T细胞，前者具有即时效应功能，但增殖能力有限；后者具有延迟效应功能，但具有广泛增殖能力。TEM在持续性感染中占主导地位，可能对病毒的监测至关重要。然而，决定细胞走向TEM或中医谱系的因素目前尚不清楚。我们最近发现，缺乏关键microRNA的CD8细胞无法适当地分化为效应细胞，而是向记忆表型倾斜。这些细胞分化成长寿命的记忆细胞很差，并且明显偏向中医，而野生型细胞主要表现为透射电子显微镜的表型。这一点很重要，因为它表明这种microRNA在对MHV-68的免疫监测中发挥着关键作用。此外，人们非常积极地寻找控制中医分化的因素，因为这些细胞的生成是针对许多感染性病原体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CD8T细胞反应的功能作用。在这项建议中，我们提出了三个假设：(I)在感染的急性期，短期效应CD8细胞的产生存在缺陷，但记忆前体细胞的产生是完整的。(2)横切面不能正确形成，但与中医辨证分型完整。(3)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细胞的反应无法控制感染。其次，在没有microRNA的情况下，潜伏的MHV-68对B细胞的定植发生了改变。我们对microRNAs功能的了解每年都在增加，使我们能够操纵它们活动的工具也在增加。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，这些免疫反应有可能被操纵以更好地控制医学上重要的病原体，如伽马疱疹病毒。

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.