Tr1在慢性HBV感染中维持T细胞免疫耐受的作用及机制

Chronic hepatitis B virus (HBV) infection is characterized by exhaustion of HBV-specific T cell immune responses, which is primarily responsible for failure of eliminating virus. Type 1 regulatory T cell (Tr1) represents an important cell population that can mediate antigen (Ag)-specific immune tolerance. However, it is still unclear whether Tr1 plays a potential role in chronicity of HBV infection. Our previous study has found that peripheral frequency of Tr1 was significantly higher in immune tolerant patients of chronic HBV infection than inactive carriers. Tr1 frequency was correlated with serum levels of both HBV DNA and HBsAg. Furthermore, Tr1 secreted large amount of IL-10 that displayed a distinct profile of cytokines production compared to other subsets of CD4+ T cells. We propose that Tr1 may induce immune tolerance of T cells through IL-10 dependent route in the setting of chronic HBV infection. In the present study, we aim to explore the relationship between Tr1 frequency and different phases of natural history after HBV infection, as well as its suppressive function on HBV specific T cells. We also intend to identify the unique characteristics of Tr1 in patients with chronic HBV infection, based on data of transcriptomics, cytokine profiles, and immunological phenotypes (ie. biomarkers for exhaustion, memory, and chemotaxis). In addition, we try to clarify, in a mouse model of chronic HBV infection, the role of IL-10 pathway in Tr1-induced exhaustion of HBV-specific T cells by using technologies including adoptive transfer, antibody blockade and lentivirus-mediated short hairpin silencing. The purpose of our study is to provide scientific evidence for elucidating the mechanism of how T cell immune tolerance develops after HBV infection goes chronicity.

慢性HBV感染时，宿主的HBV特异性T细胞应答耗竭。1型调节性T细胞（Tr1）是介导抗原特异性免疫耐受的重要细胞亚群，但在慢性HBV感染中的作用尚不清楚。我们前期研究发现：慢性HBV感染免疫耐受期患者外周血Tr1数量显著高于非活动性携带者，与血清HBV DNA和HBsAg水平正相关，并具有以分泌IL-10为主的细胞因子谱。我们推测：慢性HBV感染时，Tr1通过分泌IL-10促进T细胞免疫耐受。在本研究中，我们拟分析慢性HBV感染者外周血Tr1数量与自然史分期的关系，探索Tr1对HBV特异性T细胞功能的抑制作用，并描述Tr1的转录组学、细胞因子谱和免疫表型（耗竭、记忆、趋化）特点。建立慢性HBV感染小鼠模型，采用过继转移、抗体阻断、shRNA干扰等技术，证明IL-10通路在Tr1介导HBV特异性T细胞耗竭中的作用，为进一步阐明慢性HBV感染T细胞免疫耐受形成的机制提供科学依据。

慢性HBV感染时，宿主的HBV特异性T细胞应答耗竭。1型调节性T细胞（Tr1）是介导抗原特异性免疫耐受的重要细胞亚群，但在慢性HBV感染中的作用尚不清楚。我们前期研究发现：慢性HBV感染免疫耐受期患者外周血Tr1数量显著高于非活动性携带者，与血清HBV DNA和HBsAg 水平正相关，并具有以分泌IL-10为主的细胞因子谱。我们推测：慢性HBV感染时，Tr1通过分泌IL-10促进T细胞免疫耐受。在本研究中，我们拟分析慢性HBV感染者外周血Tr1数量与自然史分期的关系，探索Tr1对HBV特异性T细胞功能的抑制作用，并描述Tr1的转录组学、细胞因子谱和免疫表型（耗竭、记忆、趋化）特点。建立慢性HBV感染小鼠模型，采用过继转移、抗体阻断、shRNA干扰等技术，证明IL-10通路在Tr1介导HBV特异性T细胞耗竭中的作用，为进一步阐明慢性HBV感染T细胞免疫耐受形成的机制提供科学依据。