旋毛虫排泄分泌（ES）抗原诱导宿主调节性T细胞的分子基础

Trichinellosis is one of the most widespread parasitic zoonoses and a serious public threat to human health and livestock industry. The disease is caused by the consumption of meat contaminated with infective larvae of Trichinella spiralis (T. spiralis). During struggle against host immune system, the parasite, a tissue-dwelling nematode, has produced a multitude of evasion mechanisms of the host immune response, which make the prevention and control of trichinellosis exceptionally difficult. Trichinella spiralis Excretory-Secretory (ES) antigen is an important immunomodulatory protein. What are the final relationships between ES antigen and regulatory T cells of host? To answer this scientific question, we focus on the interpretation of ES antigen on murine dendritic cells (DCs) function, cytokine environment and its major molecular pathways to induce CD4+CD25+ regulatory T cell, to explore the mechanism of TsPmy antigens modulating the host immune response. So we could clarify the mechanisms of induced CD4+CD25+ regulatory T cells (iTreg) during trichinella infection, thus affect the immune response to anti-infection, and provide a new theoretical basis for the prevention and control. Disruptions of the immunomodulatory function of TsPmy could be explored as an alternative strategy to control T. spiralis infection.

旋毛虫病是一种常见的世界性分布的人兽共患寄生虫病，严重危害人类健康和畜牧业生产。人主要因食入含旋毛形线虫（简称旋毛虫）囊包幼虫的肉类而感染旋毛虫病。旋毛虫是一种组织寄生虫，在长期与宿主免疫系统抗争的过程中，形成了复杂的免疫逃避机制。旋毛虫排泄分泌(ES)抗原是一个非常重要的免疫调节蛋白分子，那么ES抗原与宿主调节性T细胞的关系究竟是怎样的呢？为回答这一科学问题，本研究聚焦于阐释旋毛虫ES抗原对小鼠树突状细胞（DCs）功能的影响，诱导小鼠CD4+CD25+调节性T 细胞的细胞因子环境及其主要分子通路，探讨ES抗原调节宿主免疫应答的机制，为进一步阐明旋毛虫感染过程中CD4+CD25+调节性T 细胞的诱导产生机制，并进而影响到抗感染免疫应答，提供新的理论依据，为寻找防控旋毛虫病提供新的思路。

旋毛形线虫是一种多细胞寄生线虫，在世界上55个国家的野生动物、家畜和人类均有感染。它具有极其多样的抗原库来调节宿主的免疫反应，一方面逃避宿主的免疫攻击得以完成生活史，另一方面又保护宿主免遭其引起的免疫损害。但宿主的免疫系统如何平衡虫体感染时引起的免疫应答尚不完全清楚。本研究以旋毛虫排泄分泌抗原（ES抗原）为研究对象，探讨旋毛虫感染过程中诱导调节性T细胞（Tregs）产生的机制。旋毛虫在肠型期和新生幼移型期可诱导小鼠Tregs的生成，其机制是ES抗原通过促进树突状细胞（DCs）活化诱导Tregs的生成，并且诱导了Foxp3、IL-10和TGF-β等转录因子和细胞因子高水平表达的耐受微环境。ES抗原负载DC，诱导其功能性成熟，即能够呈递抗原给T细胞，促进T细胞活化增殖。与对照组相比，ES抗原负载的DC具有更浓密树枝状凸起结构，CD40、CD83、CD86、MHC-II类分子表达升高，IL-12和IL-10分泌增多。另外，AES诱导CD4+CD25+Foxp3+ T细胞的产生可能通过抑制CREB的表达抑制TCR通路的激活，而MES诱导CD4+CD25− Foxp3+ Tregs的产生可能通过活化CREB依赖于TCR途径。本研究初步探讨了蠕虫疗法的细胞机制，为阐释旋毛虫ES抗原调节宿主免疫应答的机制提供了科学依据，为蠕虫源性分子作为免疫抑制剂靶向治疗过敏和/或自身免疫性疾病提供了实验依据。