Regulatory function of CD160 in helminth infection

CD160在蠕虫感染中的调节作用

• 批准号: 521628293
• 负责人: Professorin Dr. Minka Breloer
• 金额: --
• 依托单位: Arbeitsgruppe Helminthen-Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/521628293?language=en
• 关键词: Regulatory; function; CD160; helminth; infection

Helminth parasites infect every 4th human and have evolved sophisticated mechanisms to downmodulate their host`s immune system to prolong their survival. We reported previously that the parasitic nematode Strongyloides ratti delayed its immune-driven ejection from the intestine via the induction of regulatory T cells and via the upregulation of the regulatory receptor B and T lymphocyte attenuator (BTLA) on effector T cells. BTLA is part of a complex network of several regulatory receptors that bind to their ubiquitously expressed ligand Herpes Virus Entry mediator (HVEM). This application aims at elucidating the role of the alternative HVEM ligand CD160 in regulating immunity to helminths. Our research question is based on a preliminary screen of S. ratti parasite burden in mice deficient for several HVEM ligands including a newly generated CD160 ko mouse strain. To our surprise, we observed reduced intestinal parasite burden in mice lacking CD160 at early time points of infection and, in the absence of adaptive immunity, reciprocally increased parasite burden at later time points of infection. Thus, we propose that CD160-mediated signals display dual and opposing functions during intestinal helminth infection. CD160 is expressed on T and NKT cells. For innate cells, CD160 expression was described for NK cells and for innate intraepithelial intestinal cell populations, such as innate lymphoid cells and mast cells. These cells also contribute to anti-S. ratti immunity. Within this research project we will first perform a thorough characterisation of the different innate CD160-expressing cell populations in S. ratti-infected mice using multicolour flow cytometry and single cell sequencing. While CD160 is a positive regulator of NK cells, the consequences of CD160-engangement on other cell types appear to be context-dependent. We intend to compare the immune response CD160-competent and CD160-deficient mice to define immune pathways that are changed in the absence of CD160. We will focus on early time points when CD160 antagonizes S. ratti ejection from the intestine and late time points when CD160 promotes innate anti-S. ratti immunity. Comparing the function of the relevant WT and CD160 ko innate immune cells (mast cells, innate lymphoid cells, NK cells) in vitro and in vivo, we will provide a causal link between the cell populations that express CD160 during S. ratti infection and the immune pathways changed in the absence of CD160. As the CD160-ligand HVEM is also a (positive) signalling receptor we finally intend to distinguish between signals delivered into the CD160-expressing and signals delivered into the HVEM-expressing cell. In summary, we expect to elucidate in great depth the precise mechanism of action of CD160-HVEM-mediated regulation of anti-helminth immunity in the intestine and thereby our study will shed further light on the function of this network in general.

每4个人类中就有1个被寄生虫感染，它们已经进化出了复杂的机制来下调宿主的免疫系统，以延长它们的生存时间。我们之前报道过，寄生线虫ratti蛔虫通过诱导调节性T细胞和上调调节性受体B和T淋巴细胞衰减剂（BTLA）对效应T细胞的作用，延迟了其从肠道的免疫驱动排出。BTLA是由几种调节受体组成的复杂网络的一部分，这些受体与无处不在表达的配体疱疹病毒进入介质（HVEM）结合。本应用旨在阐明替代HVEM配体CD160在调节对蠕虫免疫中的作用。我们的研究问题是基于对几种HVEM配体缺乏的小鼠（包括新生成的CD160 ko小鼠品系）的ratti疟原虫负荷的初步筛选。令我们惊讶的是，我们观察到在感染的早期时间点缺乏CD160的小鼠肠道寄生虫负荷减少，并且在缺乏适应性免疫的情况下，在感染的后期时间点寄生虫负荷反过来增加。因此，我们认为cd160介导的信号在肠蠕虫感染过程中表现出双重和相反的功能。CD160在T细胞和NKT细胞上表达。对于先天细胞，CD160在NK细胞和先天上皮内肠细胞群（如先天淋巴样细胞和肥大细胞）中表达。这些细胞也参与抗s。ratti免疫力。在这个研究项目中，我们将首先使用多色流式细胞术和单细胞测序技术对大鼠链球菌感染小鼠中表达cd160的不同先天细胞群进行彻底的表征。虽然CD160是NK细胞的正调节因子，但CD160参与其他细胞类型的后果似乎与环境有关。我们打算比较CD160正常小鼠和CD160缺陷小鼠的免疫反应，以确定在缺乏CD160时发生变化的免疫途径。我们将重点关注CD160拮抗鼠链球菌肠外抛射的早期时间点和CD160促进先天抗s的晚期时间点。ratti免疫力。通过在体外和体内比较先天免疫细胞（肥大细胞、先天淋巴样细胞、NK细胞）中相关WT和CD160的功能，我们将提供在S. ratti感染期间表达CD160的细胞群与缺乏CD160时免疫途径改变之间的因果关系。由于cd160配体HVEM也是一种（阳性）信号受体，我们最终打算区分传递到表达cd160的细胞的信号和传递到表达HVEM的细胞的信号。综上所述，我们希望能够更深入地阐明cd160 - hvem介导的肠道抗蠕虫免疫调节的确切作用机制，从而进一步阐明该网络的总体功能。