Th17-Treg Antagonism: Impact on Disease Outcome in Helminth Infections

本项目将研究调节性T细胞(Treg)诱导IgG4亚类免疫球蛋白的分子机制。Treg是众所周知的免疫抑制现象的重要中介。有不同的抗原特异性和自然产生的Treg亚群，在低敏反应、慢性感染(如丙型肝炎)或寄生虫感染时诱导。我们的研究小组描述了抗原特异性Treg在人类盘尾丝虫病中的高频率发生，这是首次在人类感染中描述Treg。随后，我们发现Treg克隆与纯化的B细胞共培养时，选择性地诱导IgG4的合成。IgG4具有抗炎作用，在过敏和慢性疾病(如蠕虫疾病)中表达上调。基于我们先前的结果，本项目旨在发现Treg-B细胞相互作用的分子机制，并确定哪些分子(GITR、CTLA-4、ICOS、TLR等，见目标)诱导或抑制这些相互作用。这项工作将使用来自受破伤风类毒素刺激的健康捐赠者的细胞作为抗原模型，并使用来自盘尾丝虫病患者的细胞来将研究结果扩展到慢性蠕虫感染。这些样本是从早期研究中获得的。该项目的结果应该对传染病以及过敏症和自身免疫性疾病具有重要意义。

This project will investigate the molecular mechanisms involved in the induction of IgG4 subclass of immunoglobins by regulatory T-cells (Treg). Treg are important mediators of the well-known phenomena of immune suppression. There are distinct subgroups of antigenspecific and naturally occurring Treg that are induced in allergy during hypo-sensibilisation, in chronic infection like hepatitis C, or parasite infections. Our group described the occurrence at high frequency of antigen-specific Treg in human onchocerciasis, which was the first description of Treg in human infections at all. Subsequently, we have found that Treg clones selectively induce the synthesis of IgG4 when co-cultured with purified B cells. IgG4 are antiinflammatory and are up-regulated in allergy and chronic diseases, e.g. worm diseases. Based on our earlier results, the present project aims to find the molecular mechanisms of Treg-B cell interactions, and to determine which molecules (GITR, CTLA-4, ICOS, TLR etc., see Objectives) induce or inhibit these interactions. This work will be performed using cells from healthy donors stimulated with tetanus toxoid as antigen-model, and cells generated from onchocerciasis patients to extend the findings to a chronic helminth infection. These samples are available from earlier studies. The results from the project should have important implications for infectious diseases but also for allergy and auto-immune disorders.