4-1BB/4-1BBL共刺激信号介导B细胞诱导抗HBV特异性细胞免疫的研究

HBV感染慢性化的主要原因是宿主细胞免疫功能受损。4-1BB/4-1BBL是抗原提呈中重要的共刺激因子，也是目前抗肿瘤及抗病毒细胞免疫研究的热点。通过活化4-1BB/4-1BBL可逆转T细胞的免疫耐受，增强抗原特异性T细胞反应。B细胞是重要的抗原提呈细胞，也是体内表达4-1BBL的主要细胞；经CD40L刺激后B细胞高表达4-1BBL，且能诱导T细胞活化。我们也证实了该现象，同时发现慢性HBV感染者B细胞4-1BBL表达显著升高，但其变化特征及机制尚不明确，推测与抗原特异性T细胞活化及免疫调控相关。我们将在前期研究基础上，分析不同免疫状态慢性HBV感染者淋巴细胞4-1BB/4-1BBL表达情况及其机制，明确其在慢性HBV感染中的免疫调控作用；并通过体外细胞培养和体内HBV转基因小鼠实验，观察4-1BBL+ B细胞在诱导HBV特异性细胞免疫中的作用，探讨其在抗HBV细胞免疫治疗中的应用前景。

The main reason of chronic hepatitis B virus (HBV) infection is the dysfunction of host cellular immune responses. 4-1BB and its ligand (4-1BBL) are important costimulatory signals in antigen presentation. Currently, the 4-1BB/4-1BBL pathway is an attractive field in the cell immunotherapy for cancer and virus infection. 4-1BB/4-1BBL pathway can lead to both CD4+ and CD8+ T-cell activation. Evidences have shown that the pathway could cause the expansion and response of antigen-specific CD8+ T cells. B cells are important antigen presenting cells, and also the main cells expressing 4-1BBL in vivo. The expression of 4-1BBL on B cells can be increased after stimulated by CD40L, and the 4-1BBL+ B cells can induce T cell activation. We also have confirmed the phenomenon, and found a significant increasing expression of 4-1BBL on B cells in patients with chronic HBV infection. However, the changing characteristics and mechanism are still not yet clear. On the basis of preliminary studies and our experience in B cells study, we will explore the changing characteristics of 4-1BB and 4-1BBL on lymphocytes in chronic HBV infected patients with different immune status and reveal their clinical significances. These studies will reveal the important roles and mechanisms of 4-1BB and 4-1BBL in the immune regulation in chronic HBV infection. Meanwhile, by using cells cultured in vitro and HBV transgenic mice model experiment in vivo, we will investigate the potential roles in induction of HBV-specific cellular immune responses by the 4-1BBL+ B cells, and explore the possibility of application in the cell immunotherapy of HBV infection.