活化Treg——IL-33在日本血吸虫病免疫调控中的新机制

Schistosomiasis is an important immunological disease and remains one of major public health problems in China as well as in the world. Regulatory T cell (Treg) plays a key role in regulating of phenotypes (ILC2/Th1/Th2/Th17/Tfh) and response magnitude of the effector cells populations and the prognosis of schistosomiasis. However, mechanisms of Treg induction and activation in Schistosoma infections are poorly understood. Recent studies show that IL-33 can induce activation of Treg in some infection and immune-medited diseases. Our previous results indicated that serum IL-33 was elevated in schistosomiais japonica. And elevated IL-33 could up-regulate Treg and its effective cytokines IL-10 and TGF-β in spleen in murine schistosomiasis. Furthermore, exogenous IL-33 could promote tissue repair of hepatic granuloma and reduce inflammation in the liver. Based on these above findings, we speculate that the high expression of IL-33 induced by schistosome infection can regulate the immune system and promote tissue repair through the activation of Treg. In order to certify the hypothesis, this study is to observe effects of elevated IL-33 on frequency, function and immune-regulation of Tregs at the expression peak of IL-33 in murine schistosomiasis (8th week post infection). Then mechanism of Treg activated by IL-33 (depending on the specific receptor of ST2) is explored. More importantly, how activated Treg affects host immune responses (negative regulation of excessive immune responses ILC2/Th1/Th2/Th17/Tfh) and liver immunopathological damages (promoting tissue repair) will be investigated. This research will not only deepen our understanding of immune regulations in schistosomiasis, but also lay an experimental and theoretical foundation for exploring a new treatment target of schistosomiasis.

血吸虫病中Treg对宿主的免疫反应和疾病的转归均起着至关重要的调控作用。但是，血吸虫感染如何诱导宿主体内Treg的活化尚不清楚。新近研究证实，在某些感染和免疫性疾病中IL-33可通过诱导活化Treg发挥免疫调控或组织修复作用。我们的前期研究发现，IL-33在血吸虫感染中明显升高，在其表达高峰期可上调Treg及其免疫调控作用；而外源性IL-33可促进肝脏虫卵肉芽肿的修复，减少肝脏炎症反应。据此我们推测，血吸虫感染诱导高表达的IL-33可通过活化Treg对宿主产生免疫调控或促进组织修复，达到维持组织自稳的作用。鉴此，本项目拟观察在血吸虫感染第8周即IL-33表达的高峰期，高表达的IL-33对Treg数量、功能和免疫效应的影响，进一步探讨IL-33活化Treg的机制（依赖于ST2），并深入研究IL-33活化的Treg对宿主体内免疫效应（负向调控）和肝脏的免疫病理损害（促进组织修复）的的作用。

血吸虫病是一种严重危害人类健康并阻碍疫区社会经济发展的人畜共患病。血吸虫病中Treg对宿主的免疫反应和疾病的转归均起着至关重要的调控作用。但是，血吸虫感染如何诱导宿主体内Treg的活化尚不清楚。本课题结合国内外研究和前期实验证实IL-33具有调控Treg的基础，探讨血吸虫病中IL-33调控Treg的作用和分子机制，以及其对血吸虫病肝脏病理损害的影响。我们的研究结果显示，IL-33/ST2轴的缺失显著下调血吸虫感染小鼠Treg比例、转录因子Foxp3的表达及IL-10和TGF-β水平，并上调Th17细胞的比例、RORγt水平和IL-17的表达。腹腔注射外源性rmIL-33可逆转IL-33-/-感染组小鼠体内Treg和Th17的变化，但对ST2-/-感染组小鼠体内的上述指标却无影响。与WT感染组相比，IL-33/ST2轴的缺失加重小鼠肝脏病理损伤程度（单个虫卵肉芽肿面积，肝坏死程度，炎性细胞浸润程度，蓝色胶原纤维程度沉积水平，α-SMA和Collagen 1a1的表达水平，HMI和血清ALT的表达水平）。外源性rmIL-33可逆转IL-33-/-感染组小鼠肝脏病理损伤，但对ST2-/-感染组小鼠脏病理损伤却无影响。体外实验结果显示，IL-33可以通过促进自噬（表现为Atg5和Beclin-1升高而p62下调）促进naiveT细胞向Treg分化。综上所述，IL-33/ST2轴在日本血吸虫感染小鼠中发挥保护作用，这与Treg反应的增加和Th17反应的抑制密切相关。IL-33使Treg扩增可能与其调控自噬有关。该结果可进一步完善血吸虫病的免疫应答和免疫病理反应的调控分子机制，并为开发预防和治疗血吸虫病的新靶标提供理论和实验依据。