肝X受体α调控慢性病毒感染中CD8+T细胞功能耗竭的机制研究

Chronic virus infectious diseases are serious threats to human health. It is imminent to research and develop a new therapeutic vaccine. How to interpret the mechanism of CD8+T cell functional exhaustion is one of the key scientific issues for the development of therapeutic vaccine. In recent years, a few studies have found that some transcription factors could regulate the CD8+T cell functional exhaustion. It is deserved attention that these transcription factors did not only take part in the CD8+T cell functional exhaustion, they were also involved in the regulation of effector cells and memory cells differentiation in acute infectious progress. We have acquired three important findings in the study of LCMV infectious mice model. 1. The CD8+T cell functional exhaustion is more remarkable in the transcription factor liver x receptor alpha (LXRα) deficient mice; 2.LXRα may regulate CD8+T cell functional exhaustion through an in vivo mechanism which is confirmed in a rebuild bone marrow Chimera mice model. 3. LXR-α is not involved in the differentiations of effector cells and memory cells in acute infectious progress. Based on these findings, we suppose that LXR-α could regulate CD8+T cell functional exhaustion through an intrinsic mechanism specifically. We are going to study how LXR-α regulates the number, phenotype, function, effector, survival and proliferation of CD8+T cell exhaustion in chronic viral infection mice which were LXRa knockout, overexpression or LXRα excited. At the same time, we propose to find the target site of LXRα with microarray. So, we can look into the molecule mechanisms of LXRα regulating CD8+T cell functional exhaustion. The study could provide theoretical supports for vaccine research and development for the treatment of chronic virus infectious diseases.

慢性病毒感染疾病严重威胁人类健康，治疗性疫苗的研制迫在眉睫。对CD8+T细胞功能耗竭机制的诠释是治疗性疫苗研发的关键科学问题。转录因子对CD8+T细胞功能耗竭的调控受到关注，但已报道的转录因子并非仅参与CD8+T细胞的耗竭，他们也与急性感染时效应和记忆细胞分化的调控相关。我们利用LCMV病毒感染模型研究发现：1、转录因子肝X受体α（LXRα）缺失小鼠CD8+T细胞功能耗竭更严重；2、通过构建骨髓嵌合小鼠证实LXRα是内在（intrinsic）的调控CD8+T细胞功能耗竭；3、LXRα不参与急性感染时效应和记忆细胞的分化。基于此我们提出LXRα内在的特异性调控CD8+T细胞功能耗竭。本课题将在LXRα缺失、过表达和活化的小鼠感染模型中，从数量、表型、功能、效应、存活和增殖六要素全面认识LXRα对CD8+T细胞耗竭的调控，并深入研究调控的分子机制，为慢性病毒感染治疗性疫苗的研发提供理论支撑。