Role of TNFR2 in sepsis-induced immune suppression

TNFR2 在脓毒症诱导的免疫抑制中的作用

• 批准号: 188760962
• 负责人: Professorin Dr. Daniela N. Männel
• 金额: --
• 依托单位: Institut für Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/188760962?language=en
• 关键词: Role; TNFR2; sepsis; induced; immune

In sepsis the inflammatory phase is followed by an immune suppressive phase. In this project post-septic TNFR2-mediated immune suppressive mechanisms are being analyzed using genetically modified mice defective or transgenic for TNFR2. Splenic dendritic cells from TNFR2-deficient mice produced reduced levels of IL-12 while being highly activated for antigen presentation and skewing towards a Th2 cytokine profile. A low nitric oxide production capacity of macrophages of TNFR2-deficient mice was paralleled by increased arginase expression indicating immunosuppressive M2 characteristics similar to post-septic wild type macrophages. Taken together TNFR2-deficient mice seem to have an immune status comparable to wild type mice after sepsis. In addition, we showed that the development of Foxp3+ regulatory T cells (Treg) is TNF-dependent and identified TNFR2 as a good marker for functionally active Treg. Since TNFR2 can act in two different ways by either signaling after interaction with TNF or, alternatively, as a TNF inhibitor after being shed, experiments with bone-marrow chimeric mice will be used to determine in vivo the mechanistic function and physiological role of TNFR2. We are further interested to investigate whether and how the altered phenotype of TNFR2-deficient myeloid cells affects T cell functions and how they mediate the effects of TNFR2.

在脓毒症中，炎症期之后是免疫抑制期。在这个项目中，使用TNFR2基因缺陷或转基因小鼠分析了脓毒症后TNFR2介导的免疫抑制机制。来自tnfr2缺陷小鼠的脾树突状细胞产生IL-12水平降低，同时抗原呈递高度激活，并向Th2细胞因子谱倾斜。tnfr2缺陷小鼠的巨噬细胞产生一氧化氮的能力较低，与精氨酸酶表达增加平行，表明免疫抑制M2特征与脓毒后野生型巨噬细胞相似。综上所述，tnfr2缺陷小鼠在败血症后的免疫状态似乎与野生型小鼠相当。此外，我们发现Foxp3+调节性T细胞（Treg）的发育依赖于tnf，并确定TNFR2是功能活跃的Treg的良好标记物。由于TNFR2可以通过两种不同的方式发挥作用，要么在与TNF相互作用后发出信号，要么在脱落后作为TNF抑制剂，因此将使用骨髓嵌合小鼠实验来确定TNFR2在体内的机制功能和生理作用。我们进一步感兴趣的是研究TNFR2缺陷骨髓细胞的表型改变是否以及如何影响T细胞功能，以及它们如何介导TNFR2的作用。