The role of the Lymphotoxin beta receptor in innate immunity

淋巴毒素β受体在先天免疫中的作用

• 批准号: 5358031
• 负责人: Professor Dr. Klaus Pfeffer
• 金额: --
• 依托单位: Institut für Medizinische Mikrobiologie und Krankenhaushygiene
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2002
• 资助国家: 德国
• 起止时间: 2001-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5358031?language=en
• 关键词: role; Lymphotoxin; beta; receptor; innate

The lymphotoxin b-receptor (LTßR) is a member of the core family of tumor necrosis factor receptors (TNFR). The LTßR controls the formation of lymph nodes and Peyer´s patches during ontogeny. The known ligands for LTßR are the cytokines lymphotoxin a / lymphotoxin b in the form of a heterotrimer (LTa1b2) and LIGHT in the form of a homotrimer (LIGHT3). Recent results generated in our group indicate that LTßR-deficient mice are unable to control infections with intracellular bacteria and die within 5 to 10 days p.i.. The LD50 of Listeria monocytogenes organisms is approx. 2 log steps reduced in LTbR-/- mice (etwa 3.000 cfu) compared to wildtype controls (etwa 300.000 cfu). However, LTbb-/- mice produce high amounts of TNFa and interferong (IFNg) after listeria infection, demonstrating that the well-established antibacterial TNF/TNFRp55 or IFNg/IFNgR pathways are not defective in LTßR-deficient mice. These data suggest an hitherto unknown primary function of LTßR in the control of intracellular bacteria. Since LTßR-/- animals lack lymph nodes it might be assumed that this defect results in the impairment of natural immunity. However, wildtype recipients of LTßR-/- bone marrow cells are still highly susceptible after challenge with intracellular bacteria, suggesting an intrinsic role of the LTßR in the hematopoietic compartment. Interestingly, LTßR- and LTb-deficient mice lack specific macrophage subpopulations in the marginal zone of the spleen (metallophilic and marginal zone macophages). One of the postulated functions of these macrophage subpopulations is the recognition of "foreign" carbohydrate patterns regularly found in the cell walls of bacteria and fungi, with subsequent activation of innate immune responses. We could already show that LTb- and LTa-deficient mice have an impaired T cell independent B cell response after challenge with Ti1 and Ti2 antigens. Also the differentiation and effector function of natural killer (NK) cells appears to be defective in these animals. In summary, our data indicate that the LTßR plays an hitherto unknown role in the natural defence against intracellular bacteria. Aim of this study is the identification of the molecular antibacterial effector systems and the characterization of the cell populations of the innate immune system that are defective in the absence of the LTßR.

淋巴毒素b受体是肿瘤坏死因子受体核心家族的成员。LT？R在个体发育过程中控制淋巴结和Peyer‘S斑块的形成。已知的LT？R的配体是杂三聚体形式的淋巴毒素a/淋巴毒素b(LTa1b2)和同源三聚体形式的光(LIGHT3)。我们小组最近的研究结果表明，LTüR缺陷小鼠无法控制细胞内细菌的感染，并在5至10天内死亡。单核细胞增生性李斯特氏菌的半数致死量(LD50)约为。与野生型对照组(ETWA 300.000 CFU)相比，LTbR-/-小鼠的记录步骤减少了2次(ETWA 3.000 cfu)。然而，LTBB-/-小鼠在李斯特菌感染后产生大量的TNFa和干扰素(IFNG)，这表明在LTüR基因缺陷小鼠中，已建立的抗菌TNF/TNFRp55或IFNG/IFNgR通路没有缺陷。这些数据表明，LT？R在控制细胞内细菌方面具有迄今未知的主要功能。由于LT？R-/-动物缺乏淋巴结，因此可以认为这一缺陷会导致自然免疫功能受损。然而，接受野生型LTüR-/-骨髓细胞的人在细胞内细菌攻击后仍然高度敏感，这表明LTüR在造血室中具有内在作用。有趣的是，LT？R和LTB缺陷小鼠在脾的边缘区域(嗜金属区和边缘区巨噬细胞)缺乏特定的巨噬细胞亚群。这些巨噬细胞亚群的假定功能之一是识别细菌和真菌细胞壁中常见的“外来”碳水化合物模式，随后激活先天免疫反应。我们已经证明，LTB和LTA缺陷小鼠在用Ti1和TI2抗原攻击后，T细胞非依赖性B细胞反应受损。此外，在这些动物中，自然杀伤(NK)细胞的分化和效应功能似乎是有缺陷的。综上所述，我们的数据表明LT？R在对抗细胞内细菌的天然防御中发挥着迄今未知的作用。这项研究的目的是鉴定分子抗菌效应器系统，并表征在缺少LT？R的情况下有缺陷的天然免疫系统的细胞群。