T cell function in murine gammaherpesvirus infection

描述（由申请方提供）：γ疱疹病毒是一种普遍存在的持久性病原体，感染世界上绝大多数人口。感染在大多数健康个体中不会产生有害后果，因为存在包含感染的有效免疫应答。在艾滋病患者和其他免疫系统受抑制的人中，免疫监视的崩溃可能伴随着危及生命的γ疱疹病毒相关疾病。迫切需要了解免疫应答，特别是CD 8 T细胞应答，维持感染的最佳控制的机制。我们以前的工作，使用鼠γ疱疹病毒模型系统，清楚地表明，记忆CD 8 T细胞的分化状态是维持良性水平的持久性病毒的关键决定因素。记忆T细胞可以分为两种类型-效应记忆T细胞（TEM），具有立即效应功能但有限增殖的能力，和具有延迟效应功能但广泛增殖能力的中枢记忆T细胞（TCM）。TEM在持续性感染中占优势，并且可能对病毒的监测至关重要。然而，决定细胞向TEM或TCM谱系的命运的因素目前尚不清楚。我们最近发现，缺乏关键microRNA的CD 8细胞无法适当分化为效应细胞，而是偏向记忆表型。这些细胞分化不良，长寿命的记忆细胞，并有一个显着的倾斜向TCM，而野生型细胞主要承担TEM表型。这很重要，因为它表明这种microRNA在对MHV-68的免疫监视中起着关键作用。此外，控制中医药分化的因素是非常积极的寻求，因为这些细胞的产生是针对许多感染因子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CD 8 T细胞应答的功能作用。在这个提议中，我们提出了三个假设：（i）在感染的急性期，短期效应CD 8细胞的产生不足，但记忆前体细胞的产生是完整的。(ii)TEM未能正确形成，但与中医的鉴别是完整的。(iii)由于两个原因，MHV-68感染的控制在没有microRNA的情况下是有缺陷的。 首先，T细胞反应无法控制感染。第二，在不存在微小RNA的情况下，潜伏MHV-68的B细胞定殖被改变。我们对microRNA功能的了解每年都在增加，使我们能够操纵其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，这些作用有可能被操纵以更好地控制医学上重要的病原体，如γ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.