血吸虫病是全球危害最严重的寄生虫病之一。曼氏及日本血吸虫卵沉积于宿主肝脏引起的肉芽肿及继发纤维化是最主要免疫病理。但感染后宿主很快产生免疫负调控以防止过强、过快的病理损害，从而长时间地维持生命；但也利于虫体逃避宿主免疫攻击、从而长期存活、致感染慢性化。巨噬细胞（Mφ）是虫卵肉芽肿的重要组成细胞（约30%），对肉芽肿的发生发展有关键调控作用。PD-1为重要免疫抑制性受体，已发现可多方面抑制Mφ功能，促进免疫负调控；但Mφ表达PD-1的机制不清。我们前期发现，血吸虫感染诱导Mφ表达PD-1增加，伴随血清TGF-β增加；且发现TGF-β可大幅诱导Mφ表达PD-1。因此，本项目拟结合最新研究，阐明血吸虫感染中TGF-β通过SMAD3和FOXO1共同促进STAT3诱导Mφ表达PD-1的机制，为免疫负调控机制补充了新理论，为血吸虫病，甚至自身免疫病、肿瘤中基于Mφ的免疫干预或治疗提供了新策略。

Schistosomiasis is one of the major and typical human parasitic diseases worldwide. After Schistosoma japonicum and Schistosoma mansoni infection, much of the hepatic immunopathology is attributed to egg-induced granulomatous inflammatory response and associated fibrosis. However, the immunosuppression is typically established shortly in most of the patients after infection, limiting hepatic immunopathology in hosts and also allowing the long-term survival of both the hosts and the parasites to establish a chronic infection. Macrophages (Mφ) constitute ~30% of egg-induced liver granulomas and are important immune regulators in schistosomiasis. PD-1, an immune checkpoint receptor, has great importance in inhibiting Mφ activity and inducing their immunoregulatory function. However, little is known about the molecular mechanism by which PD-1 expression is induced on Mφ. Our preliminary experiments showed that schistosome infection induces high expression of PD-1 on Mφ, which correlates positively with the high serum levels of TGF-β. We have demonstrated that TGF-β alone induces high PD-1 expression on Mφ. This study intends to further explore the molecular mechanism(s) by which TGF-β induces high expression of PD-1 on Mφ. Our findings may be helpful to develop some novel strategies to enhance the immunosuppression to control the development of immunopathology during chronic parasitic infection, improve the protection of the potential vaccine against parasites and even treat autoimmune diseases.