调节性T细胞诱导年幼的小鼠形成免疫耐受并导致HBV感染慢性化的机制研究

Hepatitis B virus (HBV) infection remains a major global health problem, with more than 400 million individuals worldwide being chronically infected. There are striking age-related differences in the clinical outcome of acute HBV infection. Approximately 95% of infected adults clear HBV spontaneously, whereas more than 90% of exposed neonates and 30% of children (1-5 years of age) develop chronic infection. This implies significant differences in the immune response related to the age of the infected host, but what exactly these differences are remains mostly obscure...It is thought that the establishment of a persistent HBV infection in infants is due to immaturity of the neonatal immune system. But more and more studies have demonstrated that the immune effectors as well as regulatory responses are already in place during early life. Furthermore, newborns have been shown to mount a virus-specific T cell response toward viral infections in early life. The immune tolerance in the newborn is not due to an immune-cell-intrinsic defect but instead it is associated with the presence of active immunosuppression. Regulatory T cells (Tregs) are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases. But they are also the key factors of suppressing adaptive immunity and inducing chronic viral infection. Mounting evidences have shown that higher frequencies of Tregs are present in the newborns infected with virus than in the adults. And these Tregs with more immunosuppressive capacity may be the cause of inducing immune tolerance and chronic HBV infection in newborns...Our group uses the hydrodynamic injection mice model to study the immune response during HBV infection. Our previous study has showed that the HBV infection can be persistent in the young mice, while it develops to an acute and self-limiting infection in the adult mice. So we’d like to establish HBV infection mice model using the young and adult mice respectively. To clarify the mechanisms of age-related outcome in the HBV infection, we also want to measure the specific T cell response, the frequency and the function of the Treg during the HBV infection. This study will illuminate the role of Tregs in the development of chronic HBV infection in the young mice.

婴幼儿感染HBV易发展为持续性感染，成年人感染HBV后大多呈急性自限性感染。年龄因素影响HBV感染结局的免疫学机制还不清楚。婴幼儿感染病原体可诱导机体产生较成年人更强的免疫抑制因素，其中调节性T细胞（Treg）是抑制机体特异性免疫的重要原因。多种模型证实，婴幼儿感染病毒后可诱导产生更高频率、免疫抑制功能更强的Treg细胞。这可能是婴幼儿感染HBV后易形成免疫耐受并导致HBV感染慢性化的重要原因。我们前期的研究发现，用年幼的小鼠建立高压水注射的HBV感染小鼠模型可形成持续性感染，成年小鼠则形成急性感染。本研究拟利用不同年龄的小鼠建立HBV感染模型，研究不同年龄的小鼠的特异性T细胞反应、Treg细胞反应之间的差异，及其与HBV感染结局之间的相关性，阐明Treg细胞诱导年幼的小鼠形成免疫耐受并导致HBV感染慢性化的机制。本研究将为阐明HBV感染慢性化的免疫发病机制提供新的理论。